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.

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. Nachev P, Rose GE, Verity DH, Manohar SG, MacKenzie K, Adams G, Theodorou M, Pankhurst QA, Kennard C. Magnetic oculomotor prosthetics for acquired nystagmus. Ophthalmology. 2017;124:1556-1564. 2. Vestergaard N, Rosenberg T, Torp-Pedersen C, Vorum H, Andersen CU, Aasbjerg K. Increased mortality and comorbidity associated with Leber's hereditary optic neuropathy: a nationwide cohort study. Invest Ophthalmol Vis Sci. 2017;58:4586-4592. 3. Roberts DR, Albrecht MH, Collins HR, Asemani D, Chatterjee AR, Spampinato MV, Zhu X, Chimowitz MI, Antonucci MU. Effects of space flight on astronaut brain structure as indicated on MRI. N Engl J Med. 2017;377:1746-1753. 4. Klawiter EC, Bove R, Elsone L, Alvarez E, Borisow N, Cortez M, Mateen F, Mealy MA, Sorum J, Mutch K, Tobyne SM, Ruprecht K, Buckle G, Levy M, Wingerchuk D, Paul F, Cross AH, Jacobs A, Chitnis T, Weinshenker B. High risk of postpartum relapses in neuromyelitis optica spectrum disorder. Neurology. 2017;89:2238-2244. 5. Ahle G, Touitou V, Cassoux N, Bouyon M, Humbrecht C, Oesterlé H, Baraniskin A, Soussain C, Nguyen-Them L, Gaultier C, Hoang-Xuan K, Houillier C. Optic nerve infiltration in primary central nervous system lymphoma. JAMA Neurol. 2017;74:1368-1373. 6. Gelfand JM, Bradshaw MJ, Stern BJ, Clifford DB, Wang Y, Cho TA, Koth LL, Hauser SL, Dierkhising J, Vu N, Sriram S, Moses H, Bagnato F, Kaufmann JA, Ammah DJ, Yohannes TH, Hamblin MJ, Venna N, Green AJ, Pawate S. Infliximab for the treatment of CNS sarcoidosis: a multi-institutional series. Neurology. 2017;89:2092-2100. Nachev P, Rose GE, Verity DH, Manohar SG, MacKenzie K, Adams G, Theodorou M, Pankhurst QA, Kennard C. Magnetic oculomotor prosthetics for acquired nystagmus. Ophthalmology. 2017;124:1556-1564 Purpose: Acquired nystagmus, a highly symptomatic consequence of damage to the substrates of oculomotor control, often is resistant to pharmacotherapy. Although heterogeneous in its neural cause, its expression is unified at the effector-the eye muscles themselves-where physical damping of the oscillation offers an alternative approach. Because direct surgical fixation would immobilize the globe, action at a distance is required to damp the oscillation at the point of fixation, allowing unhindered gaze shifts at other times. Implementing this idea magnetically, herein, we describe the successful implantation of a novel magnetic oculomotor prosthesis in a patient. Design: Case report of a pilot, experimental intervention. Participant: A 49-year-old man with longstanding, medication-resistant, upbeat nystagmus resulting from a paraneoplastic syndrome caused by Stage 2A, Grade I, nodular sclerosing Hodgkin lymphoma. Methods: We designed a 2-part, titanium-encased, rareearth magnet oculomotor prosthesis, powered to damp nystagmus without interfering with the larger forces involved in saccades. Its damping effects were confirmed when applied externally. We proceeded to implant the device in the patient, comparing visual functions and high-resolution oculography before and after implantation and monitoring the patient for more than 4 years after surgery. Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 115-121 Main Outcome Measures: We recorded Snellen visual acuity before and after intervention, as well as the amplitude, drift velocity, frequency, and intensity of the nystagmus in each eye. Results: The patient reported a clinically significant improvement of 1 line of Snellen acuity (from 6/9 bilaterally to 6/6 on the left and 6/5-2 on the right), reflecting an objectively measured reduction in the amplitude, drift velocity, frequency, and intensity of the nystagmus. These improvements were maintained throughout a follow-up of 4 years and enabled him to return to paid employment. Conclusions: This work opens a new field of implantable therapeutic devices-oculomotor prosthetics-designed to modify eye movements dynamically by physical means in cases where a purely neural approach is ineffective. Applied to acquired nystagmus refractory to all other interventions, it is shown successfully to damp pathologic eye oscillations while allowing for normal saccadic shifts