Doc Ophthalmol (2015) 130:25–30 DOI 10.1007/s10633-014-9466-6
ORIGINAL RESEARCH ARTICLE
Diagnostic value of visual evoked potentials for clinical diagnosis of multiple sclerosis Niphon Chirapapaisan • Sawarin Laotaweerungsawat • Wanicha Chuenkongkaew • Patthanee Samsen • Ngamkae Ruangvaravate Atiporn Thuangtong • Nacha Chanvarapha
•
Received: 9 May 2014 / Accepted: 15 October 2014 / Published online: 21 October 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Prolonged latency of visual evoked potentials (VEP) has been used to identify clinically silent lesions in multiple sclerosis (MS) suspects. The objective of this study was to determine the reliability of VEP to predict the development of MS in MS suspects. Methods Retrospective hospital records of MS suspects were evaluated. VEP was analyzed together with subsequent diagnostic confirmation of MS by McDonald diagnostic criteria for MS-2005. Results MS developed in 12 of 35 patients (34 %) and 23 (66 %) failed to exhibit diagnostic characteristics. P100 latencies and interocular latency differences were longer in clinically definite multiple sclerosis (CDMS) than non-CDMS patients (p = 0.002, 0.001, respectively). All patients in the subsequent MS group had P100 latencies longer than102 ms, a mean of our MS-free subjects thus providing 100 % of sensitivity. No patient developed MS with a P100 latency \102 ms. Brain MRI lesions associated significantly with developing CDMS (p = 0.001). Predictability of developing CDMS was highest when criteria for P100 latency, interocular N. Chirapapaisan (&) S. Laotaweerungsawat W. Chuenkongkaew P. Samsen N. Ruangvaravate A. Thuangtong N. Chanvarapha Department of Ophthalmology, Faculty of Medicine, Siriraj Hospital, Mahidol University, 2 Prannok, Bangkoknoi, Bangkok 10700, Thailand e-mail: [email protected]
latency difference, and brain MRI lesions were combined. Conclusion MS suspects with a P100 latency longer than mean of MS-free subjects are more likely to develop MS than those with lower values. VEP latency combined with MRI could improve the accuracy of MS prediction. Keywords Visual evoked potentials Optic neuritis Multiple sclerosis MRI Demyelination
Introduction Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, and may exhibit various clinical presentations. Diagnosis is based on McDonald criteria for MS-2005, grouping patients into three types: clinically definite multiple sclerosis (CDMS), suspected MS, and non-MS [1]. Early therapy is effective in prevention and delay of long-term disability in MS patients. Identification of CDMS from a single undiagnosed episode of neurological disease is insufficient and requires diagnostic support. At present, magnetic resonance imaging (MRI) is the most sensitive paraclinical test to predict CDMS [2–5]. Visual evoked potentials (VEP) is useful and provides information on the integrity of the visual system and optic neuritis. Prolonged latency of VEP has been used to identify clinically silent lesions in MS
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suspects [6–8]. Previous studies showed a significant direct association between abnormal VEP and risk of developing CDMS [6–8]. Confirmed reliability of VEP to predict MS would be helpful for early detection of the disease. The objective of this study was to investigate the parameters of VEP useful in predicting MS and to compare the early predictive value of VEP with MRI.
