Literature Commentary

Our goal was to evaluate the safety and efficacy of stenting of venous sinus stenosis (VSS) in patients with medically-refractory, medically-intolerant or fulminant idiopathic intracranial hypertension (IIH) in a prospective, observational study. Thirteen patients with IIH who were refractory or intolerant to medical therapy or who presented with fulminant visual field (VF) loss underwent stenting of VSS at the transverse-sinus sigmoid sinus junction, using a Precise Pro carotid stent system (Cordis). Inclusion criteria included papilledema-related VF loss with mean deviation (MD) worse than or equal to -6.00 dB, elevated opening pressure (OP) on lumbar puncture (LP), VSS (either bilateral or unilateral in a dominant sinus), and an elevated (≥8 mm Hg) trans-stenotic gradient (TSG). The main outcome measures were pre- to post-stent change in symptoms related to intracranial hypertension, MD (in dB) on automated (Humphrey) VFs, grade of papilledema (1-5), retinal nerve fiber layer (RNFL) thickness as measured by spectral domain optical coherence tomography (SD-OCT), TSG (mm Hg), and OP on LP (cm H20). Improvement or resolution of headaches occurred in 84.7% of patients, pulse-synchronous tinnitus in 100%, diplopia in 100%, and transient visual obscuration in 100%. Out of 26 eyes, 21 showed an improvement in MD, with an average improvement of +5.40 dB. Of 24 eyes with initial papilledema, 20 showed an improvement in Frisen grade, (mean change in grade of 1.90). Of 23 eyes undergoing SD-OCT, 21 (91.3%) demonstrated a reduction in RNFL thickness, with a poststent mean thickness of 90.48 μm. Mean change in OP was -20 cm H2O (reduction in mean from 42 to 22 cm H20) with all subjects demonstrating a reduction, although a second stenting procedure was necessary in one patient. Complications of the stenting procedure included one small, self-limited retroperitoneal hemorrhage, transient head or pelvic pain, and one allergic reaction to contrast. No serious adverse events occurred. Stenting of VSS is safe and results in reduction of intracranial pressure in patients with IIH. This is associated with improvement in papilledema, RNFL thickness, VF parameters, and symptoms associated with intracranial hypertension.

Literature Commentary Section Editors: Mark L. Moster, MD M. Tariq Bhatti, MD Literature Commentary In this issue of Journal of Neuro-Ophthalmology, M. Tariq Bhatti, MD and Mark L. Moster, MD will discuss the following 6 articles: 1. Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC. Activity of selumetinib in neurofibromatosis type 1-related plexiform Neurofibromas. N Engl J Med. 2016;375:2550-2560. 2. Foutz A, Appleby BS, Hamlin C, Liu X, Yang S, Cohen Y, Chen W, Blevins J, Fausett C, Wang H, Gambetti P, Zhang S, Hughson A, Tatsuoka C, Schonberger LB, Cohen ML, Caughey B, Safar JG. Diagnostic and prognostic value of human prion detection in cerebrospinal fluid. Ann Neurol. 2017;81:79-92. 3. Kang E, Wu J, Gutierrez NM, Koski A, Tippner-Hedges R, Agaronyan K, Platero-Luengo A, Martinez-Redondo P, Ma H, Lee Y, Hayama T, Van Dyken C, Wang X, Luo S, Ahmed R, Li Y, Ji D, Kayali R, Cinnioglu C, Olson S, Jensen J, Battaglia D, Lee D, Wu D, Huang T, Wolf DP, Temiakov D, Belmonte JC, Amato P, Mitalipov S. Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations. Nature. 2016;540:270-275. 4. Cestari DM, Gaier ED, Bouzika P, Blachley TS, De Lott LB, Rizzo JF, Wiggs JL, Kang JH, Pasquale LR, Stein JD. Demographic, systemic, and ocular factors associated with nonarteritic anterior ischemic optic neuropathy. Ophthalmology. 2016;123:2446-2455. 5. van der Vuurst de Vries RM, Mescheriakova JY, Runia TF, Jafari N, Siepman TA, Hintzen RQ. Soluble CD27 levels in cerebrospinal fluid as a prognostic biomarker in clinically isolated syndrome. JAMA Neurol. 2017;74:286- 292. 6. Lee KM, Woo SJ, Hwang JM. Differentiation between optic disc drusen and optic disc oedema using fundus photography. Acta Ophthalmol. [published ahead of print January 13, 2017] doi: 10.1111/aos.13338. Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC. Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N Engl J Med. 2016;375:2550-2560. Background: Effective medical therapies are lacking for the treatment of neurofibromatosis type 1-related plexiform neurofibromas, which are characterized by elevated RASmitogen-activated protein kinase (MAPK) signaling. Methods: We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20-30 mg per square meter of body surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of neurofibromatosis type 1-related neurofibroma. Response to treatment (i.e., an increase or 210 decrease from baseline in the volume of plexiform neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma. Results: A total of 24 children (median age, 10.9 years; range, 3.0-18.5) with a median tumor volume of 1,205 mL (range, 29-8,744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6-56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of $20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of $20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed. Conclusions: Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform Moster and Bhatti: J Neuro-Ophthalmol 2017; 37: 210-215 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. For those who are involved in the surgical management of patients with neurofibromatosis Type 1 (NF1)-related plexiform neurofibromas, this Phase 1 trial provides some hope that there may be an effective treatment for patients with inoperable lesions. Selumetinib is an oral small molecule kinase inhibitor of mitogen-activated protein kinase kinase (MEK) 1 and 2 and was given an orphan drug designation in May 2016. The rationale to use this medication is based on a mouse model of NF1-deficient acute myeloid leukemia that showed tumor regression following mitogen-activated protein kinase and MEK inhibition. Four of the 24 patients enrolled in the trial had neurofibromas involving the face (it is not specified how many of these patient has periorbital involvement). Seventyone percent of the patients had a tumor volume decrease of $20%, with no patients demonstrating evidence of disease progression (volume increase of $20%). The adverse effect profile of selumetinib in the trial was good; only 1 patient stopped the medication because of side effects. Doselimiting toxic effects in later cycles were creatine kinase elevation (4 patients), oral mucositis (3 patients), and cellulitis (1 patient). There was 1 patient who developed an asymptomatic cataract during the study. I recently finished reviewing the literature on the neuroophthalmic manifestations of molecularly targeted cancer drugs for the April NANOS meeting, and I must tell you, Mark, that I could not believe the advancements in treatment that have been made in the field of oncology stemming from a better understanding of the genetic, immunologic, and molecular complexities of oncogenesis. -M. Tariq Bhatti, MD These results are encouraging. Not one of the patients progressed while on treatment. In the article, there is an impressive photo of an improvement in a patient's deformed torso to near normal after around a 40% decrease in the size of the tumor with treatment. -Mark L. Moster, MD Foutz A, Appleby BS, Hamlin C, Liu X, Yang S, Cohen Y, Chen W, Blevins J, Fausett C, Wang H, Gambetti P, Zhang S, Hughson A, Tatsuoka C, Schonberger LB, Cohen ML, Caughey B, Safar JG. Diagnostic and prognostic value of human prion detection in cerebrospinal fluid. Ann Neurol. 2017;81:79-92. Objective: Several prion amplification systems have been proposed for detection of prions in cerebrospinal fluid Moster and Bhatti: J Neuro-Ophthalmol 2017; 37: 210-215 (CSF), most recently, the measurements of prion seeding activity with second-generation real-time quaking-induced conversion (RT-QuIC). The objective of this study was to investigate the diagnostic performance of the RT-QuIC prion test in the broad phenotypic spectrum of prion diseases. Methods: We performed CSF RT-QuIC testing in 2,141 patients who had rapidly progressive neurological disorders, determined diagnostic sensitivity and specificity in 272 cases that were autopsied, and evaluated the impact of mutations and polymorphisms in the PRNP gene, and type 1 or type 2 human prions on diagnostic performance. Results: The 98.5% diagnostic specificity and 92% sensitivity of CSF RT-QuIC in a blinded retrospective analysis matched the 100% specificity and 95% sensitivity of a blind prospective study. The CSF RT-QuIC differentiated 94% of cases of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 from the sCJD MM2 phenotype and 80% of sCJD VV2 from sCJD VV1. The mixed prion types 1-2 and cases heterozygous for codon 129 generated intermediate CSF RT-QuIC patterns, whereas genetic prion diseases revealed distinct profiles for each PRNP gene mutation. Interpretation: The diagnostic performance of the improved CSF RT-QuIC is superior to surrogate marker tests for prion diseases such as 14-3-3 and tau proteins, and together with PRNP gene sequencing the test allows the major prion subtypes to be differentiated in vivo. This differentiation facilitates prediction of the clinicopathological phenotype and duration of