of gaze. COMMENTS It is no secret that symptomatic nystagmus is notoriously difficult to treat. In this case report, what the authors basically did was create an implantable therapeutic device that functions by magnetically dampening the slow drift of the nystagmus without affecting fast (saccadic) eye movements. The fact that the device works at the level of the extraocular muscles lends itself to be used for any type of nystagmus. There are 2 parts to the device: the ocular magnet 115 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary composed of samarium and cobalt and the orbital magnet composed of neodymium, iron, and boron. Both magnets, which are biologically reactive, are covered by titanium, which is a biologically inert metal. The surgical procedure itself is relatively straightforward with one magnet sutured to an extraocular muscle (underneath Tenon's sheath) and the other magnet secured to the boney orbit using cyanoacrylate glue. For vertical nystagmus, the paired magnets are situated along the orbital floor and for horizontal nystagmus along the lateral orbital wall. A significant amount of preoperative preparation was needed that included oculometric measurements and external implant testing. The patient described in this report had oscillopsia due to paraneoplastic upbeat nystagmus. After the implantation of the device, the patient reported improvement of the oscillopsia (particularly in downgaze), but it did not resolve. However, the preoperative diplopia he was experiencing worsened postoperatively requiring strabismus surgery. As mentioned by the authors, there are significant limitations in terms of future direction based on this initial case report. This is a passive device meaning it does not have the ability to change based on the patient's eye and head movements. Also being a magnet, if implanted, it does not allow a patient to undergo magnetic resonance imaging, which can be an important part of the management of a patient who has a progressive neurological disease process. Finally, the postoperative effects (i.e., ocular motility disturbance and orbital inflammation) and long-term effects of the device are unknown and obviously needs to be studied further. Although I do not know whether this magnetic oculomotor prosthetic will be the cure for nystagmus, I was impressed by the authors' innovative thinking and ingenuity to develop and execute the implantation of a unique magnetic device into a patient who was profoundly debilitated by his medically resistant oscillopsia. -M. Tariq Bhatti, MD As you noted, Tariq, our treatment for symptomatic oscillopsia is suboptimal. This technique may be helpful for some with this problem but also could induce diplopia. The patient in this report had diplopia before the implant and required treatment after the prosthetic was implanted with Fresnel prisms, occlusion, 2 botulinum toxin injections, and 3 strabismus surgeries. This allowed improvement in reading and watching television. The abstract claiming the treatment enabled the patient to return to paid employment and is more optimistic than the details cited in the article. The patient was a commercial driver for "heavy goods" and was able to return to part-time work, but not as a driver. For now, I would consider this type of treatment in the category of intraorbital botulinum injections for nystagmus, something to occasionally consider for unique patients. -Mark L. Moster, MD 116 Vestergaard N, Rosenberg T, Torp-Pedersen C, Vorum H, Andersen CU, Aasbjerg K. Increased mortality and comorbidity associated with Leber hereditary optic neuropathy: a nationwide cohort study. Invest Ophthalmol Vis Sci. 2017;58:4586-4592 Purpose: Leber hereditary optic neuropathy (LHON) is a mitochondrial genetic disease in which optic neuropathy is considered a key feature. Several other manifestations of LHON have been reported; however, only little is known of their incidence and the life expectancy in patients with LHON. Methods: This study, based on Danish nationwide health registries, included 141 patients diagnosed with LHON and 297 unaffected family members in the maternal line. The incidence of comorbidities and mortality for patients with LHON and unaffected family members