Literature Commentary

In this section of Journal of Neuro-Ophthalmology, M. Tariq Bhatti, MD and Mark L. Moster, MD will discuss thefollowing 6 articles:1. Gallina P, Savastano A, Becattini E, Orlandini S, Scollato A, Rizzo S, Carreras G, Di Lorenzo N, Porfirio B.Glaucoma in patients with shunt-treated normal pressure hydrocephalus. J Neurosurg. 2018;129:1078-1084.2. Pagovich OE, Vo ML, Zhao ZZ, Petropoulos IN, Yuan M, Lertsuwanroj B, Ciralsky J, Lai E, Kiss S, D'Amico DJ,Mezey JG, Malik RA, Crystal RG. Corneal confocal microscopy: neurologic disease biomarker in Friedreich ataxia.Ann Neurol. 2018;84:893-904.3. Albrecht P, Jansen A, Lee JI, Moll M, Ringelstein M, Rosenthal D, Bigalke H, Aktas O, Hartung HP, Hefter H.High prevalence of neutralizing antibodies after long-term botulinum neurotoxin therapy. Neurology.2019;92:e48-e54.4. Eren O, Rauschel V, Ruscheweyh R, Straube A, Schankin CJ. Evidence of dysfunction in the visual associationcortex in visual snow syndrome. Ann Neurol. 2018;84:946-949.5. Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, Kim AS, Lindblad AS, Palesch YY; ClinicalResearch Collaboration, Neurological Emergencies Treatment Trials Network, and the POINT Investigators.Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med. 2018;379:215-225.6. Scotton WJ, Botfield HF, Westgate CS, Mitchell JL, Yiangou A, Uldall MS, Jensen RH, Sinclair AJ. Topiramate ismore effective than acetazolamide at lowering intracranial pressure. Cephalalgia. 2019;39:209-218.

Literature Commentary: June Issue Double Feature Section Editors: Mark L. Moster, MD M. Tariq Bhatti, MD Literature Commentary In this section of Journal of Neuro-Ophthalmology, M. Tariq Bhatti, MD and Mark L. Moster, MD will discuss the following 6 articles: 1. Gallina P, Savastano A, Becattini E, Orlandini S, Scollato A, Rizzo S, Carreras G, Di Lorenzo N, Porfirio B. Glaucoma in patients with shunt-treated normal pressure hydrocephalus. J Neurosurg. 2018;129:1078-1084. 2. Pagovich OE, Vo ML, Zhao ZZ, Petropoulos IN, Yuan M, Lertsuwanroj B, Ciralsky J, Lai E, Kiss S, D'Amico DJ, Mezey JG, Malik RA, Crystal RG. Corneal confocal microscopy: neurologic disease biomarker in Friedreich ataxia. Ann Neurol. 2018;84:893-904. 3. Albrecht P, Jansen A, Lee JI, Moll M, Ringelstein M, Rosenthal D, Bigalke H, Aktas O, Hartung HP, Hefter H. High prevalence of neutralizing antibodies after long-term botulinum neurotoxin therapy. Neurology. 2019;92:e48-e54. 4. Eren O, Rauschel V, Ruscheweyh R, Straube A, Schankin CJ. Evidence of dysfunction in the visual association cortex in visual snow syndrome. Ann Neurol. 2018;84:946-949. 5. Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, Kim AS, Lindblad AS, Palesch YY; Clinical Research Collaboration, Neurological Emergencies Treatment Trials Network, and the POINT Investigators. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med. 2018;379:215-225. 6. Scotton WJ, Botfield HF, Westgate CS, Mitchell JL, Yiangou A, Uldall MS, Jensen RH, Sinclair AJ. Topiramate is more effective than acetazolamide at lowering intracranial pressure. Cephalalgia. 2019;39:209-218. Gallina P, Savastano A, Becattini E, Orlandini S, Scollato A, Rizzo S, Carreras G, Di Lorenzo N, Porfirio B. Glaucoma in patients with shunt-treated normal pressure hydrocephalus. J Neurosurg. 2018;129:1078- 1084 Objective: Changes in the pressure gradient between intraocular and intracranial compartments at the lamina cribrosa level are a possible explanation of normal-tension glaucoma (NTG). Shunt-treated normal pressure hydrocephalus (NPH) is a model for testing whether the increase (time from disease onset to cerebrospinal fluid (CSF) shunt placement, i.e., "protection period") and decrease (time from shunt placement to observation, i.e., "exposure period") in intracranial pressure (ICP) are glaucoma protective or risk factors, respectively. The authors estimated the prevalence of NTG in patients with shunt-treated NPH and calculated the extent of optic nerve exposure to changes in the translamina cribrosa gradient. Methods: Data obtained in patients with NPH who had undergone ventriculoperitoneal shunt placement were analyzed. Patients with more than 6 months of follow-up, no pathologies associated with ICP changes or CSF dynamic disturbances, and no surgical or valve-related complications were scheduled for ophthalmic evaluation. Results: Nine