Title | Literature Commentary |
Creator | Mark L. Moster, MD; M. Tariq Bhatti, MD |
Abstract | In this issue of Journal of Neuro-Ophthalmology, M. Tariq Bhatti, MD and Mark L. Moster, MD will discuss the following 6 articles. |
OCR Text | Show 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. Davoudi S, Ebrahimiadib N, Yasa C, Sevgi DD, Roohipoor R, Papavasilieou E, Comander J, Sobrin L. Outcomes in autoimmune retinopathy patients treated with rituximab. Am J Ophthalmol. 2017;180:124-132. 2. Metz LM, Li DKB, Traboulsee AL, Duquette P, Eliasziw M, Cerchiaro G, Greenfield J, Riddehough A, Yeung M, Kremenchutzky M, Vorobeychik G, Freedman MS, Bhan V, Blevins G, Marriott JJ, Grand'Maison F, Lee L, Thibault M, Hill MD, Yong VW; Minocycline in MS Study Team. Trial of minocycline in a clinically isolated syndrome of multiple sclerosis. N Engl J Med. 2017;376:2122-2133. 3. Höglinger GU, Respondek G, Stamelou M, Kurz C, Josephs KA, Lang AE, Mollenhauer B, Müller U, Nilsson C, Whitwell JL, Arzberger T, Englund E, Gelpi E, Giese A, Irwin DJ, Meissner WG, Pantelyat A, Rajput A, van Swieten JC, Troakes C, Antonini A, Bhatia KP, Bordelon Y, Compta Y, Corvol JC, Colosimo C, Dickson DW, Dodel R, Ferguson L, Grossman M, Kassubek J, Krismer F, Levin J, Lorenzl S, Morris HR, Nestor P, Oertel WH, Poewe W, Rabinovici G, Rowe JB, Schellenberg GD, Seppi K, van Eimeren T, Wenning GK, Boxer AL, Golbe LI, Litvan I; Movement Disorder Society-Endorsed PSP Study Group. Clinical diagnosis of progressive supranuclear palsy: the movement disorder society criteria. Mov Disord. 2017;32:853-864. 4. Sodhi M, Sheldon CA, Carleton B, Etminan M. Oral fluoroquinolones and risk of secondary pseudotumor cerebri syndrome: nested case-control study. Neurology. 2017;89:792-795. 5. Suzuki S, Ishikawa N, Konoeda F, Seki N, Fukushima S, Takahashi K, Uhara H, Hasegawa Y, Inomata S, Otani Y, Yokota K, Hirose T, Tanaka R, Suzuki N, Matsui M. Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan. Neurology. 2017;89:1127-1134. 6. Hennes EM, Baumann M, Schanda K, Anlar B, Bajer-Kornek B, Blaschek A, Brantner-Inthaler S, Diepold K, Eisenkölbl A, Gotwald T, Kuchukhidze G, Gruber-Sedlmayr U, Häusler M, Höftberger R, Karenfort M, Klein A, Koch J, Kraus V, Lechner C, Leiz S, Leypoldt F, Mader S, Marquard K, Poggenburg I, Pohl D, Pritsch M, Raucherzauner M, Schimmel M, Thiels C, Tibussek D, Vieker S, Zeches C, Berger T, Reindl M, Rostásy K; BIOMARKER Study Group. Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome. Neurology. 2017;89:900-908. Davoudi S, Ebrahimiadib N, Yasa C, Sevgi DD, Roohipoor R, Papavasilieou E, Comander J, Sobrin L. Outcomes in autoimmune retinopathy patients treated with rituximab. Am J Ophthalmol. 2017;180:124-132 Purpose: To evaluate clinical and ancillary testing, including adaptive optics, outcomes in autoimmune retinopathy (AIR) patients treated with rituximab. Design: Retrospective, interventional case series. Methods: Sixteen AIR patients treated with rituximab. Observation Procedures: All patients were treated with a loading and maintenance dose schedule of intravenous rituximab. Visual acuity (VA), electroretinography (ERG), and spectral-domain optical coherence tomography (SDOCT) and visual field (VF) results were recorded. A subset of patients was also imaged using adaptive optics scanning laser ophthalmoscopy (AO-SLO). Main Outcome Measures: Rates of VA change before vs after rituximab initiation were compared with mixed-model linear regression. Results: The rate of visual decline was significantly less after rituximab initiation compared with the rate of visual decline before rituximab initiation (P = 0.005). SeventyMoster and Bhatti: J Neuro-Ophthalmol 2017; 37: 451-457 seven percent of eyes had stable or improved VA 6 months after rituximab initiation. Amplitudes and implicit times on ERG, mean deviation on visual field, central subfield mean thickness, and total macular volume did not decrease to a significant degree over the rituximab treatment period. Six eyes had serial AO-SLO imaging. Cone densities did not change significantly over the treatment period. Conclusion: VA was stable or improved in a majority of