Cognitive Performance of Patients With Multiple Sclerosis and Optic Neuritis at Presentation

Cognitive dysfunction is common among patients with multiple sclerosis (MS), but the effect of coexisting optic neuritis (ON) at the first presentation of multiple sclerosis on the course of cognitive decline is unknown. The purpose of this study was to assess whether ON at presentation has any effect on the progression of cognitive decline in MS.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Cognitive Performance of Patients With Multiple Sclerosis and Optic Neuritis at Presentation Ari Leshno, MD, Oded Sagiv, MD, Roy Aloni, PhD, Alon Skaat, MD, Anat Achiron, MD, Ruth Huna-Baron, MD Background: Cognitive dysfunction is common among patients with multiple sclerosis (MS), but the effect of coexisting optic neuritis (ON) at the first presentation of multiple sclerosis on the course of cognitive decline is unknown. The purpose of this study was to assess whether ON at presentation has any effect on the progression of cognitive decline in MS. Methods: Historical cohort study. We retrospectively compared the cognitive performance of patients with relapsingremitting MS with and without ON at the time of MS diagnosis. Subjects were included if cognitive test results were available both at baseline and after at least 36 months from presentation and grouped based on the presence (MS-ON) or absence (MS-non-ON) of optic neuritis at presentation. Results: One hundred seventy consecutive subjects with MS were found suitable, with a 1:2 male:female ratio and a mean age at diagnosis of 33.0 ± 10.9 years. Forty-six patients (27.1%) presented with ON. No significant differences were found in cognitive performance at onset between the 2 groups. Both groups had a similar follow-up duration. The prevalence of cognitive decline in the general score was significantly higher in the MS-ON group compared with the MS-non-ON group (6.5% vs 0%, respectively; P , 0.001), as well as in the attention (8.7% vs 1.6%; P = 0.046) and the executive function (17.4% vs 2.4%; P = 0.001) domains. Conclusions: Optic neuritis at presentation of MS is associated with a higher prevalence of cognitive decline over time. Potential benefit of early intervention to prevent cognitive decline may be warranted. Journal of Neuro-Ophthalmology 2022;42:e8–e13 doi: 10.1097/WNO.0000000000001245 © 2021 by North American Neuro-Ophthalmology Society Goldschleger Eye Institute (AL, OS, AS, RH-B), Sheba Medical Center, Tel-Hashomer, Israel; Department of Behavioral Sciences and Psychology (RA), Ariel University, Ariel, Israel; Multiple Sclerosis Center (RA, AA), Sheba Medical Center, Tel Hashomer, Israel; and Sackler Faculty of Medicine (RA, AA, AL, OS, AS, RH-B), Tel Aviv University, Tel Aviv, Israel. The authors report no conflicts of interest. Address correspondence to Ari Leshno, MD, Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer, Israel 5262000; E-mail: [e-mail] e8 M ultiple sclerosis (MS) is a central nervous system demyelinating autoimmune disease affecting young adults. Although it is best known for causing severe physical disabilities, several studies have shown that 20%–65% of MS patients also undergo early cognitive decline (1–5). Recent studies have reported increased prevalence of cognitive impairment with longer disease duration, manifesting after a disease duration of 5 years (3). With several possible interventions to slow cognitive decline having been described (6–9), it is therefore important to identify related risk factors early to detect patients who may benefit from such treatments. Optic neuritis (ON) is an inflammatory disease of the optic nerve (10,11) that usually presents as a unilateral loss of vision and impaired visual field with central or paracentral scotoma and commonly associated with retrobulbar pain (12). Although ON has several known causes, MS is the most common etiology. ON can also be the presenting sign of MS in up to 20% of cases (13). One of the findings in the optic neuritis treatment trial was a low frequency of substantial disability among patients who developed MS, which raises the question as to whether MS patients with ON at onset show different frequencies and characteristics in their cognitive