of 22 patients had NTG, which is about a 40fold increase in the rate compared with the rate in the general elderly population without hydrocephalus (P , 0.001). The median protection period was 12.0 months in patients with NTG and 18.0 months in those without NTG (P = 0.033). The median ICP decrease multiplied by duration of exposure in months was 76.0 mm Hg · months in the NTG group and 24.1 mm Hg · months in the non-NTG group (P = 0.048). The patients' median adjusted age (adjusted for "protection" and "exposure" times) was 85.1 years in Moster and Bhatti: J Neuro-Ophthalmol 2019; 39: 273-278 the NTG group and 78.8 years in the non-NTG group (P = 0.001). Conclusions: A crucial risk factor for development of NTG in patients with shunt-treated NPH is the duration of optic nerve exposure to the lowering of ICP. Patients with NPH who are candidates for CSF shunting should be informed of the risk of incurring glaucoma. Longitudinal studies could provide estimates of tolerated times for a given ICP decrease. COMMENTS Unless you have been living under a rock-have you Mark? -the issue of the translaminar cribrosa pressure difference (TLPD) determined by the difference between the intraocular pressure (IOP) and the intracranial pressure (ICP) has captivated the interest of neuro-ophthalmologists, glaucomatologists, and neurosurgeons. This is a provocative small (n = 22) study of normal pressure hydrocephalus (NPH) patients undergoing the cerebrospinal fluid (CSF) shunt procedure, 9 of whom developed normal tension glaucoma (NTG), which is a 40· higher rate than the overall Italian population. Notwithstanding the conclusion of the study, which was that CSF shunting and prolonged lowering ICP is a major risk of developing NTG in patients with NPH, I found this study difficult to follow. It lacked important information that could have been presented in a table form, and disappointingly did not present a multivariate analysis. Table 1 is a basic table highlighting the demographic and ophthalmic differences between the NTG group (n = 9) and non-NTG group (n = 13). Tables 2 and 4 provide optical 273 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: June Issue Double Feature coherence tomography (OCT) and automated visual field testing data. The results section provides some details regarding the IOP, ICP, and change in pressure over time. Four of 9 NTG patients underwent a change in the valve setting compared with only 3 of 13 non-NTG patients. The median difference between the IOP and ICP was 8.3 mm Hg in the NTG group and 7.9 mm Hg in the non-NTG group. The median duration time between shunt placement and visit dates (termed "exposure period") was 76 months for the NTG group and 20 months for the non-NTG group. The median duration time between the onset of the NPH and shunt placement (termed "protection time") was 12 months in the NTG group and 18 months in the NTG group. The median value of the change in ICP multiplied by the exposure period in months was 76.0 mm Hg · months in the NTG group and 24.1 mm Hg · months in the non-NTG group. The median adjusted age {age at visit + ([exposure time/protection time] 2 1)} was 85.1 years in the NTG group and 78.8 years in the nonNTG group. What is not clear to me is the change in optic nerve appearance, OCT, and automated visual field testing before and after CSF shunting. Table 1 contains some OCT and automated visual field testing results, but it does not seem to represent changes over time and rather a value in one point in time after CSF shunt placement. -M. Tariq Bhatti, MD Although I might live under a rock, Tariq, I do get to hang out at glaucoma conferences and appreciate the exciting concept of the importance of the TLPD in glaucoma. I agree that this was a tough study to follow and have similar concerns as you as well as other concerns. For instance, "ophthalmic anamnesis" (i.e., medical history) was obtained to exclude patients with a preshunt glaucoma. However, there are many patients with NTG who are not suspected early because the IOP is normal, and it is difficult to be confident that some of these patients did not have NTG before shunting. I also question the validity of the diagnosis of NTG in this study. Patients were considered to have NTG if they had an IOP ,21 mm Hg, corneal central thickness $520 mm, and vertical cup-to-disc ratio .0.50 in association