AIR patients while they were being treated with rituximab. Optical coherence tomography (OCT) and ERG parameters, as well as AO-SLO cone densities, were stable during treatment. Studies with additional patients and longer follow-up periods are needed to further explore the utility of rituximab in the management of AIR. Nonparaneoplastic and paraneoplastic autoimmune retinopathies and optic neuropathies are not only very challenging to diagnose but also difficult to treat. This prospective, interventional case series provides some promising results for the use of rituximab in patients with autoimmune retinopathy (AIR). Let me cut to the 451 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary chase and provide the all important visual outcome data of the 28 eyes in 16 patients treated. Four eyes (14%) improved, 19 eyes (63%) stabilized, and 7 eyes (23%) worsened. The four eyes that improved received either rituximab alone or rituximab with mycophenolate mofetil with an interval time from diagnosis to treatment of 4 and 7 months. Now, these results may not seem very impressive in terms of visual improvement but I think you would agree with me Mark that often stabilizing a patient's visual loss is a victory. The results of this study need to be viewed within the context of its significant limitations. Of course, being a retrospective study casts a selection bias on the results. But probably more importantly is the heterogenous cohort of patients in terms of underlying disease and treatment course before and during rituximab therapy. Let's begin with the underlying etiology of the AIR: 1. 6 with carcinoma-associated retinopathy (CAR) 2. 1 with melanoma-associated retinopathy (MAR) 3. 9 with nonparaneoplastic AIR In terms of treatment before starting rituximab, only 1 patient was treatment naïve. Of the other 15 patients: 1. 4 treated with oral prednisone alone 2. 2 treated with intravitreal triamcinolone (IVT) 3. 2 treated with oral prednisone and IVT 4. 1 treated with oral prednisone, IVT, and periocular triamcinolone 5. 1 treated with oral prednisone, IVT, and intravenous immunoglobulin (IVIg) 6. 1 treated with oral prednisone, periocular triamciniolone, and methotrexate 7. 1 treated with oral prednisone, IVIg, bortezomeb, and mycophenolate mofetil 8. 1 treated with oral prednisone, methotrexate, cyclophosphamide, and IVT 9. 1 treated with oral prednisone, mycophenolate mofetil, and cyclosporine 10. 1 treated with oral prednisone and mycophenolate mofetil Thirteen patients were concomitantly treated with ritixumab: 1. 1 treated with mycophenolate mofetil 2. 3 treated with cyclophosphamide 3. 1 treated with IVT and cyclophosphamide 4. 1 treated with IVIg, bortezomib, mycophenolate mofetil, and cyclophosphamide 5. 1 treated with periocular triamcinolone and cyclophosphamide 6. 2 treated with IVT 7. 1 treated with IVIg and cyclophosphamide 8. 1 treated with IVIg 9. 1 treated with IVIg and IVT 10. 1 treated with periocular triamcinolone and cyclophosphamide 452 Finally, it is important to note that there were 2 different dosing schedules of rituximab used, the duration of disease/ visual loss before starting rituximab was highly variable (ranging from 4 months to 48 months) and 6 patients had an adverse event. -M. Tariq Bhatti, MD I think that the biggest problem with this study is that both patient and physician really are biased toward improvement when dealing with a progressively blinding condition treated with a very strong intravenous immunosuppressant. What impressed me was the degree of improvement in the 2 patients (visual acuity pretreatment 20/200 in 3 eyes and 20/125 in 1 eye compared with posttreatment visual acuity 20/40 in 1 eye, 20/30 in 1 eye and 20/25 in 2 eyes). As you noted, these patients were treated early in their course. They also had normal optical coherence tomography, fundus examination and autofluorescence and without severe electroretinogram abnormalities. I think future studies should focus on early treatment with rituximab. -Mark L. Moster, MD Metz LM, Li DKB, Traboulsee AL, Duquette P, Eliasziw M, Cerchiaro G, Greenfield J, Riddehough A, Yeung M, Kremenchutzky M, Vorobeychik