performance as well (14). Nilsson et al (15) described a high rate of cognitive dysfunction among patients with a history of isolated ON; however, their sample size was relatively small, and they provided no baseline cognitive data for comparison. The aim of the current study is to evaluate whether MS patients presenting with ON differ from MS patients presenting with other manifestations in terms of cognitive performance during follow-up. MATERIALS AND METHODS Study Population and Setting Data were retrospectively collected between 2001 and 2017 from the Sheba MS Center’s computerized database, which Leshno et al: J Neuro-Ophthalmol 2022; 42: e8-e13 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution is a population-based registry that documents demographic and clinical data of MS patients followed at the center. The database has been described in detail (3). Briefly, the Sheba MS Center is a national referral center for MS patients in Israel that provides multidisciplinary care and treatment for more than 4,000 MS patients. Since its establishment, the patients’ medical data have been stored on an electronic record–keeping system updated by the treating neurologists during each visit. The patients’ computerized charts include data on demographics, medical history, family history, cognitive, electrophysiological and neuroimaging tests results, and treatment, such as steroids and immunomodulatory drugs. The patient undergoes a complete neurological examination at each visit, and an Expanded Disability Status scale score is assigned and recorded. Every patient undergoes routine cognitive assessment tests within up to 3-month intervals. The integrity of the data registry is periodically evaluated by a computerized logic–algorithm– questioning process to identify errors in data entry. The present study describes long-term changes in cognitive scores among MS patients, comparing the findings for those who had ON at presentation with those who presented with symptomatology other than that associated with ON, that is, sensory, motor, or brainstem dysfunction. Study inclusion criteria were (1) diagnosis of MS according to the revised McDonald criteria (16), (2) age between 18 and 65 years at the onset of MS symptoms, and (3) performance of cognitive tests within 12 months from MS disease onset and again at follow-up at least 36 months from MS diagnosis. Each patient’s record was indexed by an anonymous code number to ensure confidentiality during statistical analyses. The subjects were grouped according to either the presence of ON or the manifestations of non-ON symptoms at the time of MS presentation. The study was approved by the Sheba IRB Committee. Cognitive Assessment Cognitive assessment was performed by means of the MindStreams computerized cognitive battery (MCCB, NeuroTrax Corp, Bellaire, TX (3)) since 2004. The MCCB has been validated in MS patients and found to have good test–retest reliability and construct validity relative to paperbased tests (17–19). Specifically, MCCB showed discriminant validity for memory, information processing, executive function, and attention and motor skills domains in MS patients (20). The test produces 65 outcome parameters from 10 tests that cover the following cognitive domains: verbal and nonverbal memory, executive function, visual spatial processing, verbal function and attention, information processing speed, and motor skills. A global cognitive score is computed as the average of the index scores. Outcome parameters (accuracy and response time) are normalized for age and education according to stratifications of a normative database of cognitively healthy subjects. All Leshno et al: J Neuro-Ophthalmol 2022; 42: e8-e13 patients treated at the MS center are referred for an annual cognitive assessment as a routine. Statistical Analysis The statistical analysis was performed with the SPSS version 25.0 software. According to the guidelines published in previous studies, a decline of 15 points (i.e., 21SD from normal test score) is considered a cutoff for moderate cognitive impairment (3,20). Therefore, a reduction from the baseline score of a least 15 points at the last follow-up was defined as representing a clinically significant cognitive decline. The