Literature Commentary

Literature Commentary Section Editors: Mark L. Moster, MD Marc J. Dinkin, MD Deborah I. Friedman, MD, MPH Literature Commentary In this issue of Journal of Neuro-Ophthalmology, Drs. Marc J. Dinkin, Deborah I. Friedman, and Mark L. Moster discuss the following 6 articles: 1. Mollan SP, Mitchell JL, Yiangou A, Ottridge RS, Alimajstorovic Z, Cartwright DM, Hickman SJ, Markey KA, Singhal R, Tahrani AA, Frew E, Brock K, Sinclair AJ. Association of amount of weight lost after bariatric surgery with intracranial pressure in women with idiopathic intracranial hypertension. Neurology. 2022;99. doi:10. 1212/WNL.0000000000200839. 2. Nia AM, Srinivasan VM, Lall R, Kan P. Dural venous sinus stenting in idiopathic intracranial hypertension: a national database study of 541 patients. World Neurosurg. 2022:S1878-8750(22)01135-4. doi: 10.1016/j.wneu.2022.08.035. 3. Eide PK, Hansson HA. A new perspective on the pathophysiology of idiopathic intracranial hypertension: role of the glia-neuro-vascular interface. Front Mol Neurosci. 2022;15:900057. 4. Shah S, Morris P, Buciuc M, Tajfirouz D, Wingerchuk DM, Weinshenker BG, Eggenberger ER, Di Nome M, Pittock SJ, Flanagan EP, Bhatti MT, Chen JJ. Frequency of asymptomatic optic nerve enhancement in a large retrospective cohort of patients with aquaporin-4+ NMOSD. Neurology. 2022;99:e851–e857. 5. Bsteh G, Krajnc N, Riedl K, Altmann P, Kornek B, Leutmezer F, Macher S, Mitsch C, Pruckner P, Rommer PS, Zulehner G, Pemp B, Berger T; Vienna Multiple Sclerosis Database Study Group. Retinal layer thinning after optic neuritis is associated with future relapse remission in relapsing multiple sclerosis. Neurology. 2022. doi: 10. 1212/WNL.0000000000200970. 6. Tsai RK, Lin KL, Huang CT, Wen YT. Transcriptomic analysis reveals that granulocyte colony-stimulating factor trigger a novel signaling pathway (TAF9-P53-TRIAP1-CASP3) to protect retinal ganglion cells after ischemic optic neuropathy. Int J Mol Sci. 2022;23:8359. doi: 10.3390/ijms23158359. Mollan SP, Mitchell JL, Yiangou A, Ottridge RS, Alimajstorovic Z, Cartwright DM, Hickman SJ, Markey KA, Singhal R, Tahrani AA, Frew E, Brock K, Sinclair AJ. Association of amount of weight lost after bariatric surgery with intracranial pressure in women with idiopathic intracranial hypertension. Neurology. 2022. doi:10.1212/WNL. 0000000000200839. Background and Objectives: The idiopathic intracranial hypertension randomized controlled weight trial (IIH:WT) established that weight loss through bariatric surgery significantly reduced intracranial pressure compared with a community weight management intervention. This substudy aimed to evaluate the amount of weight loss required to reduce intracranial pressure and to explore the impact of the different bariatric surgical approaches. Methods: IIH:WT was a multicenter randomized controlled trial. Adult women with active idiopathic intracranial hypertension and a body mass index of $35 kg/m2 were randomized to bariatric surgery or a community weight management intervention (1:1). This per-protocol analysis evaluated the relationship between intracranial pressure, weight loss, and the weight loss methods. A linear hierarchical regression model was used to fit the trial outcomes, adjusted for time, treatment arm, and weight. Results: Sixty-six women were included, of whom 23 had received bariatric surgery by 12 months; the average age was 31 (SD 8.7) years in the bariatric surgery group and e562 33.2 (SD 7.4) years in the dietary group. Baseline weight and intracranial pressure were similar in both groups, with mean weight 119.5 (SD 24.1) and 117.9 (SD 19.5) kg and mean lumbar puncture opening pressure 34.4 (SD 6.3) and 34.9 (SD 5.3) cmCSF in the bariatric surgery group and the dietary group, respectively. Weight loss was significantly associated with reduction in intracranial pressure (R2 = 0.4734, P # 0.0001). Twenty-four percent weight loss (weight loss of 13.3 kg [SD 1.76]) was associated with disease remission (intracranial pressure [ICP] # 25 cmCSF). Roux-en-Y gastric bypass achieved greater, more rapid, and sustained ICP reduction compared with the other methods. Conclusions: The greater the weight loss, the greater the reduction in ICP was documented. Twenty-four percent weight loss was associated with disease remission. Such magnitude of weight loss was unlikely to be achieved without bariatric surgery, and hence, consideration of referral to a bariatric surgery program early for those with active idiopathic intracranial hypertension may be appropriate. Classification of Evidence: This study provides Class II evidence that weight loss after bariatric surgery results in reduction in intracranial pressure in adult women with idiopathic intracranial hypertension. This study is Class II because of the use of a per-protocol analysis. COMMENTS This is a substudy of the IIH:WT study, which showed that bariatric surgery was superior than nonsurgical weight Moster et al: J Neuro-Ophthalmol 2022; 42: e562-e570 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary management intervention in treating IIH. The main finding in the current substudy is a correlation between the amount of weight loss, ICP, and clinical improvement in women with IIH. A 5% weight loss was associated with a 10% decrease in ICP, a 10% weight loss with a 14% decrease in ICP, and a 20% weight loss with a 26% decrease in ICP. Surprisingly, remission (with ICP # 25 cm H2O) required a 24% weight loss. This is in contrast to prior reports that suggested a more moderate weight loss was necessary. Although this study showed that Roux-en-Y gastric bypass was the most successful surgical intervention, the numbers were too small for this to be recommended over other techniques. How does this change my approach to treating IIH? First, I will no longer tell patients that 10% weight loss is enough. Second, I will consider bariatric surgery sooner in patients with visual changes or moderate symptoms who have difficulty losing weight and are intolerant of medications. This will be considered