the disease-2 important considerations for envisioned therapeutic interventions. Although the frequency of prior diseases is rare, as neuroophthalmologists, it is important to be cognizant of this group of disorders because the afferent and efferent visual pathways are often affected and the recognition of these clinical manifestations can be vital in securing the diagnosis. Making the diagnosis of a prion disease can be challenging not only based on the vast differential diagnosis but also due to the lack of a definitive diagnostic test aside from pathological analysis. In this retrospective (n = 126)/prospective (n = 65) study carried out by the National Prion Disease Pathology Surveillance Center at Case Western Reserve University, the National Institutes of Health, and the Centers for Disease Control and Prevention, a second-generation real-time quakinginduced conversion test (RT-QuIC), which uses recombinant prion protein as a substrate to amplify very small amounts of pathogenic prion protein (PrPSc) in the cerebrospinal fluid (CSF), was compared to CSF 14-3-3 and t-Tau protein in neuropathological validated prionpositive cases. The specificity and sensitivity of RT-QulC ranged from 98.5% to 100% and 92.1% to 95.4%, respectively (with a positive predictive value of 99.1%- 100%). In comparison, the specificity and sensitivity of 14-3-3 was 42.9%-62.7% and 81.5%-81.7%, respectively; and the specificity and sensitivity of t-Tau was 46.3%-71.4% and 90.5%-95.4%, respectively. In 211 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary addition, the study found that CSF RT-QuIC combined with prion protein gene (PRNP) sequencing differentiated the most aggressive forms of sporadic Creutzfeldt- Jakob disease (CJD) from the more slowly progressive forms. -M. Tariq Bhatti, MD The increased sensitivity and specificity of this test in patients primarily with CJD is encouraging, since brain biopsy is not optimal. However, the authors described 1 patient who had positive CSF but the neuropathology showed Lewy body disease. Reassessment of the brain specimen revealed mildly elevated PrPsc. Since the incubation period for prion diseases can be many years, the authors speculate that this patient died of Lewy body disease but was a subclinical carrier for prion disease. This case might suggest that there could be some false positives with this test in patients who do not have CJD. -Mark L. Moster, MD Kang E, Wu J, Gutierrez NM, Koski A, Tippner-Hedges R, Agaronyan K, PlateroLuengo A, Martinez-Redondo P, Ma H, Lee Y, Hayama T, Van Dyken C, Wang X, Luo S, Ahmed R, Li Y, Ji D, Kayali R, Cinnioglu C, Olson S, Jensen J, Battaglia D, Lee D, Wu D, Huang T, Wolf DP, Temiakov D, Belmonte JC, Amato P, Mitalipov S. Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations. Nature. 2016;540:270-275. Abstract: Maternally inherited mitochondrial (mt)DNA mutations can cause fatal or severely debilitating syndromes in children, with disease severity dependent on the specific gene mutation and the ratio of mutant to wild-type mtDNA (heteroplasmy) in each cell and tissue. Pathogenic mtDNA mutations are relatively common, with an estimated 778 affected children born each year in the United States. Mitochondrial replacement therapies or techniques (MRT) circumventing mother-to-child mtDNA disease transmission involve replacement of oocyte maternal mtDNA. Here, we report MRT outcomes in several families with common mtDNA syndromes. The mother's oocytes were of normal quality and mutation levels correlated with those in existing children. Efficient replacement of oocyte mutant mtDNA was performed by spindle transfer, resulting in embryos containing .99% donor mtDNA. Donor mtDNA was stably maintained in embryonic stem cells (ES cells) derived from most embryos. However, some ES cell lines demonstrated gradual loss of donor mtDNA and reversal to the maternal haplotype. In evaluating donor-to-maternal mtDNA interactions, it seems that compatibility relates to mtDNA replication efficiency rather than to mismatch or oxidative phosphorylation dysfunction. We identify a polymorphism within the conserved sequence box II region of the D-loop as a plausible cause of preferential replication of specific mtDNA haplotypes. In addition, some haplotypes confer pro- 212 liferative and growth advantages to cells. Hence, we propose a matching paradigm for selecting compatible donor mtDNA for MRT. I must say that the technical content of this article is way above my "pay grade," so I don't plan on discussing the methods of what these brilliant authors did. The purpose of my choosing this article is to increase