rates of clinically significant decline were compared between the 2 study groups in each cognitive domain by means of the chi-square test and Fisher exact tests, as appropriate. Continuous variables with normal distribution were compared using Student t-test, and variables with nonnormal distribution were compared with the Mann– Whitney test. Multivariate regression analyses were applied for variables found to have a significant effect in the univariate analysis, to eliminate the possibility of confounder effects of other variables, such as gender, age at MS onset, duration of follow-up, and years of education. RESULTS Of the entire patient cohort, 170 MS patients met the study inclusion criteria and were included in the analysis (Fig. 1). Forty-six patients (27.1%) had ON involvement at the time of first MS presentation (MS-ON group), and the remaining 124 patients (72.9%) had not (MS-non-ON group). In terms of visual function, half of the subjects in the MS-ON group (23) experienced a minor scotoma with bestcorrected visual acuity (BCVA) of 20/30 or better, 12 (26%) had BCVA between 20/30 and 20/59, 8 had a large scotoma with BCVA between 20/60 to 20/99, 2 (4.3%) had marked decrease in visual fields with BCVA between 20/100 to 20/200, and 1 subject (2.1%) had a BCVA of less than 20/200. Demographic and clinical variables at baseline of all study participants are presented in Table 1. The patients in the MS-ON group were younger by 3.8 years on average at first MS presentation compared with patients in the MS-non-ON group (P = 0.042). There were no significant differences between the groups in gender distribution, years of education, treatment status, and follow-up duration. Cognitive test scores at baseline were also similar in both groups. A significantly higher proportion of patients in the MSON group demonstrated a decline of at least 15 points in their overall cognitive score, compared with the MS-nonON group (3/46, 6.5% vs 0/124, 0%, respectively; P , 0.001). The greatest differences in the prevalence of cognitive decline were observed in the executive function domain (8/46, 17.4% vs 3/124, 2.4%, respectively; P = 0.001) and in the attention domain (4/46, 8.7% vs 2/124, 1.6%, respectively; P = 0.046). A trend toward a higher prevalence e9 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution at baseline or during last follow-up and cognitive assessments were observed. After adjustment for gender, age at MS onset, years of education, and duration of follow-up with a multivariate logistic regression model (Table 2), ON status at first MS presentation remained significant for decline in the executive function (odd ratio, 16.9; 95% confidence interval, 2.9–99.9; P = 0.002) domain and the attention domain (odds ratio, 16.3; 95% confidence interval, 1.7–155.3; P = 0.015). DISCUSSION FIG. 1. Patient cohort exclusion criteria flowchart. of cognitive decline was also observed in the MS-ON group for the information processing speed, motor skills, and verbal function domains, although they did not reach a level of statistical significance (Fig. 2). There was no significant difference in the visual spatial domain between the 2 groups. No significant associations between visual function In the current study, we investigated differences in longterm cognitive performance between MS patients among whom the initial presentation of the disease included optic neuritis and those with presenting signs other than ON. As described previously (5), most of the subjects had no detectable cognitive decline whether ON was initially present. Although no differences were found between these 2 groups in terms of cognitive function at presentation, our analysis showed a significantly higher rate of MS patients who experienced a decrease in overall cognitive function in the MSON group over time. The most affected domains responsible for this decline were executive function and attention. The multivariate regression model showed that these differences were not affected by gender, age at presentation, disease duration, or treatment. Severity of visual function loss TABLE 1. Demographic and clinical variables at baseline† Male:Female Age at MS onset, yrs Years of education, yrs Patients treated, n Time between