Patients and methods Patients suspected of having MS based on clinical manifestations of unifocal and monophasic disease were referred to the Department of Ophthalmology by neurologists. VEP was measured on all patients for evidence of optic neuritis, a diagnostic for MS. Hospital records of new patients suspected of having MS from October 2003 to December 2007 were retrospectively reviewed at the Department of Ophthalmology. The study was approved by the Institutional Review Board of Siriraj Hospital. Patients suspected of MS but without a prior optic neuritis episode, no clinical symptoms, or signs of optic neuritis were included in this study. Patients were followed until their condition was clinically diagnosed as MS or did not develop CDMS for at least another 48 months. Clinical follow-up data were obtained by reviewing patient charts which had been recorded continuously by the referring neurologists. Patient data included gender, age, ophthalmologic examination (both slit lamp and dilated fundus exams), a color vision test, VEP data, brain and spinal cord MRI data, and the presence of CDMS during the follow-up period. The diagnosis of all patients was made by the referring neurologists based on McDonald diagnostic criteria for MS-2005. Patients with previous optic nerve diseases, cortical infarction, glaucoma, or nonrecordable VEP were excluded. VEP of each patient was recorded with a Neuronica Vectra VE8 machine in a dark room. Some patients were provided the full correction of refraction if necessary. VEP was elicited by 2.1 Hz pattern reversal of high contrast black and white checkerboard; P100 latencies and amplitudes were measured. Previously, Siriraj laboratory determined a normal value for P100 latency of 102.0 ± 6.98 ms (mean ± SD) from 41 subjects free from MS and 11–80 years of age (Fig. 1). Since the assumption of prolonged P100 latency was set up to
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Fig. 1 Pattern reversal VEP responses of a MS-free subject demonstrated the normal P100 latency. The top and bottom trace were recorded from right and left eyes, respectively. Intra/ intersession of intraclass correlation coefficients of P100 latency were 0.86/0.84
mean ?2.5 SD, P100 latencies of C120 ms were regarded as prolonged latency. In this study, we selected the longer P100 latency of either eye from each patient to calculate base P100 latencies and amplitudes. Relative VEP interocular latencies and amplitudes were based on difference between P100 values of each eye. VEP patterns of all suspected MS patients (P100 latency, amplitude and interocular difference of both latency and amplitude) were analyzed along with the occurrence of subsequent CDMS using McDonald diagnostic criteria for MS-2005. Statistical analysis Statistical analyses were performed with SPSS software (version 11.5, SPSS Inc. Chicago, IL, USA). The Snellen best-corrected visual acuity (BCVA) was converted into logarithm of minimum angle of resolution (logMAR) unit for analysis. Means of parametric data were compared by a two-sample t test. Chisquare and the Fisher exact tests were applied for categorical data. A receiver operating characteristic curve (ROC curve) was used to define the threshold of P100 latency. Significance was set at p = 0.05 for all tests. Data were analyzed also for sensitivity—the probability of MS suspects developing MS with positive result of such tests, specificity—the probability of MS suspects developing MS with negative test
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27
result, positive predictive value (PPV)— the probability of MS suspects with positive test result developing MS, and negative predictive value (NPV)— the probability of MS suspects with negative test result not developing MS.
Results This study consisted of 35 MS suspects of whom 12 (34 %) developed CDMS (subsequent CDMS) within 2 years of the initial examination and 23 (66 %) did not and were classified as non-MS. None of subsequent MS was detected with optic neuritis; therefore, VEP was not indirectly used as a tool for final diagnosis of MS. Demographic characteristics, age, sex, and BCVA did not differ significantly between the two groups (Table 1). All patients in the subsequent CDMS group developed CDMS within 10.0 ± 6.32 (±SD) months (range 1–23 months) and were followed for 31.4 ± 7.82 months (range 24–40 months).
Non-MS patients were followed for a mean of 54.0 ± 6.37 months (range 48–71 months). P100 latencies in patients with subsequent CDMS were significantly longer than those in non-MS patients (p = 0.002), but P100 amplitude did not differ significantly (p = 0.24; Table 2). Seven patients had prolonged P100 latency (C120 ms; Fig. 2), and six patients (85.7 %) of these were finally diagnosed CDMS (Table 3). All patients in the subsequent MS group had P100 latencies longer than mean P100 latency. Six patients of these had latency between 103 and 120 ms. In the non-MS group, 12 patients had P100 latencies longer than 102 ms, while 11 patients had P100 latencies B102 ms. Only one patient in this group had prolonged P100 latency (C120 ms). There are not any differences of P100