the awareness of the readers of Journal of Neuro-Ophthalmology (JNO) to the technology, current status, and controversy of mitochondrial replacement therapy (MRT). When I chose to discuss this article, I wasn't aware that JNO was going to publish the excellent article by Dr. Yu-Wai-Man in the March 2017 issue (1). There are 2 basic techniques for MRT: pronuclear transfer and spindle transfer, which are explained by Dr. Yu-Wai-Man. There is also a third technique called polar body transfer, which was described in 2014 and is still undergoing preliminary investigation. MRT is very controversial for a variety of ethical reasons and although it was approved in the United Kingdom in December 2016, it has not been accepted (in fact there is a congressional spending bill ban) in the United States (2-4). Because of the restriction of MRT in the United States, Dr. John Zhang from the New Hope Fertility Center in New York City, traveled to Mexico and used the spindle transfer technique to help a couple that had 2 children with Leigh syndrome produce a healthy baby (5,6). I have listed several references below for those who may be interested in reading more about MRT. -M. Tariq Bhatti, MD This is very exciting field of study and provides hope that in the future women with known mitochondrial mutations for NARP (Neurogenic muscle weakness, Ataxia and Retinitis Pigmentosa), Leigh syndrome, and Leber hereditary optic neuropathy can undergo this technique and protect their children from the risk of the disease. Of course, these techniques are in early stages and some issues remain. For instance, some of the cell lines in this study had gradual loss of the wild-type donor mtDNA and reverted to the mother's haplotype. I also recommend Patrick Yu Wai Man's review in the March issue of JNO (1) which explains these techniques very well. -Mark L. Moster, MD REFERENCES 1. Yu-Wai-Man P. Harnessing the power of genetic engineering for patients with mitochondrial eye diseases. J Neuroophthalmol. 2017;37:56-64. 2. Bredenoord AL, Braude P. Ethics of mitochondrial gene replacement: from bench to bedside. BMJ. 2010;341: c6021. 3. Castro RJ. Mitochondrial replacement therapy: the UK and US regulatory landscapes. J Law Biosci. 2016;3:726-735. 4. Journal of the American Medical Association. The JAMA Forum: Mitochondrial Replacement Therapy: Unmade in the USA. Moster and Bhatti: J Neuro-Ophthalmol 2017; 37: 210-215 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary Available at: https://newsatjama.jama.com/2016/12/21/thejama-forum-mitochondrial-replacement-therapy-unmade-in-the-usa/. Accessed April 18, 2017. 5. Lyon J. Sanctioned UK trial of mitochondrial transfer nears. JAMA. 2017;317:462-464. 6. Science Mag. Unanswered questions surround baby born to three parents. Available at: http://www.sciencemag.org/ news/2016/09/unanswered-questions-surround-babybornthree-parents. Cestari DM, Gaier ED, Bouzika P, Blachley TS, De Lott LB, Rizzo JF, Wiggs JL, Kang JH, Pasquale LR, Stein JD. Demographic, systemic, and ocular factors associated with nonarteritic anterior ischemic optic neuropathy. Ophthalmology. 2016;123:2446-2455. Objective: Nonarteritic anterior ischemic optic neuropathy (NAION) is a devastating ocular condition causing permanent vision loss. Little is known about risk factors for developing this disease. We assessed demographic, systemic, and ocular factors associated with NAION. Design: Retrospective longitudinal cohort study. Participants: Beneficiaries between 40 and 75 years old without NAION at baseline enrolled in a large U.S. managed care network. Methods: Enrollees were monitored continuously for $2 years between 2001 and 2014 to identify those newly diagnosed with NAION (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 377.41). All persons were under ophthalmic surveillance and all cases had $1 confirmatory ICD-9-CM code for NAION during follow-up. Main Outcome Measures: Multivariable Cox regression modeling was used to generate hazard ratios (HRs) with 95% confidence intervals (CIs) to describe the statistical relationship between selected demographic characteristics, systemic and ocular conditions, and the hazard of developing NAION. Results: Of 1 ,381, 477 eligible enrollees, 977 (0.1%) developed NAION during a mean ± standard deviation (SD) follow-up of 7.8 ± 3.1 years. The mean ± SD age for NAION cases at the index date was 64.0 ± 9.2 years vs 58.4 ± 9.4 years for the remainder of the beneficiaries. After adjustment for confounding factors, each additional year older was associated with a 2% increased hazard of NAION (HR = 1.02; 95% CI: 1.01-1.03). Female