G, Freedman MS, Bhan V, Blevins G, Marriott JJ, Grand'Maison F, Lee L, Thibault M, Hill MD, Yong VW; Minocycline in MS Study Team. Trial of minocycline in a clinically isolated syndrome of multiple sclerosis. N Engl J Med. 2017;376:2122-2133 Background: On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis. Methods: During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T2weighted MRI, cumulative number of new lesions enhanced on T1-weighted MRI ["enhancing lesions"], and cumulative combined number of unique lesions [new enhancing lesions on T1-weighted MRI plus new and newly enlarged lesions on T2-weighted MRI]). Results: A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to Moster and Bhatti: J Neuro-Ophthalmol 2017; 37: 451-457 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P = 0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P = 0.01); the unadjusted risk difference was not significant at the 24-month secondary outcome time point (P = 0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo. Conclusions: The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887. Since 2000, a number of studies have evaluated interventions to reduce the risk of conversion to multiple sclerosis (MS) in patients with a first event demyelinating event or clinically isolated syndrome (CIS) (1-8). In this report by Metz et al, 142 patients with at least 2 T2-weighted brain lesions on magnetic resonance imaging (MRI) were randomized to receive either minocycline 100 mg twice a day or placebo for a period of 24 months or until the diagnosis of MS was established based on the 2005 McDonald criteria. The rationale for using minocycline was based on its immunosuppressive and immunomodulating properties. The primary outcome of the study was conversion to MS within 6 months and one of the secondary outcome measures was conversion to MS within 24 months. The primary outcome of the study was met with 33.4% of patients in the minocycline group converting to MS compared to 61% in the placebo group (absolute difference of 27.6%, P = 0.0001). After adjusting for the number of baseline enhancing lesions on MRI, there was still a robust difference between the 2 groups favoring minocycline (43% vs 61.5%, absolute difference of 18.5%, P = 0.01). Interestingly, there was no statistically significant difference between the 2 groups at 24 months, although the percentage difference still favored the minocycline group (63% vs 74.2%, absolute difference 11.2%, P = 0.17). As expected, the minocycline group had a greater percentage of adverse events (AE), 86.1% vs 61.4%, with 3 patients in the placebo group and 1 patient in the minocycline group having a serious AE. The authors stated several limitations to their study including a shorter study time and smaller sample size Moster and Bhatti: J Neuro-Ophthalmol 2017; 37: 451-457 than the previous CIS studies. In addition, 22.5% of the cohort data was censored due to multiple reasons. I suspect that given the difficulty in obtaining industry sponsorship (minocycline is a generic medication and this study was sponsored by the Multiple Sclerosis Society of Canada), it is going to be a challenge to get the necessary funding to execute future larger and longer studies on minocycline and CIS. -M. Tariq Bhatti, MD 1. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, Simonian NA, Slasor PJ, Sandrock AW. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med. 2000;343:898-904. 2. Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernández O, Hartung H, Seeldraters P, Sørensen PS, Rovaris M, Martinelli V, Hommes OR. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet. 2001;357:1576-1582. 3. Achiron A, Kishner I, Sarova-Pinhas I, Raz H, Faibel M, Stern Y, Lavie M, Gurevich M, Dolev M, Magalashvili D, Barak Y. Intravenous immunoglobulin treatment following the first demyelinating event suggestive of multiple sclerosis: a randomized, double-blind, placebo-controlled trial. Arch Neurol. 2004;61:1515-1520. 4. Kappos L, Polman CH, Freedman MS, Edan G, Hartung HP, Miller DH, Montalban X, Barkhof F, Bauer L, Jakobs P, Pohl C, Sandbrink R. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006;67:1242- 1249. 