was compared with that in the general population. Results: Having LHON was associated with an almost 2-fold risk of mortality with a rate ratio (RR) of 1.95 (95% confidence interval [CI]: 1.47-2.59; P , 0.001). The incidence of several diseases was increased for patients with LHON, but not for family members. The incidence of stroke was 5.73 per 1,000 patient years for patients with LHON compared with 2.33 for the general population, and the RR was 2.38 (95% CI: 1.58-3.58; P , 0.001). The incidence of demyelinating disorders was 2.24 compared with 0.21 for the general population; RR was 12.89 (95% CI: 6.70-24.77; P , 0.001). A 4-fold risk of dementia was seen for patients with LHON (RR: 4.26, 95% CI: 1.91-9.48; P , 0.001), incidence 1.45 for LHON, and 0.37 for the general population. Moreover, patients with LHON had an increased risk of epilepsy, atherosclerosis, nerve symptoms, neuropathy, and alcohol-related disorders. Conclusions: The manifestation of LHON was associated with increased mortality and increased incidence of several disorders including stroke, demyelinating disorder, dementia, and epilepsy. COMMENTS This population-based study from the Danish nationwide health registries provides some sobering results regarding the mortality and comorbidity rates of patients with LHON. The investigators tapped into the Danish Registry of Families and Hereditary Eye Disorders that was founded in 1985 and relies on all Danish hospital admissions. Three cohorts were analyzed: 1) patients with LHON (n = 141, $30 years of age); 2) unaffected family members of patients with LHON (n = 297); and 3) general Danish population (n = 3,753,935). Several diseases were found to be more prevalent in the LHON group compared with the general population: 1. Heart disease (RR = 1.44, P = 0.002) 2. Atherosclerosis (RR = 2.2, P = 0.03) 3. Stroke (RR = 2.38, P , 0.001) 4. Dementia (RR = 4.26, P , 0.001) 5. Epilepsy (RR = 2.99, P = 0.001) Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 115-121 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary 6. Demyelinating disorders (RR = 12.89, P , 0.001) 7. Neuropathy (RR = 1.75, P = 0.04) 8. Alcohol-related disorders (RR = 7.53, P , 0.001) Surprisingly, there was nearly a 2-fold increased risk of death in patients with LHON (RR = 1.95, P , 0.001). The authors did not provide the exact causes of death but suggested that the increased prevalence of comorbidities could have potentially contributed to this increased mortality risk. I also was surprised to read that there was no increased risk of cardiac arrhythmia (RR = 0.67, P = 0.28), which is contrary to what I was taught that patients with LHON are at increased risk of pre-excitation cardiac conduction defects. The authors comment on several limitations of the study, including inability to control for some potential confounding factors (e.g., body mass and smoking habits), lack of outpatient (nonhospital) medical records, potential error in the registered diagnoses, and absence of patients with LHON ,30 years of age. Because this is a Danish-based study, the results should be viewed with caution in other LHON cohorts such as those in the United States, United Kingdom, and other European countries because of the potential for geographic phenotypic and genotypic heterogeneity. -M. Tariq Bhatti, MD This study had a somewhat unexpected result. In patients with LHON, there was an increase in many disorders. This was not true in unaffected carriers who were the patients' relatives. I would point out that the relatives were in the ascending maternal line, so although we do not know the details of genetic testing (e.g., degree of heteroplasmy), they presumably had similar genetic risks. Although there was no increased risk of neurologic disease in relatives, the RR for demyelinating disease was 2.45 compared with the normal Danish population that almost reached statistical significance. That said, it was still much lower than the RR in the patients with LHON (12.89). -Mark L. Moster, MD Roberts DR, Albrecht MH, Collins HR, Asemani D, Chatterjee AR, Spampinato MV, Zhu X, Chimowitz MI, Antonucci MU. Effects of space flight on astronaut brain structure as indicated on MRI. N Engl J Med. 2017;377:1746-1753 Background: There is limited information regarding the effects of space flight on the anatomical configuration of the brain and on cerebrospinal fluid (CSF) spaces. Methods: We used magnetic resonance imaging (MRI) to compare images of 18 astronauts' brains before and after missions of long duration, involving stays on the International Space Station, and of 16 astronauts' brains before and after missions of short duration, involving participation in the Space Shuttle Program. Images were interpreted by readers who were unaware of the flight duration. We also generated paired preMoster and Bhatti: J Neuro-Ophthalmol 2018; 38: 115-121 flight and postflight MRI cine clips derived from high-resolution, 3-dimensional imaging of 12 astronauts after long-duration flights and from 6 astronauts after short-duration flights to assess the extent of narrowing of CSF spaces and the displacement of brain structures. We also compared preflight ventricular volumes with postflight ventricular volumes by means of an automated analysis of T1-weighted MRIs. The main prespecified analyses focused on the change in the volume of the central sulcus, the change in the volume of CSF spaces at the vertex, and vertical displacement of the brain. Results: Narrowing of the central sulcus occurred in 17 of 18 astronauts after long-duration flights (mean flight time, 164.8 days) and in 3 of 16 astronauts after short-duration flights (mean flight time, 13.6 days) (P , 0.001). Cine clips from a subgroup of astronauts showed an upward shift of the brain after all long-duration flights (12 astronauts) but not after short-duration flights (6 astronauts) and narrowing of CSF spaces at the vertex after all long-duration flights (12 astronauts) and in 1 of 6 astronauts after short-duration flights. Three astronauts in the long-duration group had optic disc edema, and all 3 had narrowing of the central sulcus. A cine clip was available for 1 of these 3 astronauts, and the cine clip showed upward shift of the brain. Conclusions: Narrowing of the central sulcus, upward shift of the brain, and narrowing of CSF spaces at the vertex occurred frequently and predominantly in astronauts after long-duration flights. Further investigation, including repeated postflight imaging conducted after some time on Earth, is required to determine the duration and clinical significance of these changes (Funded by the National Aeronautics and Space Administration). COMMENTS Before I comment on this study, I must acknowledge the contributions made by Drs. Mader et al (including our colleague Andy Lee) on the effects of long-duration space flight on the eye and optic disc (1). In fact, at the most recent American Academy of Ophthalmology meeting in New Orleans, (maybe you missed it Mark because Bourbon street was calling for you), there was a wonderful symposium, moderated by Drs. Sophia Chung and John Chen, titled "From Ground Zero to the Moon: How Intracranial and Intraocular Pressure Disparities Relate to Vision." All the speakers-Helen Danesh-Meyer, Courtney Francis, Patrick Sibony, Jonathan Fleischman, and Andy Lee-did a fantastic job discussing the issues of intraocular pressure, intracranial pressure, and the pressure gradient at the lamina cribrosa. Whether you want to call it visual impairment and intracranial pressure or space flight-associated neuro-ocular syndrome (SANS) (2), it is a very fascinating subject that has implications not just regarding space travel but disease states here on earth such as glaucoma and idiopathic intracranial hypertension (IIH). In this study, 18 astronauts involved in long-duration space flight (International Space Station) and 16 astronauts involved in short-duration space flight (space shuttle program) were examined before and after their missions with 3T MRI. In addition, cine clips from 12 of the long-duration astronauts and from 6 of the short-duration astronauts were evaluated. 