subjects had a 36% decreased hazard of developing NAION (HR = 0.64; 95% CI: 0.55-0.74) compared with male subjects. Compared with whites, Latinos had a 46% decreased hazard of developing NAION (HR = 0.54; 95% CI: 0.36-0.82), whereas African ancestry was not significantly associated with NAION (HR = 0.91; 95% CI: 0.72-1.15). Systemic diseases associated with NAION included hypertension (HR = 1.62; 95% CI: 1.26-2.07) and hypercoagulable states (HR = 2.46; 95% CI: 1.51-4.00). Although diabetes mellitus (DM) was not significantly associated with NAION compared with those without DM (P = 0.45), patients with end-organ involvement from DM had a 27% increased hazard of NAION relative to those with uncomplicated DM (HR = 1.27; 95% CI: 1.01-1.59). Ocular diseases associated with NAION were age-related macular degeneration (HR = 1.29; 95% Moster and Bhatti: J Neuro-Ophthalmol 2017; 37: 210-215 CI: 1.08-1.54) and retinal vein occlusion (HR = 3.94; 95% CI: 3.11-4.99). Conclusions: Our study identified several modifiable risk factors that may be associated with NAION. Should future studies confirm these findings, they may offer opportunities to prevent or treat this debilitating condition. Our own Dean Cestari is lead author on this study that examined a population database for demographic, systemic, and ocular factors associated with nonarteritic anterior ischemic optic neuropathy (NAION). They came up with some expected and some unexpected results. Expected were an increasing risk with age, hypertension, and hypercoagulable state [hazard ratio (HR) = 2.46]. Unexpected was a lack of increased risk with diabetes (although diabetic patients with end-organ damage were more at risk than diabetic patients without end-organ damage). Also found was a mild increased risk of macular degeneration and a large increased risk in those with history of central retinal vein occlusion (HR = 3.94). Women were affected less than men (HR = 0.64) and Latinos (HR = 0.46) less than Caucasians. Two limitations pointed out by the authors are that they lacked information on the optic disc features and on potentially relevant medications. The authors also point out the main limitation being the reliance on the use of diagnostic ICD-9 codes. My own anecdotal problem with this is based on patients referred to me with optic disc pallor who are coded by referring optometrists or ophthalmologists as NAION or those with NAION who are coded as optic neuritis or papilledema. I also imagine that a patient with prior central retinal vein occlusion who had disc edema initially and then developed pallor might be mistakenly coded as NAION. The authors raise some therapeutic questions. Because of a higher incidence of hypercoagulable state, they consider recommending aspirin. I use that anyway, not based on great data in NAION literature, but on the heart and stroke literature and the fact that our NAION patients most often have vascular risk factors. However, I would now consider testing hypercoagulable studies more often. -Mark L. Moster, MD No doubt, Dean Cestari and his colleagues are to be congratulated on this study. However, as much as it is awkward for me to say this-but because I was entrusted to provide unfiltered commentary by our fearless Editor-inChief Dr. Lanning Kline-I am a bit skeptical regarding the data set used in the study. In the methods sections, it is stated, "We required at least 1 eye examination by an ophthalmologist or optometrist during a 2-year look-back period .." Although I am sure some of the patients were seen by a neuro-ophthalmologist, it is not clear how many actually were. Furthermore, in the same sentence, it goes on to say ". and at least 1 eye examination during follow-up to give all enrollees at least 2 opportunities to get diagnosed 213 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary with NAION." Again, in my mind, this does not give me the confidence I need to believe that the correct diagnosis was reached because of the possibility of anchoring or status quo bias (1). If the diagnosis of NAION can't be confirmed reliably, then, in my opinion, the conclusions may not be dependable. As I participate in the QRK-207 NAION siRNA study, my personal experience has been that the referring diagnosis of NAION is not always the correct one. Finally, I am not sure if it is correct to state as it does in the limitations section of the discussion that, "Regardless, NAION misclassification would likely bias our findings to the null." I would argue that it would result in incorrect findings. REFERENCE 1. Wellbery C. Flaws in clinical reasoning: a common cause of diagnostic error. Am Fam Physician. 