baseline and last follow-up c ognitive tests, mo Follow-up duration from MS onset, mo Baseline parameters Time from onset to baseline cognitive assessment, mo EDSS Memory Executive function Visual spatial Verbal function Attention Information processing speed Motor skills Problem solving Global cognitive score MS-ON (N = 46) MS-non-ON (N = 124) All (N = 170) P 13:33 30.2 ± 11.2 14.0 ± 2.6 35 (76.1%) 5.9 ± 2.2 44:80 34.0 ± 10.6 14.2 ± 2.6 105 (84.7%) 6.3 ± 2.7 57:113 33.0 ± 10.9 14.1 ± 2.6 140 (82.4%) 6.2 ± 2.6 0.375 0.042* 0.558 0.192 0.445 6.2 ± 2.1 6.6 ± 2.7 6.5 ± 2.6 0.363 3.9 ± 2.8 4.5 ± 3.1 4.4 ± 3.0 0.248 1.3 ± 1.2 97.3 ± 15.1 98.2 ± 14.4 95.4 ± 17.2 96.0 ± 17.8 97.6 ± 14.0 93.1 ± 17.7 96.6 ± 15.6 111.0 ± 11.3 96.2 ± 12.4 1.6 ± 1.2 95.0 ± 14.5 95.7 ± 12.6 97.6 ± 15.8 98.0 ± 16.3 95.6 ± 12.8 92.4 ± 12.5 95.5 ± 13.1 99.4 ± 10.9 95.4 ± 9.7 1.5 ± 1.2 95.6 ± 14.7 96.4 ± 13.1 97.0 ± 16.2 97.4 ± 16.7 95.8 ± 13.2 92.6 ± 14.0 96.5 ± 13.8 101.6 ± 11.4 95.6 ± 10.4 0.166 0.358 0.261 0.432 0.493 0.277 0.802 0.943 0.210 0.695 *P value statistically significant (, 0.05) in bold. † Variable, mean±SD, unless otherwise indicated. EDSS, expanded disability status scale; MS-ON, multiple sclerosis with optic neuritis at presentation; MS-non-ON, multiple sclerosis without optic neuritis at presentation. e10 Leshno et al: J Neuro-Ophthalmol 2022; 42: e8-e13 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Prevalence of significant cognitive decline from baseline (i.e., reduction of 15 or more points) at last follow-up visit among patients with multiple sclerosis with optic neuritis at presentation (MS-ON) and those without optic neuritis at presentation (MS-non-ON). at presentation also did not seem to reflect the change in cognitive test results. Although cognitive impairment is a known sequela of MS, not all MS patients are affected. The prevalence of cognitive impairment among patients with MS has been variously estimated to occur in up to 65% of patients (21,22). The largest study to date originated at the current authors’ center from data collected between 1995 and 2013 from 1,500 patients with MS. The study showed that the rates of cognitive impairment were lower than previously reported with cognitive decline seen in 20% of subjects and sever cognitive impairment evident in only 6% of them. The cognitive impairment was found among their patients only at a disease duration greater than 5 years, suggesting the existence of a potential early therapeutic window (3). Therefore, risk factors and methods for early detection of those at risk to develop cognitive decline are of great importance. Several studies investigated the effect of MS on cognition, although the exact pathophysiologic process remains inconclusive. The lack of any strong association between specific lesion parameters and cognitive abilities (23,24) makes it even more challenging to elucidate this process and suggests that the disease affects cognition through widespread structural and functional consequences (25). Hawellek et al (26) investigated how cognitive pathology due to neurological damage in MS is reflected in changes of structural and functional connectivity. Their study showed that the reduction in cognitive ability was associated with increased functional connectivity. The increase in functional connectivity presumably represents increased rigidity and reduced diversity, which are conceptually similar to the process of dedifferentiation during aging. Levin et al published several studies on anatomical and functional changes in patients with ON. They reported that recovery after an ON episode results in holistic rather than focal changes in cortical function (i.e., affecting both eyes) (27). Their recently published article demonstrated that although the visual pathways did not change anatomically in patients with ON, functional changes were observed with TABLE 2. Association between optic neuritis status at presentation of multiple sclerosis and cognitive decline† Domain Memory Executive function Visual spatial Verbal function Attention Information processing speed Motor skills Problem solving General cognitive score Odds Ratio 3.6 16.9 0.6 2.2 16.3 2.9 2.3 0.705 3.9 95% Confidence Interval 0.6–21.1 2.9–99.9 0.1–5.4 0.4–10.5 