Literature Commentary

Literature Commentary Winthrop KL, Chen L, Fraunfelder FW, Ku JH, Varley CD, Suhler E, Hills WL, Gattey D, Baddley JW, Liu L, Grijalva CG, Delzell E, Beukelman T, Patkar NM, Xie F, Herrinton LJ, Fraunfelder FT, Saag KG, Lewis JD, Solomon DH, Curtis JR. Initiation of anti-TNF therapy and the risk of optic neuritis; from the Safety Assessment of Biologic ThERapy (SABER) Study. Am J Ophthalmol. 2012 Sep 8; (epub ahead of print). Purpose: To evaluate the incidence of optic neuritis (ON) in patients using anti-tumor necrosis factor (TNF) alpha therapy. Design: Retrospective, population-based cohort study. Methods: We identified new users of anti-TNF therapy (etanercept, infliximab, or adalimumab) or nonbiologic disease-modifying antirheumatic drugs (DMARDs) during 2000-2007 from the following data sources: Kaiser Perma-nente Northern California, Pharmaceutical Assistance Con-tract for the Elderly, Tennessee Medicaid, and National Medicaid/Medicare. Within this cohort, we used validated algorithms to identify ON cases occurring after onset of new drug exposure. We then calculated and compared ON incidence rates between exposure groups. Results: We identified 61 227 eligible inflammatory disease patients with either new anti-TNF or new nonbiologic DMARD use. Among this cohort, we found 3 ON cases among anti- TNF new users, occurring a median of 123 days (range, 37-221 days) after anti-TNF start. The crude incidence rate of ON across all disease indications among anti-TNF new users was 10.4 (95% CI 3.3-32.2) cases per 100,000 person-years. In a sensitivity analysis considering current or past anti-TNF or DMARD use, we identified a total of 6 ON cases: 3 among anti-TNF users and 3 among DMARD users. Crude ON rates were similar among anti-TNF and DMARD groups: 4.5 (95% CI 1.4-13.8) and 5.4 (95% CI 1.7-16.6) per 100,000 person-years, respectively. Conclusion: Optic neuritis is rare among those who initiate anti-TNF therapy and occurs with similar frequency among those with nonbiologic DMARD exposure. A double-masked randomized trial of anti-tumor necrosis factor (TNF) therapy for the treatment of multiple sclerosis (MS) showed that more new demyelinating events occurred in the treatment group compared to the placebo group (1). So, when patients (without MS) taking anti-TNF agents developed otherwise typical optic neuritis (ON), it was suggested that anti-TNF therapy may have played a causal role (2). However, these isolated case reports and series lacked a control group. This large database study by Withrop et al. compared incidence of an ON diagnosis code among patients on anti- TNF therapy with those on nonbiologic therapy (e.g., methotrexate, plaquenil) for an autoimmune condition. Although patients on anti-TNF therapy developed ON, it occurred at a similar rate to those individuals on other therapies. The crude incidence rates were also similar to the reported incidence of ON of 5 per 100,000. This would suggest that among patients who do not have a history of demyelinating disease, anti-TNF therapy may not be associated with new ON. -Michael S. Lee, MD The finding of a similar incidence of ON in patients on anti-TNF therapy as those on other treatments is somewhat reassuring. However, identification of these cases from data-bases using International Classification of Diseases, Ninth Revision codes without any clinical information may create errors of exclusion and inclusion. This can be especially confounding in this study with a small number of identified cases (3 on anti-TNF therapy, 3 on other therapy), so missing or erroneously including a few cases makes a large difference. However, I would agree with the authors' conclusions that until we have better studies, we should avoid these agents in patients with known MS or who develop MS while on treatment. -Mark L. Moster, MD REFERENCES 1. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group.TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology. 1999;53:457-465. 2. Foroozan R, Buono LM, Sergott RC, Savino PJ. Retrobulbar optic neuritis associated with infliximab. Arch Ophthalmol. 