5. Comi G, Martinelli V, Rodegher M, Moiola L, Bajenaru O, Carra A, Elovaara I, Fazekas F, Hartung HP, Hillert J, King J, Komoly S, Lubetzki C, Montalban X, Myhr KM, Ravnborg M, Rieckmann P, Wynn D, Young C, Filippi M; PreCISe Study Group. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet. 2009;374:1503-1511. Erratum in: Lancet. 2010;375 (9724):1436. 6. Comi G, De Stefano N, Freedman MS, Barkhof F, Polman CH, Uitdehaag BM, Casset-Semanaz F, Hennessy B, Moraga MS, Rocak S, Stubinski B, Kappos L. Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol. 2012;11:33-41. Erratum in: Lancet Neurol. 2012;11:125. 7. Ristori G, Romano S, Cannoni S, Visconti A, Tinelli E, Mendozzi L, Cecconi P, Lanzillo R, Quarantelli M, Buttinelli C, Gasperini C, Frontoni M, Coarelli G, Caputo D, Bresciamorra V, Vanacore N, Pozzilli C, Salvetti M. Effects of Bacille Calmette-Guerin after the first demyelinating event in the CNS. Neurology. 2014;82:41- 48. 8. Miller AE, Wolinsky JS, Kappos L, Comi G, Freedman MS, Olsson TP, Bauer D, Benamor M, Truffinet P, O'Connor PW; TOPIC Study Group. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol.2014;13:977-986. These results at 6 months are similar to the benefits of most of the immunomodulatory medications currently approved for MS. It would be worthwhile to see if prolonged 453 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary treatment for years would be able to maintain the benefit or add benefit to patients already on other treatments. I do think there is a problem with this study that may not be fully corrected by the authors' adjusted ratio based on the number of enhancing lesions. It's not just that there are more enhancing lesions in the placebo group, it also is that 35.7% of the placebo group met the 2010 McDonald criteria for a diagnosis of MS at baseline compared with 23.6% of the control group. I'm not sure that adjusting for the number of enhancing lesions is enough to correct an error that might really be comparing patients with MS (who will develop more lesions with time) to those without MS (merely CIS). -Mark L. Moster, MD Höglinger GU, Respondek G, Stamelou M, Kurz C, Josephs KA, Lang AE, Mollenhauer B, Müller U, Nilsson C, Whitwell JL, Arzberger T, Englund E, Gelpi E, Giese A, Irwin DJ, Meissner WG, Pantelyat A, Rajput A, van Swieten JC, Troakes C, Antonini A, Bhatia KP, Bordelon Y, Compta Y, Corvol JC, Colosimo C, Dickson DW, Dodel R, Ferguson L, Grossman M, Kassubek J, Krismer F, Levin J, Lorenzl S, Morris HR, Nestor P, Oertel WH, Poewe W, Rabinovici G, Rowe JB, Schellenberg GD, Seppi K, van Eimeren T, Wenning GK, Boxer AL, Golbe LI, Litvan I; Movement Disorder SocietyEndorsed PSP Study Group. Clinical diagnosis of progressive supranuclear palsy: the movement disorder society criteria. Mov Disord. 2017;32:853-864 Background: Progressive Supranuclear Palsy (PSP) is a neuropathologically defined disease entity. Clinical diagnostic criteria, published in 1996 by the National Institute of Neurological Disorders and Stroke/Society for PSP, have excellent specificity, but their sensitivity is limited for variant PSP syndromes with presentations other than Richardson's syndrome. Objective: We aimed to provide an evidence-based and consensus-based revision of the clinical diagnostic criteria for PSP. Methods: We searched the PubMed, Cochrane, Medline, and PSYCInfo databases for articles published in English since 1996, using postmortem diagnosis or highly specific clinical criteria as the diagnostic standard. Second, we generated retrospective standardized clinical data from patients with autopsy-confirmed PSP and control diseases. On this basis, diagnostic criteria were drafted, optimized in 2 modified Delphi evaluations, submitted to structured discussions with consensus procedures during a 2-day meeting, and refined in 3 further Delphi rounds. Results: Defined clinical, imaging, laboratory, and genetic findings serve as mandatory basic features, mandatory exclusion criteria, or context-dependent exclusion criteria. We identified 4 functional domains (ocular motor dysfunc- 454 tion, postural instability, akinesia, and cognitive