117 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary Only 3 of the 16 astronauts involved in short-duration space flights were found to have MRI changes as compared to 17 of the 18 astronauts involved in the long-duration space flights. The brain MRI changes included: 1. narrowing of the central sulcus in 20/34 (59%) astronauts 2. narrowing of the supravermian cistern in 7/34 (21%) astronauts 3. narrowing of the calcarine sulcus in 5/34 (15%) astronauts 4. enlargement of the ventricular system (mean increase in total volume of 11 ± 5.9% in the long-duration space flight group compared with 0.04 ± 1.87% in the shortduration space flight group, P , 0.001) Based on the cine clips from the 18 astronauts, there were 1. upward shift of the brain and brainstem in 12 (67%) 2. narrowing of the CSF vertex spaces in 13 (72%) 3. rotation of the cerebral aqueduct in 12 (67%) 4. pituitary stalk stretching in 11 (61%) 5. optic chiasm uplifting in 6 (33%) There was variable interobserver agreement between the 2 interpreting neuroradiologist that ranged from 59% to 91% depending on the MRI findings. Only 3 astronauts were found to have optic disc edema. All of them were involved in long-duration space flights. After return to earth, intracranial pressures measured 28 cm H2O on Day 12, 18 cm H2O on Day 8, and 21.5 cm H2O on Day 7. All 3 of these astronauts had narrowing of the central sulcus and in the one who had cine clips available, there was an upward shift of the brain; narrowing of the CSF spaces at the vertex; stretching of the pituitary stalk; and rotation of the cerebral aqueduct. The authors hypothesized that the upward shift of the brain led to crowding of brain tissue at the vertex resulting in compression of the venous sinuses culminating in elevated intracranial pressure. The authors list several limitations to their study including different MRI units used to examine the astronauts, lack of long-term follow-up to determine whether the MRI findings returned to baseline, and differences in the time interval from landing to performing the MRI between the long-duration and short-duration astronauts. I was recently in communication with Andy Lee to ask about any sex differences in terms of the ocular findings in astronauts. What he told me was that there were too few women to make any meaningful conclusions but that women were less affected. This article did not mention the sex of the astronauts. -M. Tariq Bhatti, MD I wish your comment about Bourbon Street was true. I was actually giving a lecture on optic neuropathies at the Wills Eye booth during the American Academy of Ophthalmology symposium. This report nicely demonstrates the MRI changes in long-duration space flight. What we do not 118 know is whether there were any symptoms related to these MRI changes. Indeed, astronauts diagnosed with SANS do not have the typical symptoms of patients with IIH although they have papilledema. Further evaluations of these astronauts should clarify which changes are physiologic, which are pathologic, and provide insights into pressure-related conditions including IIH and glaucoma. -Mark L. Moster, MD 1. Mader TH, Gibson CR, Pass AF, Kramer LA, Lee AG, Fogarty J, Tarver WJ, Dervay JP, Hamilton DR, Sargsyan A, Phillips JL, Tran D, Lipsky W, Choi J, Stern C, Kuyumjian R, Polk JD. Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight. Ophthalmology. 2011;118:2058-2069. 2. Lee AG, Mader TH, Gibson CR, Tarver W. Space flight-associated neuro-ocular syndrome. JAMA Ophthalmol. 2017;135:992-994. Klawiter EC, Bove R, Elsone L, Alvarez E, Borisow N, Cortez M, Mateen F, Mealy MA, Sorum J, Mutch K, Tobyne SM, Ruprecht K, Buckle G, Levy M, Wingerchuk D, Paul F, Cross AH, Jacobs A, Chitnis T, Weinshenker B. High risk of postpartum relapses in neuromyelitis optica spectrum disorder. Neurology. 2017;89:2238-2244 Objective: To study the effect of pregnancy on the frequency of neuromyelitis optica spectrum disorder (NMOSD) relapse and evaluate rates of pregnancy-related complications in an international multicenter setting. Methods: We administered a standardized survey to 217 women with NMOSD from 7 medical centers and reviewed their medical records. We compared the annualized relapse rate (ARR) during a baseline period 2 years before a participant's first pregnancy to that during pregnancy and to the 9 months postpartum. We also assessed pregnancy-related complications. Results: There were 46 informative pregnancies after symptom onset in 31 women with NMOSD. Compared with baseline (0.17), ARR was increased both during pregnancy (0.44; P = 0.035) and during the postpartum period (0.69; P = 0.009). The highest ARR occurred during the first 3 months postpartum (ARR 1.33). A total of 8 of 76 (10.5%) with onset of NMOSD before age 40 experienced their initial symptom during the 3 months postpartum, 2.9 times higher than expected. Conclusions: The postpartum period is a particularly highrisk time for initial presentation of NMOSD. In contrast to published observations in multiple sclerosis, in neuromyelitis optica, relapse rate during pregnancy was also increased, although to a lesser extent than after delivery. COMMENTS The authors of this study examined the effect of pregnancy on neuromyelitis optic spectrum disorder (NMOSD) onset, relapse rate, and pregnancy outcomes in a large, multicenter international cohort of women with NMOSD. In multiple Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 115-121 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary sclerosis (MS), relapses decrease in frequency during pregnancy and increase in the postpartum period. Previous studies in NMOSD have shown an increased risk postpartum without a protective effect during pregnancy. In this retrospective study, to determine risk of relapse related to pregnancy, the 2 years before pregnancy served as a baseline period for each patient. Of the 172 participants who had been pregnant, 46 pregnancies occurred after NMOSD symptom onset. Participants reported 9 relapses during pregnancy and 11 in the 9 month postpartum period. In 3 of these patients, there were relapses both during pregnancy and within the 9 months after delivery. Compared with the 2 years before pregnancy, the annualized relapse rate (ARR) in the first trimester increased from 0.17 to 0.73 (P = 0.037). In other trimesters of pregnancy, the ARR was unchanged compared with baseline. The relapse rate increased during the 0- to 3-month postpartum period (ARR 1.33) but not during the 3- to 6month or 6- to 9-month postpartum periods. This study also addressed whether the initial episode of NMOSD had a relationship to pregnancy. Of 76 patients who had a history of pregnancy and onset of first episode in childbearing years (20-40 years old), 6 patients (7.9%) experienced their initial NMOSD event during pregnancy, 8 (10.5%) presented within 3 months after delivery, and an additional 5 (6.6%) presented within the next 6 months. The 5 authors claim that the observed risk of onset during the 3 months postpartum (8/76 = 10.5%) exceeds the expected risk of 3.65%, which is based on number of months including the 3 postpartum months divided by the number of months of childbearing years. One benefit of this report was studying a large population from 7 medical centers. However, it is limited by being a retrospective survey with inherent recall bias. Also the baseline ARR of 0.17 is lower than most previous reports. Large prospective studies are required to validate the current findings. This article provides more information about treatment for patients with NMOSD considering pregnancy. Treating NMOSD is more complicated than treating MS because pregnancy does not provide protection against relapses and there are no clearly safe treatments for NMOSD during pregnancy. -Mark L. Moster, MD Very interesting article, Mark, and something we all need to consider for our female patients with NMOSD who may wish someday to have a family. I want to point out that the recovery from the relapses seemed better if they occurred during pregnancy as compared with the postpartum period (symptoms resolved within 6 months in all but 2 of the 10 cases [80%] during pregnancy compared with incomplete recovery at 6 months in 8 of 15 cases [53.3%] postpartum). -M. Tariq Bhatti, MD Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 115-121 Ahle G, Touitou V, Cassoux N, Bouyon M, Humbrecht C, Oesterlé H, Baraniskin A, Soussain C, NguyenThem L, Gaultier C, Hoang-Xuan K, Houillier C. Optic nerve infiltration in primary central nervous system lymphoma. JAMA Neurol. 