2002;120:985-987. Berdahl JP, Fleischman D, Zaydlarova J, Stinnett S, Allingham RR, Fautsch MP. Body mass index has a linear relationship with cerebrospinal fluid pressure. Invest Ophthalmol Vis Sci. 2012;53:1422-1427. Purpose: To examine the relationship between body mass index (BMI) and cerebrospinal fluid pressure (CSFP), as low Moster and Lee: J Neuro-Ophthalmol 2013; 33: 83-87 83 Literature Commentary Section Editors: Mark L. Moster, MD Michael S. Lee, MD Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. BMI and low CSFP have recently been described as risk factors for primary open-angle glaucoma (POAG). Methods: This was a retrospective review of the electronic medical records of patients who had CSFP measured by lumbar puncture and data to calculate BMI at the Mayo Clinic (Rochester, MN). Exclusion criteria included diagnoses, surgi-cal procedures and medications known to affect CSFP. Mean CSFP for each unit BMI was calculated. The probabilities were two-tailed, and the a level was set at P , 0.05. Patients with documented BMI, CSFP, and intraocular pressure (IOP) were analyzed for the relationship between IOP and BMI. Results: A total of 4235 patients, primarily of Caucasian descent, met the entry criteria. Median BMI was 26 and the mean CSFP was 10.9 ± 2.6 mm Hg. The increase in CSFP with increasing BMI was linear with an r(2) = 0.20 (P , 0.001). CSFP increased by 37.7% from BMI 18 (8.6 ± 2.1 mm Hg) to BMI 39 (14.1 ± 2.5 mm Hg). The r(2) (0.21) of the model of BMI and sex was similar to the r(2) of a BMI-only model (0.20). There was no relation between IOP and BMI within a subgroup of the study population (r (2) = 0.005; P = 0.14). Conclusions: CSFP has a positive, linear relationship with BMI. IOP is not influenced by BMI. If CSFP influences the risk for POAG, then individuals with a lower BMI may have an increased risk for developing POAG. Similarly, a higher BMI may be protective. This report shows a direct linear relationship between body mass index (BMI) and intracranial pressure (ICP), measured by lumbar puncture. Berdhal and colleagues found an ICP of 120 mm H2O at a BMI of 18 and 192 mmH20 at a BMI of 39. At the cutoff of their definition of obesity (BMI 30), ICP was 159 mm H20. The authors have a particular interest in glaucoma and undertook this study to look for any correla-tion between ICP and glaucoma and BMI and glaucoma. The relationship between intraocular pressure (IOP) and ICP recently has been popularized, mainly in the glaucoma literature. Compared with controls, patients with primary open-angle glaucoma have slightly lower ICP, patients with normal tension glaucoma have even lower ICP, and patients with ocular hypertension (OHT) have higher ICP. These findings are suggestive that a translaminar pressure differ-ence (IOP - ICP) may be more important in glaucoma than IOP alone. So, low ICP in open-angle glaucoma is detri-mental, and higher ICP in OHT is protective. The authors discuss that it may be the high ICP that underlies the relative protection from glaucoma recently reported in patients with a high BMI. However, this is a "hard sell" because the glaucoma literature has numerous studies with conflicting information about the relationship between BMI and glaucoma. It may be that in idiopathic intracranial hypertension (IIH) the ICP - IOP difference is important as well. It has been reported (but not yet published) that a higher ICP - IOP dif-ference is associated with more severe visual field loss in IIH (R. Friedman, MD, personal communication, March 2010). This paper adds some clarification but also raises questions. Body mass index and ICP are related. Is this real or is it an artifact of testing-a technical difference in the lumbar puncture readings related to the extra body fat? Is a higher ICP in an obese patient normal or an abnormal-ity related to the obesity? While there does appear to be a relationship between BMI and ICP, we clearly have a great deal to learn if this relationship plays any role in the pathophysiology of disease, be it ocular or neurologic. -Mark L. Moster, MD It is hard to argue with a study of over 4,200 patients. So it looks like BMI really does affect the cerebrospinal fluid opening pressure among normal individuals. Note that the authors specifically excluded patients with an opening pressure greater than 250 mm H20, so the linear relationship may not hold for patients with IIH. Although the authors do not indicate leg position or use of sedation, presumably the LPs were done in an uniform fashion and the BMI-cerebro-spinal fluid opening pressure relationship remains solid. -Michael S. Lee, MD Tarp S, Bartels EM, Bliddal H, Furst DE, Boers M, Danneskiold-Samsøe B, Rasmussen M, Christensen R. Effect of nonsteroidal anti-inflammatory drugs on the C-reactive protein level in rheumatoid arthritis: a meta-analysis of randomized controlled trials. Arthritis Rheum. 