with the mean deviation ,22 dB and pattern SD .2 dB. I am not sure that is adequate. Surprisingly, there was no difference in RNFL thickness between the NTG and those without NTG (97 vs 93, P = 0.30), which makes little sense. Some other assumptions do not make sense either. For instance, an estimated "protection period" of preshuntelevated ICP was given based on the timing of symptom onset. In addition, ICP was not measured; there was an assumption of ICP based on the valve settings. Despite the limitations, it seems that a substantial group of NPH patients who get shunted develop NTG, which 274 supports the concept that TLPD is very important in NTG and also in primary open angel glaucoma. -Mark L. Moster, MD Pagovich OE, Vo ML, Zhao ZZ, Petropoulos IN, Yuan M, Lertsuwanroj B, Ciralsky J, Lai E, Kiss S, D'Amico DJ, Mezey JG, Malik RA, Crystal RG. Corneal confocal microscopy: neurologic disease biomarker in Friedreich ataxia. Ann Neurol. 2018;84:893-904 Objective: Friedreich ataxia (FRDA), an autosomal recessive neurodegenerative disease caused by mutations in the gene encoding for the mitochondrial protein frataxin, is characterized by ataxia and gait instability, immobility, and eventual death. We evaluated corneal confocal microscopy (CCM) quantification of corneal nerve morphology as a novel, noninvasive, and in vivo quantitative imaging biomarker for the severity of neurological manifestations in FRDA. Methods: Corneal nerve fiber density, branch density, and fiber length were quantified in individuals with FRDA (n = 23) and healthy age-matched controls (n = 14). All individuals underwent genetic testing and a detailed neurological assessment with the Scale for the Assessment and Rating of Ataxia (SARA) and Friedreich Ataxia Rating Scale (FARS). A subset of individuals with FRDA who were ambulatory underwent quantitative gait assessment. Results: CCM demonstrated a significant reduction in nerve fiber density and length in individuals with FRDA compared with healthy controls. Importantly, CCM parameters correlated with genotype, SARA and FARS neurological scales, and linear regression modeling of CCM nerve parametergenerated equations that predict the neurologic severity of FRDA. Interpretation: Together, the data suggest that CCM quantification of corneal nerve morphology is a rapid, sensitive imaging biomarker for quantifying the severity of neurologic disease in individuals with FRDA. COMMENTS Over the years, a variety of techniques have been studied to assess the possibility of using the eye as a biomarker of neurological diseases. In fact, if you remember, we recently reviewed a paper that looked at optical coherence tomography angiography and Alzheimer disease. This is a study of that ilk that investigated the utility of corneal confocal microscopy (CCM) in evaluating corneal nerve morphology (fiber length, fiber density, and branch density) as a biomarker for Friedreich ataxia (FRDA). The authors point out the CCM has been evaluated in several neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson disease, multiple sclerosis, and stroke. Twenty-three patients with genetically confirmed FRDA and 14 healthy age-matched controls were studied. Corneal nerve fiber length, fiber density, and branch density (if 1 Moster and Bhatti: J Neuro-Ophthalmol 2019; 39: 273-278 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: June Issue Double Feature outlier was excluded) were found to be statistically significantly lower in patients with FRDA compared to the healthy controls. In addition, all 3 corneal nerve morphology parameters correlated with the neurological status based on the Scale for the Assessment and Rating of Ataxia and Friedreich Ataxia Rating Scale. The authors propose CCM as a quantitative technique that can be used as a clinical endpoint in treatment trials and as a biomarker of neurological disease progression. What I would like to see is a prospective study to assess the change over time of the CCM in a large FRDA cohort to get a better sense of the natural history of the disease. -M. Tariq Bhatti, MD This is a nice study demonstrating a correlation of corneal nerve features and neurologic status in patients with FRDA. It will not be helpful for clinical differential diagnosis because abnormalities are found in numerous neurologic diseases. However, it might prove useful as a biomarker in clinical trials once a diagnosis is made. -Mark L. Moster, MD Albrecht P, Jansen A, Lee JI, Moll M, Ringelstein M, Rosenthal D, Bigalke H, Aktas O, Hartung HP, Hefter H. High prevalence of neutralizing antibodies after long-term botulinum neurotoxin therapy. Neurology. 