along with the options of shunt, optic nerve sheath decompression, and stenting. —Mark L. Moster, MD This study provides convincing evidence that a 24% of body weight reduction normalizes cerebrospinal fluid (CSF) pressure. How one applies this to clinical practice depends on whether or not “worshiping the pressure” guides therapy, particularly based on a single lumbar puncture. Several studies showed that a 6%–10% reduction in weight improves visual function and papilledema. The impact of weight loss on headache is less certain. Personally, I do not recommend treating the CSF pressure or obtaining intermittent lumbar punctures to follow it. I base therapy on the patient’s clinical status. Roux-en-Y gastric bypass is the most effective bariatric surgical procedure but without significant changes in lifestyle and eating habits; the results may not be sustained. —Deborah I. Friedman, MD, MPH This study offers strong evidence that the amount of weight loss required to normalize ICP is higher than previously thought, and that bariatric surgery offers the most surefire means of achieving it. I find it especially interesting to see from these results that the reduction in ICP correlates with the degree of weight loss and does not plateau after a specific threshold. I would just note that although a 24% reduction in weight may appear necessary to reduce ICP below 25 cm H2O, such a reduction is not always necessary to resolve papilledema and clinical symptoms of IIH. As such, nonsurgical weight reduction is likely to remain an effective long-term treatment for most patients with the disease. —Marc Dinkin, MD Moster et al: J Neuro-Ophthalmol 2022; 42: e562-e570 Nia AM, Srinivasan VM, Lall R, Kan P. Dural venous sinus stenting in idiopathic intracranial hypertension: a national database study of 541 patients. World Neurosurg. 2022:S1878-8750(22) 01135-4. doi:10.1016/j.wneu.2022.08.035. Background: Dural venous sinus stenting (VSS) is an effective intervention for patients with idiopathic intracranial hypertension (IIH) refractory to medical treatment. Our goal was to evaluate the efficacy by using a large multiinstitutional sample. Methods: Five hundred forty-one patients older than 18 years who underwent VSS within 3 years of IIH diagnosis were queried using CPT and ICD-10 codes from the TriNetX Analytics Network. Patient demographics, baseline symptoms, procedures, and clinical outcomes were evaluated within 1 year postoperatively. Outcomes examined were headache, tinnitus, blindness/low vision, optic nerve sheath fenestration (ONSF), CSF shunt, and use of medications (acetazolamide, methazolamide, furosemide, topiramate, tricyclic antidepressants, and valproate) for IIH. Prestent and poststent data were compared using the Fisher exact test, and the odds ratios were computed using the Baptista–Pike method. Results: The mean age at VSS was 36.7 ± 10.6 years; 92% were female, 65% of patients were Caucasian, 25% were Black/African American, 1% were Asian, and 9% were of other/unknown race. Within the 1-year followup, acetazolamide and topiramate use were significantly reduced after VSS (P value , 0.0001*, OR: 0.45, CI: 0.35–0.57 and P value: 0.03*, OR: 0.71, CI: 0.52–0.95, respectively). Also, headaches, visual disturbance, dizziness/giddiness, and tinnitus significantly improved after VSS (P values , 0.005*). Finally, the number of CSF shunt procedures and ONSF procedures demonstrated no significant change after VSS (P values . 0.05). Conclusions: VSS is an effective and safe procedure resulting in significant improvement of headaches, visual impairment, dizziness, and tinnitus; acetazolamide and topiramate usage was lower after VSS in patients with IIH. The paucity of pre- and post-VSS CSF shunt and ONSF procedure data does not provide enough evidence to establish significance. COMMENTS I am the first to admit that I was a slow adopter of stenting, likely influenced by some very bad outcomes when it was first used to treat IIH. Early on, a death was mentioned during a presentation at a NANOS meeting and glossed over. I was asked to review a medicolegal case of a woman referred to neurosurgery for a shunt, had a stent instead, developed an epidural hematoma, herniated, and sustained major neurological damage. Based on these incidents and other reports, I was extremely cautious about recommending it to my patients and in educational presentations, particularly as a first-line interventional treatment. Working with an outstanding neuro- e563 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary interventionalist, I now incorporate stenting in selected patients with IIH. Nia et al performed an analysis of dural venous sinus stenting (DVSS) from a large data set reflecting health records of over 88 million patients. They measured outcomes within 1 year after the procedure based on CPT codes. Before stenting, 58% reported headaches, 41% reported visual symptoms/blindness, 16% had dizziness, and 12% had tinnitus. Two percent had a previous shunt or optic nerve sheath fenestration. After stenting, they found significant improvement in the number of patients taking acetazolamide and topiramate as well as the aforementioned symptoms. Only a small number of patients required additional surgery for IIH after stenting. The article does not mention complications. As there was apparently no chart review (my attempt to speak with the corresponding author to clarify the methods was not successful), it is unclear how the symptom outcomes were extracted from the database. As physicians often do not enter symptom codes in the chart, there may be considerable reporting bias. Despite the marked increase in stenting procedures performed for IIH over the past decade, there is a paucity of data in the literature regarding outcomes, particularly those assessing vision. The most careful study was performed by our own Dr. Dinkin (1). Although his cohort was small, patients were followed prospectively, evaluating neuro-ophthalmic parameters that are critical for assessing the treatment effect. Two meta-analyses