1.7–155.3 0.5–15.3 0.6–9.5 0.0–34.1 0.4–34.7 P 0.153 0.002* 0.646 0.345 0.015* 0.217 0.252 0.860 0.225 *P value statistically significant (,0.05) in bold. † Multivariate logistic regression model for each domain variable with adjustment for gender, age at onset, years of education, and duration of follow-up. Leshno et al: J Neuro-Ophthalmol 2022; 42: e8-e13 e11 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution stronger connectivity (28). Given the association between functional connectivity and cognitive function reported by Hawellek et al, the presence of increased functional connectivity in patients with ON (26) might explain the increased rate of cognitive decline in the ON-MS group found in our study. The main limitation of this study lies in its retrospective nature, limiting our analysis to the available data and causing a relatively high exclusion rate as well as possibly also resulting in selection bias. However, the consistency of data collection methods over time, as generated at a national referral center, supports the validity of our findings. In addition, we were unable to determine association between disease course and severity (e.g., imaging findings, disability etc.) and various treatments regimen to cognitive decline. Despite our relatively large sample size, due to the marked heterogeneity of our cohort, such analysis was not possible. Another potential limitation is the age difference between the groups: patients in the MS-ON group were 3.8 years younger on average than those in the MS-non-ON group. Nevertheless, because the group with the younger patients fared cognitively worse over the follow-up than the older non-ON group, we conclude that this age difference strengthens our findings. We conclude that, to the best of our knowledge, this is the first study to evaluate the effect of ON at the time of first presentation of MS on cognitive changes in patients with MS. Our results suggest that there is an association between cognitive decline and ON, with the patients in the MS-non-ON group demonstrating a significantly greater decline in the executive function and attention domains. Future prospective studies are warranted for better understanding of this association. Interventional studies should explore the potential benefit of early treatment for the prevention of cognitive decline. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. Leshno, O. Sagiv, A. Achiron, and R. Huna-Baron; b. Acquisition of data: A. Leshno, O. Sagiv, R. Aloni, A. Achiron, and R. Huna-Baron; c. Analysis and interpretation of data: A. Leshno, O. Sagiv, R. Aloni, A. Skaat, A. Achiron, and R. Huna-Baron. Category 2: a. Drafting the manuscript: A. Leshno, O. Sagiv, A. Achiron, and R. Huna-Baron; b. Revising it for intellectual content: A. Leshno, O. Sagiv, Alon Skaat, A. Achiron, and R. Huna-Baron. Category 3: a. Final approval of the completed manuscript: A. Leshno, O. Sagiv, R. Aloni, A. Skaat, A. Achiron, and R. Huna-Baron. REFERENCES 1. Schulz D, Kopp B, Kunkel A, Faiss JH. Cognition in the early stage of multiple sclerosis. J Neurol. 2006;253:1002–1010. 2. Kawahara Y, Ikeda M, Deguchi K, Hishikawa N, Kono S, Omote Y, Matsuzono K, Yamashita T, Ikeda Y, Abe K. Cognitive and affective assessments of multiple sclerosis (MS) and neuromyelitis optica (NMO) patients utilizing computerized e12 16. 17. 18. 19. 20. 21. touch panel-type screening tests. Intern Med. 2014;53:2281– 2290. Achiron A, Chapman J, Magalashvili D, Dolev M, Lavie M, Bercovich E, Polliack M, Doniger GM, Stern Y, Khilkevich O, Menascu S, Hararai G, Gurevich M, Barak Y. Modeling of cognitive impairment by disease duration in multiple sclerosis: a cross-sectional study. PLoS One. 2013;8:1–10. Glanz BI, Healy BC, Hviid LE, Chitnis T, Weiner HL. Cognitive deterioration in patients with early multiple sclerosis: a 5-year study. J Neurol Neurosurg Psychiatry. 2012;83:38–43. Achiron A, Barak Y. Cognitive changes in early multiple sclerosis: a call for a common framework. J Neurol Sci. 2006;245:47–55. Fischer JS, Priore RL, Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, Goodkin DE, Granger CV, Simon JH, Grafman JH, Lezak MD, O’Reilly Hovey KM, Perkins KK, Barilla-Clark D, Schacter M, Shucard DW, Davidson AL, Wende KE, Bourdette DN, Kooijmans-Coutinho MF. Neuropsychological effects of interferon b-1a in relapsing multiple sclerosis. Ann Neurol. 