dysfunction) as clinical predictors of PSP. Within each of these domains, we propose 3 clinical features that contribute different levels of diagnostic certainty. Specific combinations of these features define the diagnostic criteria, stratified by 3 degrees of diagnostic certainty (probable PSP, possible PSP, and suggestive of PSP). Clinical clues and imaging findings represent supportive features. Conclusions: Here, we present new criteria aimed to optimize early, sensitive, and specific clinical diagnosis of PSP on the basis of currently available evidence. As mentioned in this article authored by Hoglinger et al on behalf of the Progressive Supranuclear Palsy (PSP) Study Group of the Movement Disorder Society, the definitive confirmation of PSP requires neuropathological analysis. Therefore, the diagnosis typically is based on clinical criteria. This group of experts set out to improve on the sensitivity of the current National Institute of Neurological Disorders and Stroke and Society for PSP (NINDS-SPSP) criteria for Richardson's syndrome (PSP-RS) and the other variant PSP syndromes (1). This new criteria are based on basic features with mandatory inclusion and exclusion criteria; core clinical features with ocular motor dysfunction (Level 1 vertical supranuclear gaze palsy, Level 2 slow velocity of vertical saccades, Level 3 frequent macro square wave jerks or apraxia of eyelid opening); and supportive features (both clinical clues and imaging findings). Based on these criteria, the diagnostic certainty of PSP was characterized as either probable, possible or suggestive. As neuroophthalmologists, we can play a crucial role in the evaluation of a patient with suspected PSP given that as the article states: "high sensitivity and high specificity, for example, vertical supranuclear palsy, frequently observed in PSP with high diagnostic relevance." -M. Tariq Bhatti, MD 1. Boxer AL, Yu JT, Golbe LI, Litvan I, Lang AE, Höglinger GU. Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches. Lancet Neurol. 2017;16:552-563. Many patients with pathologically confirmed PSP do not have supranuclear palsy at the onset. Hence, many variants of PSP have been described. The value of defining characteristic criteria other than supranuclear palsy is to identify premortem patients who have PSP. This article emphasizes characteristic findings in 3 other domains- postural instability, akinesia, and cognitive dysfunction. For postural instability, repeated unprovoked falls within 3 years of onset is the strongest feature. For akinesia, progressive gait freezing within 3 years is the most important feature. For cognitive dysfunction, a speech/language disorder including a nonfluent/agrammatic variant of primary Moster and Bhatti: J Neuro-Ophthalmol 2017; 37: 451-457 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary progressive aphasia or a progressive speech apraxia are most suggestive. As neuro-ophthalmologists who are referred patients to confirm or rule out PSP, we must realize that not all patients will have typical eye movement abnormalities early in their clinical course. -Mark L. Moster, MD Sodhi M, Sheldon CA, Carleton B, Etminan M. Oral fluoroquinolones and risk of secondary pseudotumor cerebri syndrome: nested case-control study. Neurology. 2017;89:792-795 Objective: To quantify the risk of secondary pseudotumor cerebri syndrome (PTCS) with fluoroquinolones Methods: A case-control study of people 15-60 years of age from the LifeLink Database (QuintilesIMS, Parsippany, NJ) was conducted. Cases had the first ICD-9-CM code for benign intracranial hypertension (BIH) as well as having received a procedure code for an MRI or CT scan and a lumbar puncture within 15 days or 30 days of the BIH code. For each case, 10 controls were selected using density-based sampling. Current users of fluoroquinolones received a prescription within 15 days or 30 days of the date of the diagnosis. For the sensitivity analysis, risk periods for 30 and 60 days were also examined. Adjusted rate ratios (RRs) were computed from a conditional logistic regression model. Results: From a cohort of 6,110,723 people, there were 339 