based on the published literature (2,3) also showed improvement in headache, papilledema, visual acuity, and tinnitus after DVSS with stent survival rates of 85% (95% CI: 79%–87%) and stent-adjacent stenosis rates of 14% (95% CI: 11%–18%) at 18 months (2). Many conditions in neuro-ophthalmology are uncommon, so a meta-analysis may help increase the sample size and statistical power to determine a treatment effect, but meta-analysis is subject to publication bias and limited by the heterogeneity and quality of published studies (4). I invite you to read the meta-analyses of stenting, optic nerve sheath fenestration, stenting, and bariatric surgery that are based on the published literature (5–8). Take a look at the denominators in the tables—you may be surprised by the relatively small numbers of patients compared with the number of procedures performed, with only 2 randomized trials. There is more work to be done! —Deborah I. Friedman, MD, MPH 3. Nicholson P, Brinjinki W, Radovanovic I, Hilditch CA, Tsang ACO, Krings T, Pereira VM, Lench S. Venous sinus stenting for idiopathic intracranial hypertension: a systemic review and meta-analysis. J Neurointerven Surg. 2019;11:380–385. 4. Lee YH. An overview of meta-analysis for clinicians. Korean J Intern Med. 2018;33:277–283. 5. Kalyvas A, Neromyliotis E, Koutsarnakis C, Komaitis S, Drosos E, Skandalkis GP, Pantzai M, Gobin YP, Stranjalis G, Patsalides A. A systematic review of surgical treatments of idiopathic intracranial hypertension. Neurosurg Rev. 2021;44:773–792. 6. Piper R, Kalyvas AV, Young AMH, Hughes MA, Jamjoom AAB, Fouyas IP. Interventions for idiopathic intracranial hypertension. Cochrane Database Syst Rev. 2015;2015:CD003434. 7. Kalyvas AV, Hughes M, Koutsarnakis C, Moris D, Liakos F, Sakas DE, Stranjalis G, Fouyas I. Efficacy, complications and cost of surgical interventions for idiopathic intracranial hypertension: a systematic review of the literature. Acta Neurchir (Wien) 2017;1159:33–49. 8. Salih M, Enriquez-Marulanda A, Khorasanizaddeh M, Moore J, Pabhu VD, Ogilvy C. Cerebrospinal fluid shunting for idiopathic intracranial hypertension. A systemic review, meta-analysis, and implications for a modern management protocol. Neurosurgery 2022;91:529–540. I was also a slow adopter of VSS and am using it more now. I agree with your criticisms of this paper, Deb. I would note that the paper provides no information on visual function and really no legitimate clinical information. This paper, written by 4 neurosurgeons mentioning vague clinical outcomes (e.g., visual disturbance and dizziness/giddiness) and not complications, adds little to our knowledge about VSS. —Mark L. Moster, MD After many years evaluating VSS for IIH and reviewing numerous studies that have now analyzed visual outcomes after stenting, including a recent retrospective study incorporating visual fields and optical coherence tomography (1), I am convinced that it can be an effective intervention for patients with medically refractory disease. However, I agree with Dr. Friedman that serious neurological complications, including death, can rarely occur. As such, it should be reserved for patients with visionthreatening papilledema or debilitating symptoms that are clearly due to IIH. The analysis of data from a large health network database may add to our understanding of outcomes based on the large cohorts involved, but if symptom prevalence is based on diagnosis codes, there is a significant risk of a pseudoreduction in symptoms because physicians may fail to include each ongoing symptom as a diagnosis code in follow-up visits. —Marc Dinkin, MD 1. Dinkin MJ, Patsalide A. Venous sinus stenting in idiopathic intracranial hypertension: results of a prospective trial. J Neuroophthalmol. 2017;37:113–121. 2. Saber H, Lewis W, Sadeghi G, Narayanan S. Stent survival and stent-adjacent stenosis rates following venous sinus stenting for idiopathic intracranial hypertension: a systemic review and meta-analysis. Interv Neurol. 2018;7:490–500. e564 1. Oyemade K, Xu T, Binjikji W, Cutsforth-Gregory JK, Lanzino G, Kallmes DF, Moss HE, Dodd R, Bhatti MT, Chen JJ. Improved ophthalmic outcomes following venous sinus stenting in idiopathic intracranial hypertension. Front Ophthalmol. 2022. Moster et al: J Neuro-Ophthalmol 2022; 42: e562-e570 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary Eide PK, Hansson HA. A new perspective on the pathophysiology of idiopathic intracranial hypertension: role of the glia-neuro-vascular interface. Front Mol Neurosci. 2022;15:900057. Abstract: Idiopathic intracranial hypertension (IIH) is a neurological disease characterized by symptoms and signs of increased intracranial pressure (ICP) of unknown cause. Most attention has been given to the role of cerebrospinal fluid (CSF) disturbance and intracranial venous hypertension caused by sinus vein stenosis. We previously proposed that key pathophysiological processes take place within the brain at the glia-neuro-vascular interface. However, the relative importance of the proposed mechanisms in IIH disease remains unknown. Modern treatment regimens aim to reduce intracranial CSF and venous pressures, but a substantial proportion of patients experience lasting complaints. In 2010, the first author established a database for the prospective collection of information from individuals being assessed for IIH. The database incorporates clinical, imaging, physiological, and biological data and information about treatment/outcome. This study retrieved information from the database, asking the following research questions: In subjects with IIH responding to shunt surgery, what is the occurrence of signs of CSF disturbance, sinus vein stenosis, intracranial hypertension, and microscopic evidence of structural abnormalities at the glia-neuro-vascular interface? Secondarily, do semiquantitative measures of abnormal ultrastructure at the glia-neuro-vascular interface differ between subjects with definite IIH and non-IIH (reference) subjects? The study included 13 patients with IIH who