Diagnostic Algorithm for Suspected Giant Cell Arteritis: Response

Letters to the Editor Regarding hematological tests, the findings of thrombocytosis in our study are very different from those by El-Dairi et al, who stated that "the strongest association with positive TAB was an elevated platelet count," and that elevated CRP or an elevated ESR were not associated with a positive TAB. However, they went on to state that elevation of platelet count and CRP "was highly predictive of a positive TAB." Our studies (2-5) do not fully support these conclusions. Our study (5) showed that the predictive ability of elevated platelet count did not surpass elevated ESR or CRP as a diagnostic marker for GCA. The most important consideration is that GCA is an ophthalmic emergency, where early diagnosis and aggressive treatment with high-dose corticosteroid therapy prevents visual loss. The conclusion by El-Dairi et al that "None of the patients with a clinical score less than 2 had a positive TAB" is somewhat misleading. It may be valid in many GCA patients but not by any means in all. I would caution the reader to be skeptical of many of the conclusions reported by El-Dairi et al in evaluating patients suspected of having GCA. Sohan S. Hayreh, MD, MS, PhD, DSc, FRCS, FRCOphth (Hon) Diagnostic Algorithm for Suspected Giant Cell Arteritis: Response W e thank Dr. Hayreh for sharing his comments on our study. Dr. Hayreh's illustrious academic career elevated him to the status of a thought leader in many ocular vascular diseases, such as retinal vein occlusion, retinal artery occlusion, ischemic optic neuropathy, and giant cell arteritis (GCA). With such credentials, it can be a daunting task to provide a rebuttal to some of his criticisms, but we do so with great respect and admiration. Dr. Hayreh invokes the findings from his article published in 1997 (prospectively performed from 1973 to 1994) (1) to compare and contrast the results to our study (2). We will respond in a structured fashion and discuss each point made in the order presented in his letter. Pathology Electronic Database As should be done in all reports, we discussed the limitations of our study, which included a lack of complete clinical and paraclinical information in the medical records of some patients. Such shortcomings are often the situation in many retrospective studies. Even in Dr. Hayreh's prospective study, C-reactive protein (CRP) values were not available for all patients. Letters to the Editor: J Neuro-Ophthalmol 2016; 36: 221-229 Department of Ophthalmology and Visual Sciences, College of Medicine, University of Iowa, Iowa city, IA The author reports no conflict of interest. REFERENCES 1. El-Dairi MA, Chang L, Proia AD, Cummings TJ, Stinnett SS, Bhatti MT. Diagnostic algorithm for patients with suspected giant cell arteritis. J Neuroophthalmol. 2015;35:246-253. 2. Hayreh SS, Podhajsky PA, Raman R, Zimmerman B. Giant cell arteritis: validity and reliability of various diagnostic criteria. Am J Ophthalmol. 1997;123:285-296. 3. Hayreh SS, Podhajsky PA, Zimmerman B. Ocular manifestations of giant cell arteritis. Am J Ophthalmol. 1998;125:509-520. 4. Hayreh SS, Podhajsky PA, Zimmerman B. Occult giant cell arteritis: ocular manifestations. Am J Ophthalmol. 1998;125:521-526, 893. 5. Costello F, Zimmerman MB, Podhajsky PA, Hayreh SS. Role of thrombocytosis in diagnosis of giant cell arteritis and differentiation of arteritic from non-arteritic anterior ischemic optic neuropathy. Eur J Ophthalmol. 2004;14:245-257. 6. Hayreh SS, Baines JAB. Occlusion of the posterior ciliary artery I. Effects on choroidal circulation. Br J Ophthalmol. 1972;56:719- 735. We used the Department of Pathology electronic database to identify patients who had been evaluated for GCA at Duke University Medical Center based on the results of temporal artery biopsy (TAB). We chose to use this data set because it allowed us to capture for analysis as many patients as possible who underwent a TAB from the entire medical center and not just from the Department of Ophthalmology. In comparison, it seems to be somewhat of a unique situation that at the University of Iowa Hospitals and Clinics, all TABs were performed by ophthalmologists during the period of Dr. Hayreh's study. Length of Temporal Artery Specimen, Serial Sectioning, and Previous Corticosteroid Therapy We agree with Dr. Hayreh's statement that length of the temporal artery specimen and serial sectioning are important to eliminate "skip areas." We also agree that the optimal length of a TAB should be at least 1 inch. To explain the variation in the length of TAB in our study, it should be kept in mind that there were not only multiple ophthalmologists who performed the TAB but also surgeons from other specialties (otolaryngology, neurosurgery, vascular surgery, and general surgery). However, we did not find that a longer TAB was associated with a higher rate of a