Table 1 Demographics of patients with non- and subsequent multiple sclerosis (MS) Characteristic
Subsequent MS
Non-MS
P value
Number of patients (%)
12 (34 %)
23 (66 %)
–
Age (years)
34.0 ± 14.2 (16–52)
38.4 ± 15.5 (21–58)
0.42
3 (25 %)
6 (26.1 %)
1.00
9 (75 %) 0.10 ± 0.12 (0–0.3)
17 (73.9 %) 0.09 ± 0.12 (0–0.45)
0.98
Sex Male Female BCVA (log MAR)
BCVA best-corrected visual acuity
Fig. 2 Pattern reversal VEP responses of a subsequent CDMS demonstrated the prolonged P100 latency. The top and bottom trace were recorded from right and left eyes, respectively. Intra/ intersession of intraclass correlation coefficients of P100 latency were 0.86/0.84
Table 2 The P100 latency, amplitude and their interocular differences of visual evoked potentials in patients with non- and subsequent multiple sclerosis (MS) VEP
Subsequent MS
Non-MS
p value
Mean difference (95 % CI)
Latency (ms)
119.08 ± 15.72 (103–141)
103.48 ± 9.23 (87–130)
0.002*
15.60 (5.10, 26.10)
Amplitude (lV) Interocular latency difference (ms) Interocular amplitude difference (lV)
8.33 ± 2.74 (5.11–13.48)
9.83 ± 3.83 (4.35–13.80)
6.9792 ± 4.9537 (0–15.5) 0.9286 ± 0.8255 (0.19–2.80)
2.6703 ± 1.835 (0–7.0) 0.9125 ± 0.7309 (0.05–2.50)
0.24
1.49 (-4.03, 1.05)
0.001* 0.953
4.31 (1.97, 6.65) 0.02 (-0.54, 0.57)
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Table 3 The P100 latency of visual evoked potentials (VEP) in patients with non- and subsequent multiple sclerosis (MS) P100 latency of VEP (ms)
Non-MS Subsequent MS
B102
103–120
C120
11
11
1
0
6
6
latency from 103 to 120 ms in both non-MS and subsequent MS. The calculated predictive values of CDMS are shown in Table 4. P100 latency C120 provided low sensitivity (50 %) but high specificity (95.7 %) while P100 latency [102 provided high sensitivity (100 %) but low specificity (47.8 %). Interocular latency differences were significantly higher in patients with subsequent CDMS than nonMS (p = 0.001). In contrast, interocular amplitude differences did not differ significantly between the two groups (p = 0.953, Table 2). An interocular latency difference of 3.5 ms (0.5 of our normal population SD) predicted the majority of subsequent CDMS patients (Table 4). The majority of patients (83 %) with subsequent MS had at least one MS-like brain lesion, while those with non-MS had lesions in only 4 of 21 (19 %) patients. These three of four patients had been followed-up over 5 years (61, 64, and 71 months), while one patient was diagnosed with systemic lupus
erythematosus in 4 years. The presence of MRIdetected brain lesions was significantly associated with developing CDMS (p = 0.001) and hence highly predictive (Table 4). The presence of spinal lesions was not significantly associated with developing CDMS (p = 0.741) with 58 % of patients (7 of 12) with subsequent MS and 52 % with non-MS (11 of 21) exhibiting spinal lesions. Predictability of MS from P100 latency values [102 ms performed best with 100 % sensitivity and NPV while the specificity and PPV were not high; however, a brain MRI lesion provided generally high predictive values (Table 4). The combination of a P100 latency[102 ms and an interocular latency difference [3.5 ms associated significantly with the eventual development of CDMS (p = 0.001; Table 5). Greater significance was found by combining a P100 latency [102 ms with the presence of brain MRI lesions (p \ 0.001). Interestingly, combining P100 latency, interocular latency difference, and brain MRI lesion frequency was equally associated with subsequent CDMS (p \ 0.001) and demonstrated high specificity and PPV (100 %; Table 5). However, the results of the average P100 latencies were not different from those of the longer P100 latencies, and the predictive values were also not different even when combined with interocular latency difference and brain MRI lesion (data not shown).
Table 4 Predictive values of paraclinical tests in diagnosed clinically definite multiple sclerosis (CDMS) Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
p value
P 100 latency C120 ms
50
95.7
85.7
78
0.001
P 100 latency [102 ms
100
47.8
50
100
0.001
Interocular latency difference [3.5 ms
75
52.5
45
80
0.001
brain MRI C1 lesion
83.3
81
71.4
89.5
0.001
PPV positive predictive value and NPV negative predictive value
Table 5 Predictive values of combined paraclinical tests in diagnosed clinically definite multiple sclerosis (CDMS) Combined tests
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
p value
1?2
75
78.3
64.3
85.7
p \ 0.001
1?3
83.3
95.7
90.9
91.7
p \ 0.001
1?2?3
58.3
100
100
82.1
p \ 0.001
PPV positive predictive value and NPV negative predictive value (1 = P100 latency [102 ms, 2 = Interocular latency [3.5 ms, 3 = brain MRI C1 lesion)