fulfilled the diagnostic criteria and who improved after shunt surgery, that is, patients with definite IIH. Comparisons were done regarding MRI findings, pulsatile and static ICP scores, and immune-histochemistry microscopy. Among these 13 subjects with IIH, 6 (46%) patients presented with MRI signs of CSF disturbance (empty sella and/or distended perioptic subarachnoid spaces), 0 (0%) patients with IIH had MRI signs of sinus vein stenosis, 13 (100%) patients with IIH presented with abnormal preoperative pulsatile ICP [overnight mean ICP wave amplitude (MWA) above thresholds], 3 (23%) patients showed abnormal static ICP (overnight mean ICP above threshold), and 12 (92%) patients with IIH showed abnormal structural changes at the glia-neuro-vascular interface. Comparisons of semiquantitative structural variables between IIH and age- and gender-matched reference (REF) subjects showed IIH abnormalities in glial cells, neurons, and capillaries. The present data suggest a key role of disease processes affecting the glia-neuro-vascular interface. COMMENTS Despite numerous lines of evidence supporting a role for venous hypertension, neuroinflammation, and glymphatic dysfunction in the pathophysiology of idiopathic intracranial hypertension (IIH), the disease remains true to its namesake. In this setting, the work of Eide and Hansson, published this summer in Frontiers in Molecular Neuroscience (1), provides a step forward, arguing strongly for a contribution by dysfunction of the glia-neuro-vascular interface. Moster et al: J Neuro-Ophthalmol 2022; 42: e562-e570 The authors’ work followed up on their 2016 paper in which they took small cortical biopsies at the time of placement of an intracranial pressure sensor in the right frontal cortex in 13 patients with IIH (2). These biopsies demonstrated histological abnormalities as compared to biopsies from patients with non-IIH including patchy astrogliosis (clustering of hypertrophic astrocytes), loss of astrocytic domains, synaptic stripping (where astrocytic processes form membranes that surround more than half of the neuronal cell body), and elevated aquaporin-4 (AQP4) immunoreactivity within astrocytic perivascular processes as compared to control specimens. Moreover, they found that the degree of astrogliosis correlated with the degree of astrocytic perivascular process AQP4 expression. Of note, they found no evidence of cerebral edema and no elevation in activated microglial cells to suggest inflammation. The authors hypothesized that astrocytic hypertrophy in IIH crowded the paravascular and intercellular spaces, leading to compromised glymphatic system dysfunction and elevated ICP. Elevated AQP4 expression was interpreted as a compensatory mechanism to try to enhance water outflow. In the current study, the authors included only patients who were treated with CSF shunt placement with a good response, yielding 13 subjects who had a mean disease duration of 5.1 years. They then looked at clinical features, biopsy samples, ICP monitoring, and MRI findings such as empty sella, perioptic sheath expansion, and venous sinus stenosis. They found empty sella or distended perioptic space in 46%, but 0% had venous sinus stenosis. All patients showed abnormal pulsatile ICP, defined as increased mean wave amplitude (MWA), the difference in ICP between the diastolic minimum and systolic maximum in the ICP waveform, but only 23% showed abnormal mean ICP. Histopathology again showed increased occurrence of patchy astrogliosis and loss of astrocyte domains. Light microscopy again showed increased paravascular AQP4 reactivity, although this was not confirmed with transmission electron microscopy (TEM). Impaired neuronal function was suggested by a significantly reduced mitochondria to endoplasmic reticulum length (MERC) distance and decreased postsynaptic density length in the patients with IIH. Finally, IIH subjects’ specimens were more likely to demonstrate capillary pericyte or basement membrane degeneration, both indicators of blood–brain barrier (BBB) dysfunction. Increased fibrinogen reactivity in the neuropil was also demonstrated, consistent with BBB incompetence. Eide and Hansson’s work offers strong evidence for the emerging hypothesis that dysfunction of the glymphatic system plays a role in the pathophysiology of IIH. Specifically, the notion that increased astrocytic mass results in crowding and reduces paravascular egress, while also reducing intracranial compliance, both resulting in elevated ICP, would suggest that IIH is an astrocytopathy at heart. The apparent capillary structural abnormalities point to BBB dysfunction, although this theoretically could result from elevated ICP. At the same time, the lack of activated e565 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary microglial cells or other signs of inflammation in this study casts doubt on theories of neuroinflammation in IIH. Their observation of multiple markers of neuronal dysfunction may explain the prevalence of cognitive dysfunction in IIH (3,4) and has significant implications for the way we think about IIH. Assuming that such neuronal injury is not a primary component of IIH pathophysiology, but instead is a consequence of prolonged intracranial hypertension, the importance of expedited reduction of ICP in IIH is highlighted to protect not only the optic nerves but also the central nervous system in general. There are a few limitations to the study. For example, the prevalence of obesity in the reference group was significantly lower than that of the IIH group, so that some of the pathological observations could be the result of chronic obesity as opposed to IIH. Some of the authors’ conclusion from this study could be qualified. For example, the authors concluded that because none of their patients’ MRVs demonstrated venous stenosis, “the data do not add support to the assumption that sinus vein stenosis is a significant player in IIH pathophysiology.” However, it is notable that in the past 10 years, patients with IIH in need of surgical intervention