2017;74:1368-1373 Importance: Visual impairment in primary central nervous system lymphoma (PCNSL) is caused mostly by intraocular lymphomatous involvement (vitritis and retinal infiltration), whereas optic nerve infiltration (ONI) is a rare condition. Objective: To describe the clinical presentation of ONI, its imaging characteristics, and outcome. Design, Setting, and Participants: A total of 752 patients diagnosed with PCNSL were retrospectively identified from the databases of 3 French hospitals from January 1, 1998, through December 31, 2014. Of these, 7 patients had documented ONI. Exclusion criteria were intraocular involvement, orbital lymphoma, or other systemic lymphoma. Clinical presentation, neuroimaging, biological features, treatment, and outcomes were assessed. Main Outcomes and Measures: Treatment response was evaluated clinically and radiologically on follow-up MRI according to the International PCNSL Collaborative Group response criteria. Results: The 7 patients included 5 women and 2 men. Median age at diagnosis was 65 years (range, 49-78 years). Two patients had initial ONI at diagnosis and 5 had ONI at relapse. Clinical presentation was marked by rapidly progressive and severe visual impairment for all patients. The MRI findings showed optic nerve enlargement in 3 patients and contrast enhancement of the optic nerve in all patients. Additional CNS lesions were seen in 4 patients. Examination of cerebrospinal fluid samples detected lymphomatous meningitis in 2 patients. Clinical outcome was poor and marked by partial recovery for 2 patients and persistent severe low visual acuity or blindness for 5 patients. Median progression-free survival after optic nerve infiltration was 11 months (95% CI, 9-13 months), and median overall survival was 18 months (95% CI, 9-27 months). Conclusions and Relevance: Optic nerve infiltration is an atypical and challenging presentation of PCNSL. Its visual and systemic prognosis is particularly poor compared with vitreoretinal lymphomas even in response to chemotherapy. Although intraocular involvement is frequent in PCNSL and clinically marked by slowly progressive visual deterioration, lymphomatous ONI is rare and characterized by rapidly progressive severe visual impairment. COMMENTS This article describes the findings in 7 patients with primary central nervous system lymphoma (PCNSL) with optic nerve involvement (ONI). In contrast to intraocular involvement in PCNSL, which occurs in 20% of patients, direct ONI is much rarer. In a retrospective review of 752 patients with PCNSL, excluding any with previous ocular or systemic involvement, 7 patients were identified with 119 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary ONI. All presented with rapidly progressive severe visual loss and none had intraocular involvement. Two patients had bilateral disease, 2 had pain, and all 7 declined to a vision of 20/200 within 14 days. Two patients had bitemporal hemianopia, and for 2 patients, the ONI was the initial presentation of PCNSL. Five were women and median age was 65 years. Two of 6 who had lumbar puncture had lymphomatous meningitis. Initial misdiagnosis included one each of giant cell arteritis, nonorganic visual loss, optic neuritis, and ocular lymphoma. The presence of miRNAs in the cerebrospinal fluid of 3 patients was useful for the diagnosis. MRI was abnormal in all and showed chiasmal involvement in 3, prechiasmal/cisternal in 3, intracanalicular in 4, and intraorbital in 5. Three patients had sheath involvement and 4 had entire optic nerve involvement. Various chemotherapy regimens were used, but prognosis at 13-month follow-up was poor with only 2 patients having some improvement. All patients died, with median survival after ONI of 18 months (range: 9-27 months). Radiological response was complete in 4, partial in 1, and unchanged in 2. The 2 patients with partial recovery were rapidly treated and had complete resolution on MRI. The authors recommend intravenous high-dose steroids followed by specific treatment for lymphoma. Study limitations include the small number of patients in the examined cohort and its retrospective nature. This study helps clarify the presentation of ONI that is much rarer than intraocular involvement with PCNSL and presents more acutely, severely, and with poorer prognosis. Methods: Investigators at 6 US centers retrospectively identified patients with CNS sarcoidosis treated with infliximab, including only patients with definite