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Discussion In previous studies, paraclinical tests for diagnosis of MS consisted of MRI, evoked potentials, and CSF oligoclonal banding and showed that an abnormal brain MRI was strongly suggestive for MS [2–5]. Among multimodal evoked potentials, VEP has the greatest predictive value, which demonstrated clinically that silent lesions occur more frequently than somatosensory and auditory EPs as reported in numerous studies [3–7]. Despite previous reports that multifocal VEP is better performance than conventional VEP in diagnosed optic neuritis, but multifocal VEP takes a long time and less available [9, 10]. Conventional VEP is usually more sensitive to optic nerve demyelination than routine MRI but is not sensitive in the diagnosis of CDMS [3, 11]. An association between abnormal VEP and an increased risk of CDMS has been established [7, 8]. Prolonged latency of VEP was determined when the test value was longer than 2.5–3 SD of the norm, or interocular latency difference was more than 6–7 ms (83 %) [3, 11, 12]. In MS suspects with no evidence of optic neuritis, an abnormal latency of VEP could unveil some demyelination of the optic nerve and provide some suggestion of MS development. However, the sensitivity and specificity of VEP in anticipation of MS development varied between 25–83 and 63–87.8 %, respectively [8]. Difference between these studies may be due to variations in patient populations, diagnostic criteria, and VEP techniques and criteria for abnormalities. The present study revealed a direct association between VEP latency and development of MS in MS suspects and confirmed that a prolonged latency can identify a clinically silent lesion of the optic nerve [2]. Furthermore, some studies also showed a decease in VEP amplitude in MS patients without optic nerve diseases [13] in contrast to the results of the present study. Since the assumption of prolonged P100 latency was set up to mean ?2.5 SD, P100 latencies of C120 ms were regarded as prolonged latency. At this threshold (mean ?2.5SD), the present study found seven patients qualified as prolonged P100 latency with 6 (85.7 %) finally diagnosed CDMS. The calculated predictive value of CDMS resulted in a sensitivity of 50 %, specificity of 95.7 %, PPV of 85.7 %, and NPV of 78 %. This outcome was similar to previous studies that found the incidence of CDMS
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detection was rather low [11, 14]. As we knew, early diagnosis and early treatment of CDMS would be decreased long-term disability. If we used mean P100 latency for screening CDMS, the results allowed high sensitivity and NPV (100 %) but only low specificity and PPV (47.8 and 50 %) to predict the development of CDMS. It implied that MS suspects with P100 latency ([102 ms) would have a chance to develop MS of 50 %, and patients with latency \102 ms will not develop MS. There are not any differences of P100 latency from 103 to 120 ms in both non-MS and subsequent MS. In this study, VEP was not indirectly used as a tool for final diagnosis of MS. The diagnosis of MS was made by neurologists based on McDonald diagnostic criteria for MS-2005. For only the interocular latency difference, the predictive value was not suggestive. And for the brain MRI lesion, though the sensitivity was not the best (83.3 %), the PPV and specificity were rather good (71.4 and 81 %). It was still signified as being worth as in other previous reports. We have randomized combining the paraclinical tests together and the result turned out best when all three paraclinical tests (P100 latency more than 102 ms, interocular latency difference more than 3.5 ms, at least 1MS-like lesion on brain MRI) were met. The specificity and PPV reached to 100 %. An early diagnosis of MS is important as early treatment could reduce long-term disability. From the present study, only patients with P100 latency [102 ms developed CDMS. Thus, we propose to use mean P100 latency as the primary screening test for MS. We did not denote to use over mean P100 latency as prolonged latency for diagnosis CDMS. This high sensitivity test would increase the probability of identifying patients that could develop CDMS. However, mean P100 latency has a shortcoming in that it provides a low specificity. Therefore, we recommend merging the other two paraclinical tests (interocular latency difference and MS-like lesion on brain MRI) to improve the accuracy of CDMS prediction in MS suspects. In this study, the mean BCVA (log MAR) in both groups were about 0.10 (6/7.5). Most patients’ visual acuity was 6/6–6/7.5. Only one patient in subsequent MS was 6/12 and one in non-MS was 6/18. The cause of mild reduced visual acuity was mild cataract. However, these mild cataracts were not affecting the VEP results [15]. Every patient with subsequent
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CDMS had developed CDMS within 24 months while our follow-up time of non-MS was assigned C48 months. We have presumed that the other nonMS would not eventually turn to CDMS. This study might be limited by a small number of patients and the retrospective, possibly dated, McDonald diagnostic criteria for MS-2005. The predictive validity of VEP in MS suspects should be further confirmed in prospective studies and with multivariate analysis; however, in prospective study, the probability of patients having MS would be greatly reduced, thus reducing PPV, NPV, and sensitivity. The cost-effectiveness between VEP and the MRI then would be evaluated. Moreover, the threshold of P100 latency might then be verified for the best predictive value.