with venous sinus stenosis are likely to be sent to interventionalists for stenting, whereas those without actionable stenosis are more likely to be sent for shunting. This confounder may help explain the discrepancy between the incidence of stenosis in this group vs that found by Farb et al (5) (93%). Furthermore, the absence of stenosis in 100% of these patients raises the question of whether the findings in this study are applicable to those patients who do have stenosis, with the assumption that there may be several subtypes of IIH with varying underlying pathological underpinnings. The lack of elevated mean ICP in these cases likely reflects discrepancies between lumbar puncture measurements and intraparenchymal monitoring. In addition, because all 13 patients were on ICPlowering medications, the ICP monitoring results do not suggest that ICP in de novo IIH is not elevated. Finally, and most importantly, the degree to which the histopathological findings in this study such as patchy astrogliosis and blood–brain barrier dysfunction are a primary driver of high ICP in IIH, rather than resulting from chronically elevated ICP, remains unclear, especially given the mean disease duration of 5.1 years. Comparisons with pathology from patients with alternative causes of chronic ICP would help strengthen their conclusions. —Marc Dinkin, MD 1. Eide PK, Hansson HA. A new perspective on the pathophysiology of idiopathic intracranial hypertension: role of the glia-neurovascular interface. Front Mol Neurosci. 2022;15:900057. 2. Eide PK, Eidsvaag VA, Nagelhus EA, Hansson HA. Cortical astrogliosis and increased perivascular aquaporin-4 in idiopathic intracranial hypertension. Brain Res. 2016;1644:161–175. e566 3. Fermo OP, Rao A, Schwartzbaum A, Sengupta S, Zhang Y, Wang J, Moghekar A. Predictors of cognitive impairment in pseudotumor cerebri. Neurol Neurochir Pol. 2021;55:394–402. 4. Zur D, Naftaliev E, Kesler A. Evidence of multidomain mild cognitive impairment in idiopathic intracranial hypertension. J Neuroophthalmol. 2015;35:26–30. 5. Farb RI, Vanek I, Scott JN, Mikulis DJ, Willinsky RA, Tomlinson G, terBrugge KG. Idiopathic intracranial hypertension: the prevalence and morphology of sinovenous stenosis. Neurology. 2003;60:1418–1424. I don’t know about this paper, Marc. I agree with your concerns and have others. Why do I see venous sinus stenosis in most patients with IIH and they saw it in none? How do we know that their findings are not secondary to elevated ICP rather than causative? This paper also has it as a given that patients with IIH have cognitive dysfunction. How well has that been studied? What would be the subjective answer of whether there is cognitive dysfunction if you surveyed a population with daily headache and/or blurred vision and/or pulsatile tinnitus? How about in neuro-ophthalmologists without elevated ICP? —Mark L. Moster, MD I agree with Mark that the issue of cognitive dysfunction may be confounded by headaches or medications, including acetazolamide. I was a little surprised that the investigators chose empty sella for an MRI biomarker because this finding is not specific to IIH and is present in at least 20%–25% of the general population. The lack of transverse venous sinus stenosis in any of the patients with IIH is also unusual. Patients with IIH do not generally have shunts placed early in their course, unless they have significant visual compromise. Thus, this IIH cohort had the disease for 5.2 ± 3.4 years. Changes in the brain this long after disease onset may not inform us of the primary pathogenesis of IIH but reflect ongoing intracranial hypertension. The selection of patients with epilepsy as the control group perhaps was not the best choice. Using patients with hydrocephalus from other causes requiring shunts would provide better insight as to whether the study findings are specific to IIH or indicate changes occurring with hydrocephalus in general. —Deborah I. Friedman, MD, MPH Shah S, Morris P, Buciuc M, Tajfirouz D, Wingerchuk DM, Weinshenker BG, Eggenberger ER, Di Nome M, Pittock SJ, Flanagan EP, Bhatti MT, Chen JJ. Frequency of asymptomatic optic nerve enhancement in a large retrospective cohort of patients with aquaporin-4+ NMOSD. Neurology. 2022. doi:10.1212/WNL.0000000000200838. Background and Objectives: Asymptomatic or persistent optic nerve enhancement in aquaporin (AQP)-4immunoglobulin G (IgG)-positive neuromyelitis optica spectrum Moster et al: J Neuro-Ophthalmol 2022; 42: e562-e570 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary disorder (NMOSD) is thought to be rare. Improved understanding may have important implications for the assessment of treatment efficacy in clinical trials and in clinical practice. Our objective was to characterize NMOSD interattack optic nerve enhancement. Methods: This was a retrospective cohort study performed between 2000 and 2019 (median follow-up 5.5 [range 1– 35] years) of patients with AQP4-IgG–positive optic neuritis (ON) evaluated at Mayo Clinic. MRI orbits were reviewed by a neuroradiologist, neuro-ophthalmologist, and neuroimmunologist blinded to clinical history. Interattack optic nerve enhancement (.30 days after attack) was measured. The correlation between interattack enhancement and Snellen visual acuity, converted to logarithm of the minimum angle of resolution (LogMAR), at attack and at follow-up was assessed. Results: One hundred ninety-eight MRI scans in 100 patients with AQP4-IgG+ NMOSD were identified, with 107 interattack MRI scans from 78 unique patients reviewed. Seven scans were performed before any ON (median 61 days before attack [range 21–271 days]) and 100 after ON (median 400 days after attack [33–4,623 days]). Optic nerve enhancement was present on 18 of 107 (16.8%) interattack scans (median 192.5 days from attack [33– 2,943]) of patients with preceding ON. On 15 scans, enhancement occurred at the site of prior attacks; the lesion location was unchanged, but the lesion length was shorter. Two scans (1.8%) demonstrated new asymptomatic lesions (prior scan