or probable neurosarcoidosis after rigorous exclusion of other causes. Results: Of 66 patients with CNS sarcoidosis (27 definite, 39 probable) treated with infliximab for a median of 1.5 years, the mean age was 47.5 years at infliximab initiation (SD 11.7, range 24-71 years); 56.1% were women; 62.1% were white, 37.0% African-American, and 3% Hispanic. Sarcoidosis was isolated to the CNS in 19.7%. Using infliximab doses ranging from 3 to 7 mg/kg every 4-8 weeks, MRI evidence of a favorable treatment response was observed in 82.1% of patients with imaging follow-up (n 5.56), with complete remission of active disease in 51.8% and partial MRI improvement in 30.1%; MRI worsened in 1 patient (1.8%). There was clinical improvement in 77.3% of patients, with complete neurologic recovery in 28.8%, partial improvement in 48.5%, clinical stability in 18.2%, worsening in 3%, and 1 lost to follow-up. In 16 patients in remission when infliximab was discontinued, the disease recurred in 9 (56%), typically in the same neuroanatomic location. Conclusions: Most patients with CNS sarcoidosis treated with infliximab exhibit favorable imaging and clinical treatment responses, including some previously refractory to other immunosuppressive treatments. Classification of Evidence: This study provides Class IV evidence that for patients with CNS sarcoidosis infliximab is associated with favorable imaging and clinical responses. -Mark L. Moster, MD This retrospective multicenter study described the response of 66 patients with neurosarcoidosis to infliximab. Twentyfour percent had optic nerve involvement, but no further details on this subgroup were mentioned. Remission occurred in 28.8% with improvement in another 48.5%. Forty percent were able to come off prednisone while on infliximab, and 86% were able to wean to 10 mg daily or less. However, 56% of patients in remission recurred when infliximab was discontinued. Infliximab is an excellent steroid-sparing agent but is accompanied by increased risk of malignancy and infection as well as infusion and hypersensitivity reactions. I found it interesting and somewhat perplexing that an alternative diagnosis to ONI was considered in 2 of the 5 patients who had established PCNSL. I was taught to try and follow Occam's razor to the best of my ability. For those 2 patients that developed an optic neuropathy during the relapse of their disease, the initial diagnoses were ocular lymphoma and optic neuritis. One of the patients did not have a MRI study that included the optic nerves contributing to the misdiagnosis. -M. Tariq Bhatti, MD COMMENTS -Mark L. Moster, MD Gelfand JM, Bradshaw MJ, Stern BJ, Clifford DB, Wang Y, Cho TA, Koth LL, Hauser SL, Dierkhising J, Vu N, Sriram S, Moses H, Bagnato F, Kaufmann JA, Ammah DJ, Yohannes TH, Hamblin MJ, Venna N, Green AJ, Pawate S. Infliximab for the treatment of CNS sarcoidosis: a multi-institutional series. Neurology. 2017;89:2092-2100 Objective: To describe clinical and imaging responses in neurosarcoidosis to infliximab, a monoclonal antibody against tumor necrosis factor-a. 120 Despite being Class IV evidence, it is important to know that there are medications at our disposal like infliximab that are effective for patients with neurosarcoidosis. I want to point out that nearly 80% of patients also were taking another immunosuppressive agent in addition to the infliximab. Combination therapy was associated with a favorable treatment response (odds ratio 4.8, 95% CI 1.2-19.3, P = 0.03, in a logistic regression model; odds ratio 6.9, 95% CI 1.2-41.3, P = 0.03, in a logistic regression model adjusting for age, sex, and time from disease onset to infliximab initiation). Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 115-121 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary I agree with you that infliximab is an excellent steroid-sparing agent, but as you listed, it carries some significant risks including the initiation of central nervous system demyelination (1). Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 115-121 1. Kemanetzoglou E, Andreadou E. CNS demyelination with TNF-a blockers. Curr Neurol Neurosci Rep. 2017;17:36. -M. Tariq Bhatti, MD 121 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.