2019;92:e48-e54 Objective: To investigate the prevalence of neutralizing antibodies (NAbs) against botulinum neurotoxin type A (BoNT/A) during long-term BoNT/A treatment in different neurologic indications. Methods: In this monocentric, observational, crosssectional study, 596 outpatients treated with BoNT/A for different indications were tested for BoNT/A binding antibodies by ELISA. Positive samples were investigated for NAbs with the mouse hemidiaphragm test. The prevalence of NAbs was analyzed for different indications: facial hemispasm, blepharospasm, cervical dystonia, other dystonia, and spasticity. Besides the rate of NAbpositive patients overall and per patient subgroup, a Kaplan-Meier analysis of the probability of remaining NAb negative with duration of treatment is provided, and a stepwise binary logistic regression analysis is performed to identify factors significantly contributing to the induction of NAbs. Results: Overall, 83 of 596 patients (13.9%) had measurable NAbs. The probability of developing NAbs increased with the single and cumulative dose of treatment and was influenced by the BoNT/A formulation, whereas all other factors analyzed, including disease entity and treatment duration, had no additional influence. Conclusions: We present the largest study to date of the prevalence of BoNT/A NAbs in a large unbiased cohort of patients including the relevant neurologic indications. Repeated injections of BoNT/A inevitably bear the risk of developing NAbs. However, in addition to avoiding booster Moster and Bhatti: J Neuro-Ophthalmol 2019; 39: 273-278 injections and providing short intervals between injections, reducing the individual injected doses may diminish the risk of NAb induction independently of the indication for which BoNT/A is used. COMMENTS Many of us use botulinum neurotoxin (BoNT) in our clinical practice; therefore, I thought this was a worthy publication to review in terms of understanding the frequency of neutralizing antibodies (NAbs). This was a single center, cross-sectional study that included a total of 596 patients with the following patient breakdown: 47 hemifacial spasm (HFS), 54 blepharospasm (BSP), 408 cervical dystonia (CD), 52 other dystonia (ODT), and 33 spasticity (SPAS). All patients received a minimum of 4 injections over a 1-year period of time. In addition, 3 type A formulations of BoNT were used: abo-BoNT/A (Dysport, Ipsen Biopharm Ltd, Wrexham, United Kingdom), ona-BoNT/A (Botox, Allergan, Irvine, CA), and incoBoNT/A (Xeomin, Merz Pharmaceuticals, Frankfurt, Germany). Most patients (n = 324) received aboBoNT/A injections. Before I point out the major findings of the paper, I think it is important to understand that the study did not analyze the biological effect of NAbs. In fact, a potential bias of the study was the exclusion of treatment-failure patients who may have had NAbs, thereby lowering the prevalence rate. From a personal perspective, I have never ordered BoNT NAbs. If a HFS or BSP patient is not responding to treatment despite increasing the dose, I will switch to another BoNT formulation without checking NAbs. The pertinent findings of the study are the following: • NAbs prevalence by patient subgroups: 0% HFS, 5.56% BSP, 15.69% CD, 17.31% ODT, and 15.15% SPAS. • NAbs prevalence by formulation: 6% abo-BoNT/A, 7% ono-BoNT/A, and 0% inco-BoNT/A. • Mean single dose (uDU): 82 HFS, 112 BSP, 641 CD, 356 ODT, and 957 SPAS. • The major influence in the presence of NAbs was the type of formulation and single dose per session (0.350 uDU). • The probability of remaining NAb positive decreased over time. • The low prevalence of NAbs in patients with HFS and BSP is most likely due to the lower mean single dose of BoNT/A used in these patients. The take-home point for me from this study is that in our neuro-ophthalmic patients with HFS and BPS, the prevalence of BoNT NAbs is low, and from a cost-effective and practical perspective, this does not need to be assessed. -M. Tariq Bhatti, MD 275 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: June Issue Double Feature It makes sense that