demonstrated no enhancement). In a third patient with subjective blurry vision, MRI showed enhancement preceding detectable eye abnormalities on examination noted 15 days later. There was no difference in visual acuity at preceding attack nadir (LogMAR VA 1.7 vs 2.1; P = 0.79) or long-term visual acuity (LogMAR VA 0.4 vs 0.2; P = 0.56) between those with and without interattack optic nerve enhancement. Discussion: Asymptomatic optic nerve enhancement occurred in 17% of patients with NMOSD at the site of prior ON attacks and may represent intermittent blood–brain barrier breakdown or subclinical ON. New asymptomatic enhancement was only seen in 2% of patients. Therapeutic clinical trials for NMOSD require blinded relapse adjudication when assessing treatment efficacy, and it is important to recognize that asymptomatic optic nerve enhancement can occur in patients with ON. COMMENTS Most of us taking care of patients with aquaporin4+ neuromyelitis optica spectrum disease (AQP4-IgG+ NMOSD) have encountered optic nerve enhancement on MRI despite no new visual complaints suggestive of optic neuritis (ON). The approach to these patients can be challenging—should they be treated for an “asymptomatic” ON? Should the finding suggest that current diseasemodifying agents are failing? These silently enhancing lesions can be problematic in clinical trials as well: are they consistent with drug failure? To address these questions, Shah et al (1) reviewed 198 MRI scans in 100 patients with AQP4-IgG+ NMOSD seen at the Mayo Clinic. Images were independently reviewed by researchers blinded to the clinical details. MRI scans were categorized as either attack associated or interattack (.30 days after Moster et al: J Neuro-Ophthalmol 2022; 42: e562-e570 attack without new visual loss) and assessed for new or worsening enhancement. The authors identified 91 attack scans and 107 interattack scans among 78 patients out of which 18 (17%) displayed enhancement. Fifteen of these cases showed improvement at the location of the prior attack, one of which persisted at 20 months. In the 3 remaining cases, the asymptomatic enhancement was new, remaining asymptomatic in 2 but heralding clinical ON 2 weeks later in the third. Young age predicted interattack enhancement (mean age of 27.5 vs 50 years in those without). Interattack enhancement did not correlate with lesion length, visual nadir of the preceding attack, or long-term visual outcomes. Shah et al’s results demonstrate that a minority of MRI scans performed in the absence of clinical ON will show optic nerve enhancement. Most of these will simply reflect a slowly improving prior ON. Because final visual outcomes were not worse in patients with persistent lesions, their presence does not in and of itself necessitate further treatment with corticosteroids or plasmapheresis. They may simply reflect a more profound, long-lasting breakdown of the blood–brain barrier by ON, rather than ongoing inflammation. As the authors point out, a higher prevalence of slowly improving enhancing lesions among younger patients may reflect a more powerful autoimmune response with younger age. It is unlikely that the difference reflects better blood–brain repair with age (2). Among the 3 patients in whom the enhancement was new, only 1 developed clinical ON. I would still favor treatment for such de novo enhancing lesions even before clinical symptoms, to cover the 1 of 3 patients in whom clinical symptoms will occur, given the data in favor of timely treatment of NMOSD attacks (3). The results of the study also serve to caution those designing clinical trials for NMOSD that ON enhancement may not reflect disease recurrence or suggest drug failure. Prospective studies including optical coherence tomography (OCT) simultaneous with and after the interattack MRI scans would be helpful to screen for any developing atrophy consistent with occult ON. Because, in the absence of disc edema, OCT would not demonstrate any changes at the time of a new attack, visual evoked potentials (VEPs) would increase sensitivity of an associated occult ON. —Marc Dinkin, MD 1. Shah S, Morris P, Buciuc M, Tajfirouz D, Wingerchuk DM, Weinshenker BG, Eggenberger ER, Di Nome M, Pittock SJ, Flanagan EP, Bhatti MT, Chen JJ. Frequency of asymptomatic optic nerve enhancement in a large retrospective cohort of patients with aquaporin-4+ NMOSD. Neurology. 2022. doi: 10.1212/WNL.0000000000200838. 2. Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, Toga AW, Jacobs RE, Liu CY, Amezcua L, Harrington MG, Chui HC, Law M, Zlokovic BV. Blood brain barrier breakdown in the aging human hippocampus. Neuron 2015;85:296–302. 3. Bonnan M, Valentino R, Debeugny S, Merle H, Fergé JL, Mehdaoui H, Cabre P. Short delay to initiate plasma exchange is the strongest predictor of outcome in severe attacks of NMO e567 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary spectrum disorders. J Neurol Neurosurg Psychiatry. 2018;89:346–351. This study raises some questions. First, is an asymptomatic ON enhancement something to be concerned about and prompt a change in treatment? Second, is subclinical enhancement in the optic nerve due to immunosuppressant activity dampening an acute episode and making it asymptomatic? As you mention, VEP might be helpful. It would also be helpful to follow OCTs for a few months after noting the MRI change. I’ve always thought that, in contrast to MS, OCTs will not change between attacks because NMOSD is not a neurodegenerative disease. Now, if I see OCT change, I will consider that there may have been a subclinical attack of ON. —Mark L. Moster, MD It’s always difficult to know what to do with asymptomatic patients having neuroimaging abnormalities. For example, we don’t recommend diagnosing and treating IIH when the clinical context doesn’t support the imaging findings. One of my guiding mantras (which is admittedly not applicable to all medical diseases) is that you can’t make an asymptomatic patient better. Is it prudent to treat all patients with NMOSD with new interictal optic nerve enhancement when two-thirds will not have a clinical attack? The jury is still out on this one. —Deborah I. Friedman, MD, MPH Bsteh G, Krajnc N, Riedl K, Altmann P, Kornek B, Leutmezer F, Macher S, Mitsch C, Pruckner P, Rommer PS, Zulehner G, Pemp B, Berger T; Vienna Multiple Sclerosis Database Study Group. Retinal layer thinning after optic neuritis is associated with future relapse remission in relapsing multiple sclerosis. Neurology. 