2000;48:885–892. Barak AYA. Effect of interferon-beta-1b on cognitive functions in multiple sclerosis. Eur Neurol. 2002;47:11–14. Krupp LB, Christodoulou C, Melville P, MacAllister WS, Elkins LE. Donepezil improved memory in multiple sclerosis in a randomized clinical trial. Neurology. 2004;63:1579–1585. Jønsson A, Korfitzen EM, Heltberg A, Ravnborg MH, ByskovOttosen E. Effects of neuropsychological treatment in patients with multiple sclerosis. Acta Neurol Scand. 1993;88:394–400. Shams PN, Plant GT. Optic neuritis: a review. Int MS J. 2009;16:82–89. Zeid NA, Bhatti MT. Acute inflammatory demyelinating optic neuritis: evidence-based visual and neurological considerations. Neurologist. 2008;14:207–223. The Optic Neuritis Study Group. The clinical profile of optic neuritis: experience of the optic neuritis treatment trial. Arch Ophthalmol. 1991;109:1673–1678. Beck RW, Cleary PA, Backlund J yu C. The course of visual recovery after optic neuritis: experience of the optic neuritis treatment trial. Ophthalmology. 1994;101:1771–1778. Brodsky M, Nazarian S, Orengo-Nania S, Hutton GJ, Buckley EG, Massey EW, Bhatti MT, Greer M, Goodwin J, Wall M, Savino PJ, Leist T, Miller NR, Irani D, Trobe JD, Cornblath W, Kaufman DI, Eggenberger E, Kupersmith MJ, Shults WT, McAllister L, Hamilton S, Beck RW, Dontchev M, Gal RL, Kollman C, Keltner JL, Smith CH. Multiple sclerosis risk after optic neuritis: final optic neuritis treatment trial follow-up. Arch Neurol. 2008;65:727–732. Nilsson PC, Rorsman I, Larsson EM, Norrving B, SandbergWollheim M. Cognitive dysfunction 24-31 years after isolated optic neuritis. Mult Scler. 2008;14:913–918. Montalban X. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. J Neurol. 2012;259:S8. Dwolatzky T, Whitehead V, Doniger GM, Simon ES, Schweiger A, Jaffe D, Chertkow H. Validity of a novel computerized cognitive battery for mild cognitive impairment. BMC Geriatr. 2003;3:1–12. Schweiger A, Doniger GM, Dwolatzky T, Jaffe D, Simon ES. Reliability of a novel computerized neuropsychological battery for mild cognitive impairment. Neuropsychologica. 2003;1:407–413. Abramovitch A, Dar R, Hermesh H, Schweiger A. Comparative neuropsychology of adult obsessive-compulsive disorder and attention deficit/hyperactivity disorder: implications for a novel executive overload model of OCD. J Neuropsychol. 2012;6:161–191. Achiron A, Doniger GM, Harel Y, Appleboim-Gavish N, Lavie M, Simon ES. Prolonged response times characterize cognitive performance in multiple sclerosis. Eur J Neurol. 2007;14:1102–1108. Medaer R, De Smedt L, Swerts M, Geutjens J. Use of rating scales to reflect cognitive and mental functioning in multiple sclerosis. Acta Neurol Scand. 1984;70:65–67. Leshno et al: J Neuro-Ophthalmol 2022; 42: e8-e13 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 22. Staples BYD, Lincoln NB. Intellectual Impairment in Multiple Sclerosis and its Relation to Functional Abilities, 1979:153– 160. 23. Filippi M, Rocca MA, Benedict RHB, DeLuca J, Geurts JJG, Rombouts SARB, Ron M, Comi G. The contribution of MRI in assessing cognitive impairment in multiple sclerosiss. Neurology. 2010;75:2121–2128. 24. Chiaravalloti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurol. 2008;7:1139–1151. 25. Filippi M, Rocca MA. MRI evidence for multiple sclerosis as a diffuse disease of the central nervous system. J Neurol. 2005;252(suppl 5). doi:10.1007/s00415-005-5004-5. Leshno et al: J Neuro-Ophthalmol 2022; 42: e8-e13 26. Hawellek DJ, Hipp JF, Lewis CM, Corbetta M, Engel AK. Increased functional connectivity indicated the severity of cognitive impairment in multiple sclerosis. Proc Natl Acad Sci U S A. 2011;108:19066–19071. 27. Benoliel T, Raz N, Ben-Hur T, Levin N. Cortical functional modifications following optic neuritis. Mult Scler. 2017;23:220–227. 28. Backner Y, Kuchling J, Massarwa S, Oberwahrenbrock T, Finke C, Bellmann-Strobl J, Ruprecht K, Brandt AU, Zimmermann H, Raz N, Paul F, Levin N. Anatomical wiring and functional networking changes in the visual system following optic neuritis. JAMA Neurol. 2018;75:287–295. e13 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.