positive TAB (mean biopsy length, 225 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor 21.6 6 4.1 mm for a negative TAB vs 21.6 6 6.8 mm for a positive TAB; P = 0.49). Our Department of Pathology performs "step sections" ("levels") when processing TABs. Although not as thorough as serial sections, which would require examining hundreds of slides from each biopsy, we consider our technique more than adequate to avoid skip areas and minimize falsenegative results. Regarding previous corticosteroid therapy, we examined each TAB for features of treated or healed arteritis. Prevalence of Systemic Signs and Symptoms We have no reason to disagree with the odds ratios that were published by Dr. Hayreh because "numbers do not lie." However, given the different study design and methodologies used between the 2 studies, the argument could be made that such a comparison is akin to comparing "apples to oranges" and not "apples to apples." We stand by the results of our study because the "numbers do not lie," but with the caveat that our study had limitations, in particular that it was a retrospective chart review and that we did not compare our findings to normal controls. Headache Table 3 of Dr. Hayreh's article indicates that headaches were present in 55.7% of TAB-positive patients and 45.5% of TAB-negative patients (P = 0.084). However, the location (temporal, frontal, etc.), type (sharp, dull, pounding, etc.), and time course (acute, subacute, or chronic) of the headaches are not described. Evaluate for Alternative Diagnosis Based on our algorithm, we state that if the patient has only 1 positive finding of the 7 listed, an alternative diagnosis should be sought. Dr. Hayreh suggests that jaw claudication in and of itself (i.e., normal erythrocyte sedimentation rate [ESR], normal CRP, normal platelet count, no neck pain, no scalp tenderness, and no constitutional or systemic symptoms) should be an indication for performing a TAB in a patient more than 50 years. However, we were unable to determine how many of his 106 patients with a positive TAB had jaw claudication as their only manifestation of GCA. Furthermore, Dr. Hayreh states "However, when we considered a multivariate logistic regression model that included ESR and age, the only significant systemic symptoms were jaw claudication and neck pain (mostly in the occipital and back parts of the neck)." This implies that jaw claudication and neck pain were indicators of a positive biopsy, independent of ESR and age. 226 Hematological Tests We would like to reiterate what we wrote regarding hematological tests: "Having any isolated laboratory value elevated (ESR, CRP, or platelet count) was not associated with a positive TAB; however, when 2 or more inflammatory markers were elevated, the RR was 3.4 (P , 0.0001) (23/25 patients with elevated platelet count also had a high ESR, and 63/76 patients with a high CRP also had high ESR). An increase in ESR, CRP, and platelet count was present in 11 of 77 patients (14.7%) and was not associated with positive TAB. Two patients with positive TAB had normal ESR, CRP, and platelet counts." We acknowledge differences in the results of our study compared to the study of Dr. Hayreh, but because of the different study design, demographic/geographic/genetic cohort profile, and period of the studies, it is not reasonable to just dismiss such differences in favor of one study over another. It is more important to understand why these discrepancies exist between the 2 studies, without just insinuating it is simply inaccurate or wrong because it is not in alignment with previously published results. Giant Cell Arteritis is an Ophthalmic Emergency Based on clinical evidence and clinical experience, it is abundantly clear that GCA is a heterogeneous disease in terms of clinical presentation, clinical manifestations, and inflammatory markers. Because the stakes are so high, in terms of not only visual loss but also systemic morbidity and mortality, it is crucial that the diagnosis of GCA be made correctly and promptly. The nidus of our study was to attempt to create an easy-to-use diagnostic algorithm for clinicians to use when trying to decide on whether to proceed with a TAB or not. In no way does our algorithm claim to have 100% sensitivity in detecting GCA. Because of the variable phenotypic expression of GCA and the fact that there can be no systemic symptoms (occult GCA) and normal inflammatory markers (CRP and ESR), the decision to perform a TAB should be made on a case-bycase basis. We take issue with Dr. Hayreh for dismissing our study results and stating that readers should be skeptical of "many" of our conclusions. We believe that the decision to perform a TAB should not be based on just 1 clinical or laboratory finding but rather integrating all data to increase the yield of obtaining a positive TAB and preventing unnecessary TABs. We stand by our study and will