the higher the dose and the longer one receives BoNT/A, the more frequent NAbs occur. In interpreting this study, it should be noted that 1 unit of Botox or Xeomin is equal to 2.5 units of Dysport. Most of the patients in the study were on Dysport, which is not approved in the United States for HFS or BSP. One interesting observation in this study was that not one of the 46 patients on Xeomin developed NAbs. This might be confounded by the fact that Xeomin is the medicine most recently approved and patients are not on it that long. The take-home message for neuro-ophthalmologists is that it is quite uncommon to have NAbs in our patients with HFS and BSP at the dosages that we use. tomography (PET) scans. The late component of the P100 wave and its transition to N145 has been attributed to an adjacent area, the fusiform gyrus. So, we have some evidence in favor of involvement of the visual association area in these patients. It might be useful in diagnosis and in clinical trials with treatment. For instance, the visual evoked potential can be studied before and after treatment in clinical trials with one of the medications anecdotally reported to be helpful, such as lamotrigine. Some issues with this study are that many of the patients with VS had migraine as a comorbidity. In addition, many more patients in the migraine and control group were females than in the VS group. -Mark L. Moster, MD -Mark L. Moster, MD Eren O, Rauschel V, Ruscheweyh R, Straube A, Schankin CJ. Evidence of dysfunction in the visual association cortex in visual snow syndrome. Ann Neurol. 2018;84:946-949 Abstract: Patients with visual snow (VS) syndrome suffer from a debilitating continuous visual disturbance of unknown mechanism. This study tested the hypothesis of dysfunctional visual processing using visual evoked potentials. Eighteen patients were compared with age-matched migraineurs (M) and healthy controls (C) using a 2-way analysis of variance with group (VS, M, and C) and gender as factors. Visual evoked potentials from patients with VS demonstrated increased N145 latency (in milliseconds, VS: 152.7 ± 7.9 vs M: 145.3 ± 9.8 vs C: 145.5 ± 9.4; F = 3.28; P = 0.046) and reduced N75-P100 amplitudes (in microvolts, VS: 7.4 ± 3.5 vs M: 12.5 ± 4.7 vs C: 10.8 ± 3.4; F = 3.16; P = 0.051). The Dunnett post hoc analysis was significant for all comparisons between VS and controls. These findings are in agreement with the idea that the primary disturbance in VS is a dysfunction of the visual association cortex. COMMENTS One of the most dramatic teaching moments in my clinic is when I discuss a visual snow (VS) patient with residents and students and I suggest they have an organic disorder. How could this bizarre symptom in an otherwise young and healthy patient be organic? Well, the symptoms are so stereotyped and similar between patients that I can almost write the history in the chart without speaking with the patient, so unless there is a mass conspiracy providing the script, there must be something to it. This study shows a mild but statistically significant delay of the N145 potential and a trend for a lower amplitude P100 in VS patients compared with migraine or control patients. A previous study on VS patients showed hypermetabolism in the lingual gyrus on 18FDG positron emission 276 I can just see you now Mark, standing in front of your residents, speaking poetically and dramatically, declaring VS as an organic disease. well not so fast my friend. If you recall, there have been some members of NANOS who have commented on NANOSNET that they can perceive VS but choose not to, suggesting that at least in some people VS is a heightened perception of a normal sensory phenomenon. When I read these personal accounts, I thought about the phenomenon of physiological diplopia that occurs if one chooses to "look" outside Panum's area of fusion. Now, before you get too dramatic on me, I think VS is an organic disease, but I wonder if it is a hypersensory phenomenon that many of us can suppress or ignore and others for whatever reason (may be due to faulty signaling) cannot. -M. Tariq Bhatti, MD I hate to say it, Tariq, but you may be correct! -Mark L. Moster, MD Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, Kim AS, Lindblad AS, Palesch YY; Clinical Research Collaboration, Neurological Emergencies Treatment Trials Network, and the POINT Investigators. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med. 2018;379:215-225 Background: Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population. Methods: In a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of 600 mg on Day 1, followed by 75 mg per day, plus aspirin (at a dose of 50-325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site Moster and Bhatti: J Neuro-Ophthalmol 2019; 39: 273-278 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: June Issue Double Feature investigator. The primary efficacy outcome in a time-to-event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days. Results: A total of 4,881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2,432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2,449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59-0.95; P = 0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10-4.87; P = 0.02). Conclusions: In patients with minor ischemic stroke or highrisk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone (funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029). COMMENTS This study randomized patients with transient ischemic attack or minor ischemic stroke to a combination of clopidogrel (Plavix) + aspirin or to aspirin alone. The primary efficacy outcome was the risk of an ischemic stroke, myocardial infarction, or death from ischemic vascular causes. The primary safety outcome was the risk of major hemorrhage, which was defined as symptomatic intracranial hemorrhage, intraocular bleeding causing vision loss, transfusion of 2 or more units of red cells or an equivalent amount of whole blood, hospitalization or prolongation of an existing hospitalization, or death due to hemorrhage. The findings were that the combination treatment prevented more ischemic events than aspirin alone but was also associated with a greater risk of hemorrhage. The trial was terminated early because of hemorrhages in the combined treatment group. Based on the data, the authors estimate that for every 1,000 patients who are treated with clopidogrel plus aspirin during a period of 90 days, such treatment would prevent approximately 15 ischemic events and would cause 5 major hemorrhages. One limitation of the study is that the dose of aspirin ranged from 50 to 325 mg daily and was the choice of the physician. Another limitation is that the study only included a small subpopulation of stroke types. The results are particularly hard to generalize for our neuroophthalmologic patient population because patients with Moster and Bhatti: J Neuro-Ophthalmol 2019; 39: 273-278 isolated visual change or isolated vertigo were excluded in this trial. What I come away with is this: Antiplatelet treatment is helpful. Too much antiplatelet treatment is harmful. I will continue treatment with aspirin as a first line and add or change to clopidogrel if another ischemic event occurs on aspirin and full anticoagulation is not a better fit for the patient. In summary, a nice scientific article that brings us back to needing the "art" of medicine. -Mark L. Moster, MD I want to focus on something you mentioned which was numbers need to treat (NNT) and numbers need to harm (NNH) that drives many of the treatment recommendations we make for our patients. The NNT represents the number of patients who need a specific treatment to prevent one additional poor outcome. The NNH represents the number of patients who need to be exposed to a risk factor to cause harm in 1 patient who would not otherwise have been harmed. A low NNT is good, and a low NNH is bad. The equation for NNT is the inverse of the absolute risk reduction, with the absolute risk reduction determined by the control event rate (CER) minus the experimental event rate (EER). The equation for NNH is the inverse of the absolute risk increase, with the absolute risk increase determined by EER-CER. For this study, the NNT was 67 patients (1/0.015) and the NNH (for major hemorrhage) was 200 (1/0.005) patients. Are these numbers good enough to put everyone on aspirin + clopidogrel? By the way Mark, I like your poetic theme in this issue of Literature Commentary invoking the "art of medicine." -M. Tariq Bhatti, MD Scotton WJ, Botfield HF, Westgate CS, Mitchell JL, Yiangou A, Uldall MS, Jensen RH, Sinclair AJ. Topiramate is more effective than acetazolamide at lowering intracranial pressure. Cephalalgia. 