Conclusion The P100 latency of VEP is beneficial for predicting the development of MS in potential MS patients. MS Suspects with P100 latency longer than mean of MSfree subjects are more likely to develop MS. In the early stage of MS, VEP latency combined with MRI is recommended to the accuracy of MS prediction. Acknowledgments We would like to thank Ms. Julaporn Pooliam, MS.C for the statistical calculations ,and Dr. William Beamish in reviewing of this manuscript. Conflict of interest The authors declare that there is no conflict of interest. Ethical standard Hospital.
The Institutional Review Board of Siriraj
References 1. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O’Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS (2005) Diagnostic criteria for multiple sclerosis: 2005 revisions to the ‘‘McDonald Criteria’’. Ann Neurol 58(6):840–846. doi:10.1002/ana.20703 2. Beer S, Rosler KM, Hess CW (1995) Diagnostic value of paraclinical tests in multiple sclerosis: relative sensitivities and specificities for reclassification according to the poser committee criteria. J Neurol Neurosurg Psychiatry 59(2): 152–159
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3. Filippini G, Comi GC, Cosi V, Bevilacqua L, Ferrarini M, Martinelli V, Bergamaschi R, Filippi M, Citterio A, D’Incerti L et al (1994) Sensitivities and predictive values of paraclinical tests for diagnosing multiple sclerosis. J Neurol 241(3):132–137 4. Lee KH, Hashimoto SA, Hooge JP, Kastrukoff LF, Oger JJ, Li DK, Paty DW (1991) Magnetic resonance imaging of the head in the diagnosis of multiple sclerosis: a prospective 2-year follow-up with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT. Neurology 41(5):657–660 5. Rot U, Mesec A (2006) Clinical, MRI, CSF and electrophysiological findings in different stages of multiple sclerosis. Clin Neurol Neurosurg 108(3):271–274. doi:10.1016/ j.clineuro.2005.11.021 6. Gronseth GS, Ashman EJ (2000) Practice parameter: the usefulness of evoked potentials in identifying clinically silent lesions in patients with suspected multiple sclerosis (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology. Neurology 54(9):1720–1725 7. Hume AL, Waxman SG (1988) Evoked potentials in suspected multiple sclerosis: diagnostic value and prediction of clinical course. J Neurol Sci 83(2–3):191–210 8. Matthews WB, Wattam-Bell JR, Pountney E (1982) Evoked potentials in the diagnosis of multiple sclerosis: a follow up study. J Neurol Neurosurg Psychiatry 45(4):303–307 9. Grover LK, Hood DC, Ghadiali Q, Grippo TM, Wenick AS, Greenstein VC, Behrens MM, Odel JG (2008) A comparison of multifocal and conventional visual evoked potential techniques in patients with optic neuritis/multiple sclerosis. Doc ophthalmol 117(2):121–128. doi:10.1007/s10633-0079112-7 10. Klistorner A, Fraser C, Garrick R, Graham S, Arvind H (2008) Correlation between full-field and multifocal VEPs in optic neuritis. Doc ophthalmol 116(1):19–27. doi:10. 1007/s10633-007-9072-y 11. Matthews WB, Small DG, Small M, Pountney E (1977) Pattern reversal evoked visual potential in the diagnosis of multiple sclerosis. J Neurol Neurosurg Psychiatry 40(10):1009–1014 12. Paty DW, Oger JJ, Kastrukoff LF, Hashimoto SA, Hooge JP, Eisen AA, Eisen KA, Purves SJ, Low MD, Brandejs V et al (1988) MRI in the diagnosis of MS: a prospective study with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT. Neurology 38(2):180–185 13. Diem R, Tschirne A, Bahr M (2003) Decreased amplitudes in multiple sclerosis patients with normal visual acuity: a VEP study. J clin neurosci 10(1):67–70 14. Mizota A, Asaumi N, Takasoh M, Adachi-Usami E (2007) Pattern visual evoked potentials in Japanese patients with multiple sclerosis without history of visual pathway involvement. Doc ophthalmol 115(2):105–109. doi:10. 1007/s10633-007-9062-0 15. Adachi-Usami E (2006) Aging and pattern visual evoked cortical potential. In: Heckenlively JR, Arden GB (eds) Principles and practice of clinical electrophysiology of vision, 2nd edn. MIT press, London, pp 361–367
ORIGINAL RESEARCH ARTICLE
Diagnostic value of visual evoked potentials for clinical diagnosis of multiple sclerosis Niphon Chirapapaisan • Sawarin Laotaweerungsawat • Wanicha Chuenkongkaew • Patthanee Samsen • Ngamkae Ruangvaravate Atiporn Thuangtong • Nacha Chanvarapha
•