let the reader determine the validity of the results and the utility of our algorithm. M. Tariq Bhatti, MD Departments of Ophthalmology and Neurology, Duke Eye Center and Duke University Medical Center, Durham, North Carolina Letters to the Editor: J Neuro-Ophthalmol 2016; 36: 221-229 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor Mays A. El-Dairi, MD Department of Ophthalmology, Duke Eye Center and Duke University Medical Center, Durham, North Carolina Thomas J. Cummings, MD Alan D. Proia, MD, PhD Departments of Ophthalmology and Pathology, Duke Eye Center and Duke University Medical Center, Durham, North Carolina A General Decline in Cerebrospinal Fluid Flow: An Overlooked Risk Factor for Glaucoma? W e read with great interest the article by McCulley et al (1) entitled "Intracranial pressure and glaucoma." We are grateful to the authors for sharing their valuable insights with the scientific community, and we would appreciate the opportunity to comment. In their article, the authors discuss the evolving role of intracranial pressure (ICP) in the pathophysiology of glaucoma and note that it is plausible that local alterations in optic nerve structure, blood supply, or axonal transport could result from changes in ICP. However, the authors do not discuss the potential role of a diminished cerebrospinal fluid (CSF) circulation in the development of glaucoma. We believe that a general decline in CSF flow may be an overlooked factor in the debate on the potential role of low ICP in glaucoma. The hypothesis of low ICP as pathogenetically important for glaucoma has attracted a lot of attention in recent years. Retrospective studies conducted by Berdahl et al (2,3) have provided intriguing findings in relation to ICP among patients with glaucoma, and they were confirmed by a more recent prospective study by Ren et al (4). The lower ICP reported in primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG) patients could play a role in the pathogenesis of glaucoma through a higher pressure difference across the lamina cribrosa influencing the physiology and pathophysiology of the optic nerve head (5). However, a number of objections have been raised regarding the speculation that the mismatch in pressures across the lamina cribrosa may indeed contribute to glaucomatous optic nerve damage. According to Hayreh (6,7), there is no scientifically valid support for the concept that the translaminar imbalance between the intraocular pressure and ICP caused by low ICP can cause bowing back of the rigid, compact band of lamina cribrosa and consequently cause glaucomatous optic disc cupping. In view of many arguments against a simple biomechanical mechanism, our group recently presented an alternative Letters to the Editor: J Neuro-Ophthalmol 2016; 36: 221-229 The authors report no conflicts of interest. REFERENCES 1. Hayreh SS, Podhajsky PA, Raman R, Zimmerman B. Giant cell arteritis: validity and reliability of various diagnostic criteria. Am J Ophthalmol. 1997;123:285-296. 2. El-Dairi MA, Chang L, Proia AD, Cummings TJ, Stinnett SS, Bhatti MT. Diagnostic algorithm for patients with suspected giant cell arteritis. J Neuroophthalmol. 2015;35:246-253. viewpoint that the harmful effect of lower ICP in patients with NTG could be due, at least in part, to a biochemical mechanism (8). Indeed, given that the lower ICP in patients with NTG may result from decreased CSF production (9), we postulated that this lack of CSF production and the resulting general decline in CSF flow could ultimately result in reduced neurotoxin clearance along the optic nerves and lead to glaucomatous damage. Interestingly, a study in an experimental animal model provided evidence for a possible toxic effect of stagnant CSF on the optic nerve (10). Therefore, we believe that a general decline in CSF flow could be an alternative explanation as to why glaucoma develops in patients with low ICP. Given that ICP is lower in patients with POAG when compared with nonglaucomatous control subjects and, additionally, is lower in the normal-tension vs. the high-tension form of POAG (2-4), the reduction in CSF production and turnover, with diminished clearance of neurotoxins, might be the necessary, if not sufficient, factor in the pathogenesis of glaucoma. Given the above considerations and given that both the hydrostatic pressure and the dynamics of CSF may be potentially important for the physiological stability of the optic nerve (11), it may be worth discussing and exploring the potential role of a general decline in CSF flow in the pathogenesis of glaucoma. Peter Wostyn, MD Department of Psychiatry, PC Sint-Amandus, Beernem, Belgium Veva De Groot, MD, PhD Department of Ophthalmology, Antwerp University Hospital, Antwerp, Belgium Debby Van Dam, PhD Department of Biomedical Sciences, Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 227 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.