2011;84:1042-1048. -M. Tariq Bhatti, MD van der Vuurst de Vries RM, Mescheriakova JY, Runia TF, Jafari N, Siepman TA, Hintzen RQ. Soluble CD27 levels in cerebrospinal fluid as a prognostic biomarker in clinically isolated syndrome. JAMA Neurol. 2017;74:286-292. Importance: There is a growing number of therapies that could be administered after the first symptom of central nervous system demyelination. These drugs can delay multiple sclerosis (MS) diagnosis and slow down future disability. However, treatment of patients with benign course may not be needed; therefore, there is a need for biomarkers to predict long-term prognosis in patients with clinically isolated syndrome (CIS). Objective: To investigate whether the T-cell activation marker soluble CD27 (sCD27) measured in cerebrospinal fluid of patients at time of a first attack is associated with a subsequent diagnosis of MS and a higher relapse rate. Design, Setting, and Participants: This prospective study included 77 patients with CIS between March 2002 and May 2015 in a tertiary referral center for multiple sclerosis, in collaboration with several regional hospitals. Patients with CIS underwent a lumbar puncture and magnetic resonance imaging scan within 6 months after first onset of symptoms. Main Outcomes and Measures: Soluble CD27 levels were determined in cerebrospinal fluid using a commercially available enzyme-linked immunosorbent assay. Cox regression analysis was used to calculate univariate and multivariate hazard ratios for MS diagnosis. Association between sCD27 levels and relapse rate was assessed using a negative binomial regression model. Results: Among 77 patients with CIS, 50 were female (79.5%), and mean (SD) age was 32.7 (7.4) years. Mean (SD) age in the control individuals was 33.4 (9.5) years, and 20 were female (66.7%). Patients with CIS had higher cerebrospinal fluid sCD27 levels than control individuals (geometric mean, 31.3 U/mL; 95% CI, 24.0-40.9 vs mean, 214 4.67 U/mL; 95% CI, 2.9-7.5; P , 0.001). During a mean (SD) follow-up of 54.8 (35.1) months, 39 of 77 patients (50.6%) were diagnosed as having MS. In a model adjusted for magnetic resonance imaging and cerebrospinal fluid measurements, sCD27 levels were associated with a diagnosis of MS (hazard ratio, 2.4 per 100 U/mL increase in sCD27 levels; 95% CI, 1.27-4.53; P = 0.007). Additionally, patients with MS with high sCD27 levels (median, .31.4 U/mL) at the time of CIS had a 5.5 times higher annualized relapse rate than patients with low sCD27 levels (annualized relapse rate, 0.06 vs 0.33; P = 0.02). Conclusions and Relevance: Soluble CD27 in cerebrospinal fluid of patients with CIS was associated with MS diagnosis and a high relapse rate. Therefore, sCD27 is an activation molecule directly related to the immunopathology of the disease and is a potential clinical marker to help in treatment decisions after a first attack of suspected MS. Tariq, you're going to say "There you go again."-reviewing articles with really great results that are not available clinically. Guilty as charged. One of the tough decisions we face with a patient with a clinically isolated syndrome (CIS), most often optic neuritis, is whether to treat with multiple sclerosis (MS) disease-modifying therapies (DMTs). Because of potentially adverse effects, we want to treat only those at risk for eventually developing MS. Our best predictor to date is brain magnetic resonance imaging (MRI). However, a patient with a normal MRI still has a 25% chance of clinically definite MS at 15 years and a patient with an abnormal MRI still has a 28% chance of not developing MS at 15 years according to the Optic Neuritis Treatment Trial data. Therefore, we need additional biomarkers to help determine who will go on to clinically definite MS (CDMS). Soluble CD27 (sCD27) is considered a biomarker of active intrathecal T-cell-mediated inflammation. This study found that a higher level of cerebrospinal fluid (CSF) sCD27 was associated with increased conversion to CDMS, a shorter time to developing MS, and more frequent relapses in those who developed MS. In a subgroup analysis, those with at least 1 subclinical MRI lesion had an odds ratio of 3.0 of developing MS with a high sCD27 level. There were not enough patients with a normal MRI (n = 6) to be able to analyze the predictive value in this subgroup. Although not yet ready for prime time, it is possible that a combination of a low sCD27 with an abnormal MRI might predict those 28% who don't need treatment, and a negative MRI and a high sCD27 will predict a higher risk for conversion and therefore deserve