2022. doi:10.1212/WNL. 0000000000200970. Introduction: Remission of relapses is an important contributor to both short- and long-term prognosis in relapsing multiple sclerosis (RMS). In MS-associated acute optic neuritis (MS-ON), retinal layer thinning measured by optical coherence tomography (OCT) is a reliable biomarker of both functional recovery and the degree of neuroaxonal damage. However, prediction of non-ON relapse remission is challenging. We aimed to investigate whether retinal thinning after ON is associated with relapse remission after subsequent non-ON relapses. Methods: For this longitudinal observational study from the Vienna MS database (VMSD), we included patients with MS with 1) an episode of acute ON; 2) available spectraldomain OCT scans within 12 months before ON onset (OCTbaseline), within 1 week after ON onset (OCTacute), and 3–6 months after ON (OCTfollow-up); and 3) at least 1 nonON relapse after the ON episode. Subsequent non-ON relapses were classified as displaying either complete or incomplete remission based on change in the Expanded e568 Disability Status Scale (EDSS) assessed at 6 months after relapse. The association of retinal thinning in the peripapillary retinal nerve fiber layer (DpRNFL) and macular ganglion cell and inner plexiform layer (DGCIPL) with incomplete remission was tested by multivariate logistic regression models adjusting for age, gender, disease duration, relapse severity, time to steroid treatment, and DMT status. Results: We analyzed 167 patients with MS (mean age 36.5 years [SD 12.3], 71.3% female, and mean disease duration 3.1 years [SD 4.5]) during a mean observation period of 3.4 years (SD 2.8) after the ON episode. In 61 patients (36.5%), at least 1 relapse showed incomplete remission. In the multivariable analyses, incomplete remission of non-ON relapse was associated with DGCIPL thinning both from OCTbaseline to OCTfollow-up and from OCTacute to OCTfollow-up (odds ratio [OR] 2.4 per 5 mm, P , 0.001), independently explaining 29% and 27% of the variance, respectively. DpRNFL was also associated with incomplete relapse remission when measured from OCTbaseline to OCTfollow-up (OR 1.9 per 10 mm, P , 0.001), independently accounting for 22% of the variance, but not when measured from OCTacute to OCTfollow-up. Conclusions: Retinal layer thinning after optic neuritis may be useful as a marker of future relapse remission in RMS. COMMENTS Increased OCT thinning of the RNFL and GCIPL after optic neuritis has been associated with suboptimal recovery of visual function. As a sign of neuroaxonal damage, thinning of these structures independent of acute optic neuritis has been associated with disability in patients with MS. The authors, noting that individual patients tend to have either good or poor recovery on all their early relapses, sought to determine whether an increase in thinning on OCT in patients with optic neuritis would predict a poorer recovery on subsequent relapses not affecting the optic nerve. The findings were that from a baseline some time before ON, an increase in thinning of both RNFL and GCIPL was associated with poorer recovery. From an OCT at the time of ON, GCIPL thinning was associated with poor recovery, but thinning of the RNFL was not. This makes sense because often the RNFL is thickened initially in ON, but the GCIPL is not. This study confirmed the findings that better recovery is also associated with milder relapses, younger age, and being on a highly effective disease-modifying therapy. Of note, patients with excellent visual recovery but more severe OCT thinning also had poorer recovery on future relapses. On average, those with subsequent incomplete relapse remission had 30.4 mm thinning of RNFL and 16.3 mm thinning of GCIPL from baseline compared with 22.1 mm and 9.5 mm, respectively, for those with complete remission. This study provides further support for early OCT in patients with MS as a baseline, both for any future optic neuritis and for prognosis for recovery of non-ON events, because many patients with MS will have early episodes of Moster et al: J Neuro-Ophthalmol 2022; 42: e562-e570 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary ON. Based on this study, the OCT may inform prognosis and help decide on the strength of DMT prescribed. —Mark L. Moster, MD The study demonstrates that those patients with MS with greater RNFL and GCL loss after ON have a higher chance of incomplete remission on future flare-ups. The suggestion is that certain types of MS are more prone to axonal loss with exacerbations and therefore more irreversible neurological disability. However, the correlation may simply reflect the efficacy of current DMA as opposed to the severity of the underlying disease. In either case, based on these results, I would recommend referring MS specialists to lowering the threshold for acute treatment of relapses in patients in whom I find greater RNFL or GCL loss after recent ON. —Marc Dinkin, MD The correlation with RNFL and GCL loss after an episode of ON and improvement after subsequent non-ON MS attacks suggest that 1) certain individuals either have a more (or less) “resilient” nervous system or 2) reflect the effectiveness of disease-modifying therapies. It would be interesting to know whether any of the therapies had better outcomes in this regard, but given the number and varied mechanism of the available therapies, a much larger and stratified study is needed to sort this out. —Deborah I. Friedman, MD, MPH Tsai RK, Lin KL, Huang CT, Wen YT. Transcriptomic analysis reveals that granulocyte colony-stimulating factor trigger