cases of PTCS and 3,390 corresponding controls. In the primary analysis, the adjusted RRs for current users of fluoroquinolones for both the 15-day and 30-day definitions were 5.67 (95% confidence interval [CI], 2.72-11.83) and 4.15 (95% CI, 2.29-7.50), respectively. The risk with tetracycline antibiotics was also increased, with RRs for 15 and 30 days of current use of 2.68 (0.89-8.11) and 3.64 (1.67-7.91), respectively. Conclusion: Our study suggests an increase in the risk of PTCS with current users of fluoroquinolones. Although this adverse event is rare, patients who experience symptoms of raised intracranial pressure including headaches, tinnitus, and double vision while taking fluoroquinolones should seek medical attention. This was a case-control study using information from a database of over 6 million patients. The authors identified 339 cases of pseudotumor cerebri syndrome (PTCS) defined by the ICD9 code, an MRI or CT and a lumbar puncture time linked to the diagnosis. The authors then looked for a time-linked prescription for a flouroquinolone (FQ). FQs included ciprofloxacin, levofloxacin, moxifloxacin, gemifloxacin, norfloxacin, and ofloxacin. This seemingly well done study has a surprising result for me: an increased risk of PTCS from FQs. I always ask patients about tetracycline use but my actual question to them is about any antibiotic and I don't recall positive responses about fluoroquinolones. The authors postulate a possible pathophysiologic mechanism: FQs are GABAA receptor antagonists and glutamate receptor agonists. Glutamate receptor upregulation and increased excitatory neurotransmission Moster and Bhatti: J Neuro-Ophthalmol 2017; 37: 451-457 may cause intracranial hypertension, and antagonizing glutamate receptors can decrease brain tissue water content. One very surprising and not believable part of this study is the calculation of the number of new PTCS cases annually due to FQs. Using the epidemiologic measure population attributable risk (PAR), these investigators calculated that approximately 2,000 (from a total of 6,000 annual cases) new cases of PTCS in the United States may be due to FQ use. Although I can't argue with the statistical method, I know that much fewer than one-third of my patients with PTCS recently have been on FQs. -Mark L. Moster, MD I must say that I am quite surprised by the findings of this study. Admittedly, I did not have FQs on my list of medications associated with an increased risk of secondary pseudotumor cerebri or as medications that my patients with pseudotumor cerebri should avoid. It is very interesting that the more well-known association between the cycline antibiotics (e.g., tetracycline, minocycline, and doxycycline) and intracranial hypertension had a lower adjusted rate ratio (2.68) for the 15-day definition than the oral FQs (5.67). -M. Tariq Bhatti, MD Suzuki S, Ishikawa N, Konoeda F, Seki N, Fukushima S, Takahashi K, Uhara H, Hasegawa Y, Inomata S, Otani Y, Yokota K, Hirose T, Tanaka R, Suzuki N, Matsui M. Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan. Neurology. 2017;89:1127-1134 Objective: To report the clinical features of myasthenia gravis (MG) induced by treatment with immune checkpoint inhibitors using 2-year safety databases based on postmarketing surveys in Japan. Methods: We studied 10,277 patients with cancer who had received monotherapy with either nivolumab or ipilimumab between September 2014 and August 2016. As the control group, 105 patients with idiopathic MG were used. Results: There were 12 MG cases (0.12%) among 9,869 patients with cancer who had been treated with nivolumab, but none among 408 patients treated with ipilimumab. These 12 patients included 6 men and 6 women with a mean age of 73.5 ± 6.3 years. MG onset occurred in the early phase after nivolumab treatment and rapidly deteriorated. Nivolumab-related MG (nivoMG) included 4 patients with mild involvement and 8 patients with severe involvement. Bulbar symptoms and myasthenic crisis were observed more frequently in nivoMG than idiopathic MG. Ten patients were positive for antiacetylcholine receptor antibodies. Serum creatine kinase levels