2019;39:209-218 Background: The management of idiopathic intracranial hypertension focuses on reducing intracranial pressure (ICP) to preserve vision and reduce headaches. There is sparse evidence to support the use of some of the drugs commonly used to manage idiopathic intracranial hypertension; therefore, we propose to evaluate the efficacy of these drugs at lowering ICP in healthy rats. Methods: We measured ICP in female rats before and after subcutaneous administration of acetazolamide, topiramate, furosemide, amiloride, and octreotide at clinical doses (equivalent to a single human dose) and high doses (equivalent to a human daily dose). In addition, we measured ICP after oral administration of acetazolamide and topiramate. Results: At clinical and high doses, subcutaneous administration of topiramate lowered ICP by 32% (P = 0.0009) and 21% (P = 0.015), respectively. There was no significant 277 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: June Issue Double Feature reduction in ICP noted with acetazolamide, furosemide, amiloride, or octreotide at any dose. Oral administration of topiramate significantly lowered ICP by 22% (P = 0.018), compared to 5% reduction with acetazolamide (P = .0.999). Conclusions: Our in vivo studies demonstrated that both subcutaneous and oral administration of topiramate significantly lowers ICP. Other drugs tested, including acetazolamide, did not significantly reduce ICP. Future clinical trials evaluating the efficacy and side effects of topiramate in idiopathic intracranial hypertension patients would be of interest. COMMENTS This study in rats looked at the intracranial pressure (ICP)lowering effect of 5 medications purported to lower ICP, including the only one with Class 1 evidence in human clinical trials-acetazolamide. Topiramate was the only one with benefit in the subcutaneous study. In the oral study, topiramate lowered ICP by 22% compared with a 5% reduction with acetazolamide. The study has some limitations. First, only 1 dose of drug was given, so we do not know what would have been found with continued treatment. Second, the study was in healthy rats, not those with elevated ICP. Third, the study was in rats, not humans. An additional concern I have is that if one looks at the graphs of the data, there was a nice decrease in ICP with acetazolamide; however, it was compared with a control group receiving 4% sodium chloride, which also decreased ICP significantly. This was chosen because of a similar osmolarity to the acetazolamide preparation but may not be an appropriate control group. Clinicians have been using topiramate for idiopathic intracranial hypertension (IIH) for a while based on it 278 being a carbonic anhydrase inhibitor. It is worth studying further in clinical trials because of its additional benefits as a preventative headache medication and its other side effects of weight loss in some patients. -Mark L. Moster, MD An interesting rat study but as you know Mark, it is difficult to extrapolate the results to humans. First, let me point out that although acetazolamide did not lower ICP significantly in rats, we know it works in humans. In fact, I just saw a nice young woman whose papilledema responded beautifully to acetazolamide going from Grade 4 papilledema to Grade 2 in a matter of less than 8 weeks. I think the IIH treatment trial was a move in the right direction in allowing us to practice some sort of evidencebased medicine (1). The surgical IIH treatment trial (https://clinicaltrials.gov/ct2/show/NCT03501966), which is now recruiting patients, will hopefully provide us with some more important data; but what I think we also need is a head-to-head randomized double-dummy trial comparing topiramate with acetazolamide, not just an open-label study (2). -M. Tariq Bhatti, MD REFERENCES 1. NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee, Wall M, McDermott MP, Kieburtz KD, Corbett JJ, Feldon SE, Friedman DI, Katz DM, Keltner JL, Schron EB, Kupersmith MJ. Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial. JAMA. 2014;311:1641-1651. 2. Celebisoy N, Gökçay F, Sirin H, Akyürekli O. Treatment of idiopathic intracranial hypertension: topiramate vs acetazolamide, an open-label study. Acta Neurol Scand. 2007;116:322-327. Moster and Bhatti: J Neuro-Ophthalmol 2019; 39: 273-278 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.