treatment. -Mark L. Moster, MD Having had the privilege to work with you, the one nice thing I can say about you, Mark, is that you are certainly ahead of your time (and way out there!). It certainly would be nice to have a reliable biomarker that can accurately predict those CIS patients that will go on Moster and Bhatti: J Neuro-Ophthalmol 2017; 37: 210-215 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary to develop MS. However, let's all take a deep breath because I am sure you remember back in the day when there was excitement that an antibody test could predict MS(1), but in less than 4 years, it proved not to be the case(2). REFERENCES 1. Berger T, Rubner P, Schautzer F, Egg R, Ulmer H, Mayringer I, Dilitz E, Deisenhammer F, Reindl M. Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N Engl J Med. 2003;349:139-145. 2. Kuhle J, Pohl C, Mehling M, Edan G, Freedman MS, Hartung HP, Polman CH, Miller DH, Montalban X, Barkhof F, Bauer L, Dahms S, Lindberg R, Kappos L, Sandbrink R. Lack of association between antimyelin antibodies and progression to multiple sclerosis. N Engl J Med. 2007;356:371-378. -M. Tariq Bhatti, MD Lee KM, Woo SJ, Hwang JM. Differentiation between optic disc drusen and optic disc oedema using fundus photography. Acta Ophthalmol. [published ahead of print January 13, 2017] doi: 10.1111/aos. 13338. Purpose: To describe a funduscopic sign that can be used to differentiate between optic disc drusen (ODD) and optic disc edema (ODE). Methods: A total of 73 eyes from 73 consecutive subjects with disc margin blurring who had been evaluated using spectral-domain optical coherence tomography (SD-OCT) were included. Final diagnosis was made by SD-OCT; ODD was defined by direct visualization of ODD, whereas ODE was defined by documentation of retinal nerve fiber layer edema (nasal retinal nerve fiber layer thickness .78.0 mm). Peripapillary retina was selected as a 2-disc-diametersized square image from the fundus photograph. Using MATLAB software, color photographs were converted to indexed image of 8 colors. Presence of a smooth contour strip between the nasal disc margin and juxtapapillary retina was defined as a halo. Whether the halo could predict the ODD was analyzed retrospectively. Results: The halo sign was detected in 45 eyes (100%) with ODD, including 1 eye with both ODD and ODE. No eyes with ODE alone showed the halo sign. The halo sign implied the presence of ODD (Cohens kappa = 1.000, P , 0.001) and the absence of ODE (Cohen kappa = 0.971, Moster and Bhatti: J Neuro-Ophthalmol 2017; 37: 210-215 P , 0.001). The halo sign showed a good interobserver reliability [intraclass correlation (2, 1) = 0.944, 95% confidence interval, 0.912-0.964]. SD-OCT images showed that halos represented retinal elevations above ODD. Conclusions: In the patients with blurred disc margin, the presence of a halo strongly suggested underlying ODD rather than ODE. In this study, fundus photographs were taken and converted with MATLAB software into indexed images of 8 colors. When viewing these converted images, the authors describe a sign that they propose distinguishes buried optic disc drusen (ODD) from optic disc edema (ODE). It is a smooth C-shaped strip on the nasal side between the optic disc and adjacent retina. In patients with ODE, a strip might be visible but it had a more "serrated" contour and was also present on the temporal side of the disc. We often encounter the clinical question of buried drusen vs papilledema and, on occasion, remain uncertain of the diagnosis even after optical coherence tomography (OCT), fundus autofluorescence, ocular ultrasound, and neuroimaging. Therefore, a new reliable sign based on fundus photographs is welcome. However, I have numerous concerns about this study. First, the authors used spectral-domain OCT as the standard to diagnose ODD and ODE and that is far from a "gold standard." Second, they excluded patients with ODD without blurred margins or mildly blurred margins where they couldn't see the halo. Third, when the first 2 adjudicators disagreed on whether there was a halo, a third adjudicator stepped in and was not masked to the ultimate diagnosis. Finally, I looked at a lot of the photos and I think the C-shaped strip is a fairly subtle finding and equivocal in numerous cases. What do you think Tariq? -Mark L. Moster, MD As much as I enjoy disagreeing with you, on this I am going to have to say you are spot on! I just don't think this method is going to solve the clinical dilemma between ODD and ODE, so the quest continues. -M. Tariq Bhatti, MD 215 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.