were markedly elevated to an average level of 4,799 IU/L. Among the 12 patients with nivoMG, 4 had myositis and 3 had myocarditis, with 1 of these patients having both. Immunosuppressive therapy was effective. Postintervention status showed that pharmacologic remission or minimal manifestations were obtained in 4 patients; 455 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary however, 2 patients died. Immune-related adverse events triggered by nivolumab impaired the patients' daily living activity. Conclusions: The prompt and correct recognition of MG following treatment with immune checkpoint inhibitors in patients with cancer is important. Immune checkpoint inhibitors (ICIs) enhance antitumor responses by targeting T cell regulatory pathways. They have improved treatments for cancers such as melanoma and nonsmall cell lung cancer. There are prior isolated reports of ICI induced myasthenia gravis (MG) or exacerbation of MG by ICIs. In this postmarketing surveillance study, 12 MG cases (0.12%) developed among 9869 treated with nivolumab. Average time was 29 days into treatment. None developed thymoma. Eight patients had severe symptoms with rapid progression and 4 had mild symptoms. Ten had acetylcholine receptor antibodies and none had anti-MUSK antibodies. Ten also had markedly elevated creatine kinase (CK) levels, attributed to coexisting myositis and/or myocarditis. Those with high CK had severe MG. Nine had diplopia, 8 had ptosis which fluctuated, but the bulbar and extremity symptoms were progressive and crisis was frequent. Immunosuppression was efficacious in most patients but 2 died-one from myocarditis and one from myasthenic crisis. In contrast to other medications that impair neuromuscular transmission, ICIs activate autoreactive T cells causing antibody production. Since we are likely to see these patients and their progression may be rapid, it is important for us to be aware of this complication of these new cancer treatments. Reindl M, Rostásy K; BIOMARKER Study Group. Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome. Neurology. 2017;89:900-908 Objective: To assess the prognostic value of myelin oligodendrocyte glycoprotein (MOG) antibodies (abs) in the differential diagnosis of acquired demyelinating syndromes (ADS). Methods: Clinical course, MRI, MOG-abs, AQP4-abs, and CSF cells and oligoclonal bands (OCB) in children with ADS and 24 months of follow-up were reviewed in this observational prospective multicenter hospital-based study. Results: Two hundred ten children with ADS were included and diagnosed with acute disseminated encephalomyelitis (ADEM) (n = 60), neuromyelitis optica spectrum disorder (NMOSD) (n = 12), clinically isolated syndrome (CIS) (n = 101), and multiple sclerosis (MS) (n = 37) after the first episode. MOG-abs were predominantly found in ADEM (57%) and less frequently in NMOSD (25%), CIS (25%), or MS (8%). Increased MOG-ab titers were associated with younger age (P = 0.0001), diagnosis of ADEM (P = 0.005), increased CSF cell counts (P = 0.011), and negative OCB (P = 0.012). At 24-month follow-up, 96 children had no further relapses. Thirty-five children developed recurrent non-MS episodes (63% MOG-abs, 17% AQP4-abs at onset). Seventy-nine children developed MS (4% MOG-abs at onset). Recurrent non-MS episodes were associated with high MOG-ab titers (P = 0.0003) and older age at onset (P = 0.024). MS was predicted by MSlike MRI (P , 0.0001) and OCB (P = 0.007). An MOG-ab cutoff titer $1:1,280 predicted a non-MS course with a sensitivity of 47% and a specificity of 100% and a recurrent non-MS course with a sensitivity of 46% and a specificity of 86%. Conclusions: Our results show that the presence of MOGabs strongly depends on the age at disease onset and that high MOG-ab titers were associated with a recurrent non-MS disease course. -Mark L. Moster, MD I couldn't agree with you more, Mark, as neuroophthalmologist it is very important that we are aware of the potential side effects of ICIs. It is just not MG and myositis that has been associated with ICIs but other autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, Graves' disease, Vogt-Koyanagi-Harada