2012;64:3511-3521. Objective: To evaluate the effects of oral nonsteroidal anti-inflammatory drugs (NSAIDs) on C-reactive protein (CRP) levels in rheumatoid arthritis (RA) patients, with a prespeci-fied focus on the different NSAIDs. Methods: We performed a systematic search in Medline via PubMed, the Cochrane Central Register of Controlled Trials, EMBase via OVID, the Institute for Scientific Information Web of Science, and other sources. Eligible trials were parallel-group, randomized, placebo-controlled trials of oral NSAID therapy in RA patients for which there were extractable CRP data. Standardized mean differences (SMDs) with 95% confidence intervals (95% CIs) were calculated from the differences in means of CRP levels between groups (active treatment minus placebo) divided by the pooled SDs. For the meta-analysis, a random-effects model was used to estimate the overall change in CRP level, and stratified analysis was used to examine differences among NSAIDs. Results: We included 19 trials of 10 different NSAIDs. Overall, NSAIDs showed no effect on the CRP level (SMD 0.01 [95% CI 20.03, 0.06], P = 0.62). However, the prespe-cified stratified analysis indicated varying effects on the CRP level according to the different NSAIDs; lumiracoxib caused a statistically significant and consistent (I(2) = 0%) increase in the CRP level (SMD 0.13 [95% CI 0.01, 0.25], P = 0.037), whereas naproxen caused a statistically significant and con-sistent (I(2) = 0%) decrease in the CRP level (SMD 20.11 [95% CI 20.20, 20.02], P = 0.022). Conclusion: Overall, NSAIDs have no effect on the CRP level. However, the nonselective NSAID naproxen was associated with a significant decrease in the CRP level, whereas the cyclooxygenase 2-selective NSAID lumiracoxib was associated with a significant increase in the CRP level. 84 Moster and Lee: J Neuro-Ophthalmol 2013; 33: 83-87 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. This finding is interesting considering the suspected influ-ence of NSAIDs on cardiovascular complications. Last year in the Journal of Neuro-Ophthalmology, Hegg et al (1) reported that statins and nonsteroidal anti-inflammatory drugs (NSAIDs) reduced erythrocyte sedi-mentation rate but not C-reactive protein (CRP) among 161 patients with biopsy-proven giant cell arteritis (GCA). The numbers looked robust for erythrocyte sedimentation rate but not so much for CRP. Personally, I questioned whether the lack of an effect on CRP was more about a lack of numbers. Although Tarp et al looked only at patients with rheumatoid arthritis, I believe that the results are still applicable to GCA and support the findings of Hegg et al that NSAIDs generally do not affect CRP. Interestingly, lumiracoxib, a selective COX-2 inhibitor, caused a consistent and significant increase in CRP compared with controls. Fortunately, it is not on the market in the US or Europe. Naproxen was the only NSAID that consistently lowered the CRP, and this medication should be noted when evaluating a patient for GCA. Finally, the authors note that ibuprofen was not studied in this meta-analysis, so we do not know if it affects CRP or not. -Michael S. Lee, MD As the authors point out, many of these patients were on other medications for RA and for other medical conditions that might also affect CRP. Additionally, there was not enough information to report on ibuprofen, the most commonly used NSAID. Finally, the only NSAID that did decrease CRP-naproxen-only decreased the CRP by 14% on average (e.g., from 3.0 to 2.58), not likely enough to change a clinical decision. Therefore, CRP will still be quite helpful clinically in patients being treated with NSAIDs. -Mark L. Moster, MD REFERENCE 1. Hegg R, Lee AG, Tagg NT, Zimmerman MB. Statin or nonsteroidal anti-inflammatory drug use is associated with lower erythrocyte sedimentation rate in patients with giant cell arteritis. J Neuroophthalmol. 2011;31:135-138. Lungu C, Considine E, Zahir S, Ponsati B, Arrastia S, Hallett M. Pilot study of topical acetyl hexapeptide- 8 in the treatment for blepharospasm in patients receiving botulinum toxin therapy. Eur J Neurol. 2012; (epub ahead of print). Background and Purpose: Injectable botulinum neurotoxin (BoNT) is the principal effective treatment for blepharo-spasm (BSP). This trial explores the safety and efficacy of topical acetyl hexapeptide-8 (AH8), a competitive synapto-somal- associated protein 25 (SNAP-25) inhibitor, as a poten-tial new therapy in BSP. Methods: Double-blind, placebo-controlled, randomized trial of daily topical application of AH8 in 24 patients with BSP. The primary outcome was time to return to baseline Jankovic Rating Scale (JBRS) after a BoNT injection simul-taneously with the initiation of AH8. Patients displaying a strictly regular pattern of response to 3-monthly injections of BoNT were included. Results: There were no significant adverse events. There was a trend for longer time until return to baseline JBRS after injection in the active group compared to placebo (3.7 months vs. 3.0 months), and for better scores in the active group. One-third (4/12) of the patients in the active group had a considerable extension of symptom control after BoNT (range: 3.3-7.1 months). Conclusions: Topical AH8 is safe and promising