a novel signaling pathway (TAF9-P53TRIAP1-CASP3) to protect retinal ganglion cells after ischemic optic neuropathy. Int J Mol Sci. 2022;23:8359. Abstract: Optic nerve head (ONH) infarct can result in progressive retinal ganglion cell (RGC) death. The granulocyte colony-stimulating factor (GCSF) protects the RGC after ON infarct. However, protective mechanisms of the GCSF after ONH infarct are complex and remain unclear. To investigate the complex mechanisms involved, the transcriptome profiles of the GCSF-treated retinas were examined using the microarray technology. The retinal mRNA samples on Days 3 and 7 after rat anterior ischemic optic neuropathy (rAION) were analyzed by microarray and bioinformatics analyses. GCSF treatment influenced 3,101 genes and 3,332 genes on Days 3 and 7 after rAION, respectively. ONH infarct led to changes in 702 and 179 genes on Days 3 and 7 after rAION, respectively. After cluster analysis, the levels of TATA box-binding protein (TBP)-associated factor were significantly reduced after ONH infarct, but these significantly increased after GCSF treatment. The network analysis revealed that TBP-associated factor 9 (TAF9) can bind to P53 to induce TP53-regulated inhibitor of apoptosis 1 (TRIAP1) expression. To evaluate the function of TAF9 in RGC apoptosis, GCSF plus TAF9 siRNA-treated rats were evaluated using retrograde labeling with Fluoro-Gold assay, TUNEL assay, and Western blotting in an rAION model. Moster et al: J Neuro-Ophthalmol 2022; 42: e562-e570 The RGC densities in the GCSF plus TAF9 siRNA-treated rAION group were 1.95-fold (central retina) and 1.75-fold (midperipheral retina) lower than those in the GCSF-treated rAION group (P , 0.05). The number of apoptotic RGC in the GCSF plus TAF9 siRNA-treated group was 3-fold higher than that in the GCSF-treated group (P , 0.05). Treatment with TAF9 siRNA significantly reduced GCSF-induced TP53 and TRIAP1 expression by 2.4-fold and 4.7-fold, respectively, in the rAION model. Overexpression of TAF9 significantly reduced apoptotic RGC and CASP3 levels and induced TP53 and TRIAP1 expression in the rAION model. Therefore, we have demonstrated that GCSF modulated a new pathway, TAF9-P53-TRIAP1-CASP3, to control RGC death and survival after ON infarct. COMMENTS Nonarteritic anterior ischemic optic neuropathy (NAION) is a vexing problem for neuro-ophthalmologists because there is no effective prevention or treatment for it. Numerous unsuccessful therapeutic approaches include antiplatelet treatment, anticoagulation, calcium channel blockers, levodopa, memantine, anti-inflammatory agents, corticosteroids, growth factors, neuroprotective agents, optic nerve sheath fenestration, and hyperbaric oxygen (1). A greater understanding of the mechanisms leading to retinal ganglion cell death after an attack of NAION may open avenues for new treatments. Granulocyte colony-stimulating factor (GCSF) is a member of the hematopoietic growth factor family that is expressed in various neural and glial cells, activating pathways involved in cell growth and differentiation. It is used in clinical practice to treat neutropenia. The authors previously showed that GCSF exhibited the ability to protect and rescue retinal ganglion cells (RGCs) from apoptosis in a rat model. The researchers used a microarray technique to study retinal changes using a rat model of AION, specifically looking at transcriptome changes after optic nerve infarction and GCSF treatment. They targeted the most upregulated transcriptome factor, TATA box-binding protein (TBP)associated factor-9 (TAF9), which is involved in a pathway that increases angiogenesis, DNA repair, and cell survival. A series of experiments showed that TAF expression in general was suppressed by optic nerve ischemic injury and induced by GCSF treatment, so TAF9 was selected as the candidate gene to test. TAF9 knockdown impaired the protective effect and antiapoptotic action of GCSF on RCG density in the midperipheral retina. It also reduced GCSF-induced expression of an apoptosis gene inhibitor (TRIAP1). Overexpression of TAF9 in the rat AION model resulted in a 3-fold decrease in RGC death compared with controls. In summary, TAF9 knockdown reduced the effects of GCSF in the rat model, and TAF9 overexpression inhibited apoptosis. Thus, the researchers discovered a novel GCSF-regulated pathway involved in RBC death and survival. TAF9 and TRIAP1 may be potential targets of gene therapy for NAION in the future. I hope to see some preclinical testing in the near future! —Deborah I. Friedman, MD, MPH e569 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary This elegant study provides strong evidence that the TAF9 pathway is an important component of GCSF-induced neuroprotection of RGC. It takes its place alongside multiple other studies that demonstrate neuroprotective effects involving the inhibition of apoptosis by various molecules, including n-butylidenephthalide (1) and bardoxolone methyl (2) in rat models of NAION. The results provide hope for targeted antiapoptosis therapy for patients with NAION through upregulation of TAF9 at a time when vision-saving treatments are still desperately needed. —Marc Dinkin, MD 1. Chou YY, Chien JY, Ciou JW, Huang SP. The protective effects of n-butylidenephthalide on retinal ganglion cells during ischemic injury. Int J Mol Sci. 2022;23:2095. e570 2. Chien JY, Chou YY, Ciou JW, Liu FY, Huang SP. The effects of two Nrf2 activators, bardoxolone methyl and omaveloxolone, on retinal ganglion cell survival during ischemic optic neuropathy. Antioxidants (Basel). 2021;10:1466. This paper has a whole lot of words “I ain’t learnt in school.” We have heard about so many neuroprotective mechanisms with not one yet approved in humans. I remain only somewhat cautiously optimistic for true neuroprotection in the near future. —Mark L. Moster, MD Bless your heart, Mark, I didn’t know you were from the South. I translated the paper for you! Deb Moster et al: J Neuro-Ophthalmol 2022; 42: e562-e570 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.