syndrome, multiple sclerosis, and giant cell arteritis. Because ICIs activate the immune system and can cause an increase in autoimmunity, this unique adverse event profile has been termed "immune-related adverse events" (IRAEs). -M. Tariq Bhatti, MD Hennes EM, Baumann M, Schanda K, Anlar B, BajerKornek B, Blaschek A, Brantner-Inthaler S, Diepold K, Eisenkölbl A, Gotwald T, Kuchukhidze G, Gruber-Sedlmayr U, Häusler M, Höftberger R, Karenfort M, Klein A, Koch J, Kraus V, Lechner C, Leiz S, Leypoldt F, Mader S, Marquard K, Poggenburg I, Pohl D, Pritsch M, Raucherzauner M, Schimmel M, Thiels C, Tibussek D, Vieker S, Zeches C, Berger T, 456 This study looked at the course of patients presenting with an acute demyelinating syndrome and its relationship to myelin oligodendrocyte glycoprotein (MOG) antibodies (abs). After 24 months, 96 children still had a monophasic diseases course (42% with MOG-abs at onset), 35 children developed further demyelinating episodes other than multiple sclerosis (MS) (63% MOG-abs and 17% aquaporin-4 (AQP4)-abs at onset), and 79 children were diagnosed with MS (4% MOG-abs at onset). Of note, 28/35 (80%) patients with a recurrent non-MS course had abs to either MOG (63%) or AQP4 (17%). Children with a median age of 10 years, female sex, MOGabs or AQP4-abs, and MS-atypical magnetic resonance imaging (MRI) at onset have a high risk of developing a non-MS-like recurrent disease course independent from the initial diagnosis. These recurrent non-MS disease courses were diagnosed as multiphasic acute disseminated encephalomyelitis (ADEM) or ADEM with subsequent optic neuritis (ON) (ADEM-ON) (11 patients had these 2 diagnoses), followed by recurrent ON (8 patients), and NMO spectrum disorder (NMOSD) (3 patients). The patients in this study Moster and Bhatti: J Neuro-Ophthalmol 2017; 37: 451-457 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary had a higher risk for ON during the course of disease (26/35, 74%) compared with patients with a monophasic disease. Forty of 65 (61%) MOG-ab-seropositive children had a monophasic disease course, 22 (34%) developed a recurrent non-MS disease course and only 3 children (5%) were diagnosed with MS. MOG-ab-positive patients with a recurrent non-MS disease course. Sixteen of 22 (73%) patients with a recurrent disease course had ON at beginning or during follow-up compared with 13/40 (32%) patients with a monophasic disease and 2/3 (66%) with MS. Of note, an MS-like MRI (e.g., lesions perpendicular to the long axis of the corpus callosum) was absent in the monophasic and recurrent non-MS patients. MOG-ab testing, which is now only selectively available, may become more helpful in the near future in predicting Moster and Bhatti: J Neuro-Ophthalmol 2017; 37: 451-457 the subsequent course in patients with acute demyelination and guiding treatment decisions. -Mark L. Moster, MD I commend the authors of this study in advancing our understanding of the clinical relevance of MOG antibodies in the pediatric population. I am hopeful that with time many of these demyelinating diseases that we seem to have lumped together but are phenotypically heterogeneous will ultimately be split into distinct disease entities. I just want to add one more comment, which is that the arrows in Figure 1 illustrate the change in diagnosis that often occurs over time from the initial presentation of a patient with a first demyelinating event. -M. Tariq Bhatti, MD 457 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. |
Date | 2017-12 |
Language | eng |
Format | application/pdf |
Type | Text |
Publication Type | Journal Article |
Source | Journal of Neuro-Ophthalmology, December 2017, Volume 37, Issue 4 |
Collection | Neuro-Ophthalmology Virtual Education Library: Journal of Neuro-Ophthalmology Archives: https://novel.utah.edu/jno/ |
Publisher | Lippincott, Williams & Wilkins |
Holding Institution | Spencer S. Eccles Health Sciences Library, University of Utah |
Rights Management | © North American Neuro-Ophthalmology Society |
ARK | ark:/87278/s66b1g91 |
Setname | ehsl_novel_jno |
ID | 1400776 |
Reference URL | https://collections.lib.utah.edu/ark:/87278/s66b1g91 |