for extend-ing the duration of action of BoNT therapy for BSP. Acetyl hexapeptide 8 (AH8) has been used for the cosmetic treatment of wrinkles in the form of a topically applied cream. Its mechanism of action is analogous to botulinum toxin-competitive inhibition of the synaptosomal-associ-ated protein 25 (SNAP-25) component of the soluble NSF attachment protein receptor (SNARE) complex that medi-ates neurotransmitter exocytosis at the neuromuscular junction. This study added daily topical AH8 to the pa-tient's regular schedule of botulinum toxin injections. The primary outcome was time to return to the baseline Jan-kovic Blepharospasm Rating Scale. Although the primary outcome in the study did not reach statistical significance, this pilot study found a trend toward longer benefit after botulinum injection in those who received the medication (3.7 months) vs placebo (3.0 months). A subgroup had an even greater benefit with 1 patient benefiting up to 7 months. The study demonstrated safety and promise for this additional treatment for blepharospasm. The dose used was the same as for cosmetic wrinkles, and future studies using higher doses will likely be necessary to gain greater effect on eyelid muscles. -Mark L. Moster, MD Although the concept is interesting, I do not think that this study gives us much valuable information. The total number of patients was too small (n = 24) to generate conclusive evidence about the benefit or lack of benefit for AH8 in the treatment of blepharospasm. Although the authors report a "trend" toward a benefit, they do not pro-vide a P value to allow the reader to decide how "trend-y" the data looks. Finally, the study only involved the response to one injection along with AH8 use. It would have been of greater value to see several injections to assess the effect of AH8. -Michael S. Lee, MD Cull GA, Reynaud J, Wang L, Cioffi GA, Burgoyne CF, Fortune B. Relationship between orbital optic nerve Moster and Lee: J Neuro-Ophthalmol 2013; 33: 83-87 85 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. axon counts and retinal nerve fiber layer thickness measured by spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2012; (epub ahead of print). doi:10.1167/iovs.12-10752. pii: iovs. 12-10752v1. Purpose: To determine the relationship between total optic nerve axon counts and peripapillary retinal nerve fiber layer thickness (RNFLT) measured in vivo by spectral domain optical coherence tomography (SDOCT). Methods: Twenty-two rhesus macaques had three or more baseline measurements in both eyes of peripapillary RNFLT made by SDOCT (Spectralis, Heidelberg Engineering GmbH). Laser photocoagulation was then applied to the trabecular meshwork of one eye to induce chronic unilat-eral IOP elevation. SDOCT measurements of RNFLT continued approximately every two weeks until the pre-defined study endpoint was reached in each animal. At endpoint, animals were sacrificed and the optic nerve was sampled approximately 2 mm behind the globe to obtain thin sections for histological processing and automated axon counting across 100% of the optic nerve cross-sectional area. Results: At the final imaging session, the average loss of RNFLT was 20 ± 21%, ranging from essentially no loss to nearly 65% loss. Total optic nerve axon count in control eyes ranged from 812,478 to 1,280,474. The absolute number of optic nerve axons was linearly related to RNFLT (axon count = 12336*RNFLT(mm) - 257050, R2 = 0.65, P , 0.0001), with a Pearson correlation coefficient of 0.81. There was also a strong linear relationship between relative optic nerve axon loss (glaucomatous:control eye) and rela-tive RNFLT at the final imaging session, with a slope close to unity but a significantly negative intercept (relative axon loss(%) = 1.05*relative RNFLT loss(%) - 14.4%, R2 = 0.75, P , 0.0001). The negative intercept was robust to varia-tions of fitted model because relative axon loss was 214% on average for all EG eyes within 6% (measurement noise) of zero relative loss. Conclusions: There is a strong linear relationship between total optic nerve axon count and RNFLT measured in vivo by SDOCT. However, substantial loss of optic nerve axons (w10-15%) exists before any loss of RNFLT manifests and this discrepancy persists systematically throughout a wide range of damage. Using a unilateral experimental glaucoma (EG) model in rhesus macaque monkeys, the authors measured retinal nerve fiber layer (RNFL) with spectral-domain optical coherence tomography of both eyes. At various time points, the authors took cross sections of EG and control optic nerves, stained them, and performed automated counts of all axons. They made 2 major observations: 1) There was definite correlation between RNFL and total axon counts in EG eyes and 2) significant (10%-15%) loss of optic nerve axons occurred prior to any change in RNFL. While it has always been assumed that RNFL can reliably estimate axon count, this study proves it longitu-dinally. We have also known that a substantial loss of axons precedes functional visual field loss in glaucoma, but this study also shows that structural measure of RNFL cannot detect axonal loss early on. Therefore, among patients followed for progressive RNFL loss, what may seem a small change in RNFL (6%) may represent something clinically significant and should warrant close observation. -Michael S. Lee, MD This study is reassuring that RNFL thinning has a linear correlation with orbital nerve axon counts. Some of the discrepancy in the amount of thinning noted (10%-15% more in the orbital axon count) may be due to the fact that the optical coherence tomography was performed on aver-age 7.6 days prior to sacrifice of the animal. Also, the find-ings in glaucoma may be different compared with optic atrophy from compression or demyelination because of dif-ferences in the site of optic nerve damage. -Mark L. Moster, MD Chang M, Baek S, Lee TS. Long-term outcomes of unilateral orbital fat decompression for thyroid eye disease. Graefes Arch Clin Exp Ophthalmol. 2012 Nov 9; (epub ahead of print). Background: The aim of this study was to evaluate the long-term outcomes after unilateral orbital fat decompression in patients with thyroid eye disease. Design: Retrospective, comparative, cross-sectional study. Participants: Thirty-three orbits of 33 patients were included in this study. Of the 33 patients, 13 underwent fat decompres-sion (group A), and the other 20 had bony decompression (group B). Methods: The medical records of patients who underwent orbital decompression to reduce proptosis for thyroid eye disease were retrospectively reviewed. The degrees of proptosis were measured by Hertel exophthalmometry pre-operatively and over a follow-up period of more than 3 years. We evaluated the change in proptosis after surgery. Main Outcome Measures: Postoperative change in exoph-thalmos. Results: A recurrence in proptosis from fat decompression was seen in ten patients (76.9%) in group A and in only two patients (10%) in group B. The amount of regression due to surgery after 3 years was 2.3 ± 1.4 mm and 0.7 ± 0.9 mm in groups A and B respectively. The tendency of regression was more prominent in group A than in group B. Conclusion: The long-term effect of unilateral orbital fat decompression for the reduction of proptosis in patients with thyroid eye disease may be weak, leading to regression. Care should be taken when determining the extent of fat decompression with consideration for this tendency. Prior reports have shown orbital fat decompression to be relatively safe and effective to reduce proptosis for the short-term. The benefit over bony decompression is a lower incidence of postoperative diplopia. This study found that 86 Moster and Lee: J Neuro-Ophthalmol 2013; 33: 83-87 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. early on the reduction of proptosis was as good with fat decompression as with bony decompression and in fact occurred sooner (2 months vs 7 months). However, there was recurrence of proptosis much more frequently with fat than with bony decompression (77% vs 10%). The study, involving a relatively small number of patients, has numerous limitations, not the least of which being that the same surgeon operated on all the patients, did all the follow-up measurements, and was unmasked. -Mark L. Moster, MD These patients with unilateral disease seem to run a different course than those with bilateral disease, and so the results may not apply to all patients with thyroid eye disease. I agree with you, Mark, that there are a lot of limitations. However, if more studies continue to show this trend, we may need to rethink using fat decompres-sion alone for the treatment of proptosis in thyroid eye disease. -Michael S. Lee, MD REFERENCES 1. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology. 1999;53:457-465. 2. Foroozan R, Buono LM, Sergott RC, Savino PJ. Retrobulbar optic neuritis associated with infliximab. Arch Ophthalmol. 2002;120:985-987. 3. Berdahl JP, Fleischman D, Zaydlarova J, Stinnett S, Allingham RR, Fautsch MP. Body mass index has a linear relationship with cerebrospinal fluid pressure. Invest Ophthalmol Vis Sci. 2012;53:1422-1427. 4. Hegg R, Lee AG, Tagg NT, Zimmerman MB. Statin or nonsteroidal anti-inflammatory drug use is associated with lower erythrocyte sedimentation rate in patients with giant cell arteritis. J Neuroophthalmol. 2011;31:135-138. Moster and Lee: J Neuro-Ophthalmol 2013; 33: 83-87 87 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.