Received: 9 May 2014 / Accepted: 15 October 2014 / Published online: 21 October 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Prolonged latency of visual evoked potentials (VEP) has been used to identify clinically silent lesions in multiple sclerosis (MS) suspects. The objective of this study was to determine the reliability of VEP to predict the development of MS in MS suspects. Methods Retrospective hospital records of MS suspects were evaluated. VEP was analyzed together with subsequent diagnostic confirmation of MS by McDonald diagnostic criteria for MS-2005. Results MS developed in 12 of 35 patients (34 %) and 23 (66 %) failed to exhibit diagnostic characteristics. P100 latencies and interocular latency differences were longer in clinically definite multiple sclerosis (CDMS) than non-CDMS patients (p = 0.002, 0.001, respectively). All patients in the subsequent MS group had P100 latencies longer than102 ms, a mean of our MS-free subjects thus providing 100 % of sensitivity. No patient developed MS with a P100 latency \102 ms. Brain MRI lesions associated significantly with developing CDMS (p = 0.001). Predictability of developing CDMS was highest when criteria for P100 latency, interocular N. Chirapapaisan (&) S. Laotaweerungsawat W. Chuenkongkaew P. Samsen N. Ruangvaravate A. Thuangtong N. Chanvarapha Department of Ophthalmology, Faculty of Medicine, Siriraj Hospital, Mahidol University, 2 Prannok, Bangkoknoi, Bangkok 10700, Thailand e-mail: [email protected]
latency difference, and brain MRI lesions were combined. Conclusion MS suspects with a P100 latency longer than mean of MS-free subjects are more likely to develop MS than those with lower values. VEP latency combined with MRI could improve the accuracy of MS prediction. Keywords Visual evoked potentials Optic neuritis Multiple sclerosis MRI Demyelination
Introduction Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, and may exhibit various clinical presentations. Diagnosis is based on McDonald criteria for MS-2005, grouping patients into three types: clinically definite multiple sclerosis (CDMS), suspected MS, and non-MS [1]. Early therapy is effective in prevention and delay of long-term disability in MS patients. Identification of CDMS from a single undiagnosed episode of neurological disease is insufficient and requires diagnostic support. At present, magnetic resonance imaging (MRI) is the most sensitive paraclinical test to predict CDMS [2–5]. Visual evoked potentials (VEP) is useful and provides information on the integrity of the visual system and optic neuritis. Prolonged latency of VEP has been used to identify clinically silent lesions in MS
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suspects [6–8]. Previous studies showed a significant direct association between abnormal VEP and risk of developing CDMS [6–8]. Confirmed reliability of VEP to predict MS would be helpful for early detection of the disease. The objective of this study was to investigate the parameters of VEP useful in predicting MS and to compare the early predictive value of VEP with MRI.
Patients and methods Patients suspected of having MS based on clinical manifestations of unifocal and monophasic disease were referred to the Department of Ophthalmology by neurologists. VEP was measured on all patients for evidence of optic neuritis, a diagnostic for MS. Hospital records of new patients suspected of having MS from October 2003 to December 2007 were retrospectively reviewed at the Department of Ophthalmology. The study was approved by the Institutional Review Board of Siriraj Hospital. Patients suspected of MS but without a prior optic neuritis episode, no clinical symptoms, or signs of optic neuritis were included in this study. Patients were followed until their condition was clinically diagnosed as MS or did not develop CDMS for at least another 48 months. Clinical follow-up data were obtained by reviewing patient charts which had been recorded continuously by the referring neurologists. Patient data included gender, age, ophthalmologic examination (both slit lamp and dilated fundus exams), a color vision test, VEP data, brain and spinal cord MRI data, and the presence of CDMS during the follow-up period. The diagnosis of all patients was made by the referring neurologists based on McDonald diagnostic criteria for MS-2005. Patients with previous optic nerve diseases, cortical infarction, glaucoma, or nonrecordable VEP were excluded. VEP of each patient was recorded with a Neuronica Vectra VE8 machine in a dark room. Some patients were provided the full correction of refraction if necessary. VEP was elicited by 2.1 Hz pattern reversal of high contrast black and white checkerboard; P100 latencies and amplitudes were measured. Previously, Siriraj laboratory determined a normal value for P100 latency of 102.0 ± 6.98 ms (mean ± SD) from 41 subjects free from MS and 11–80 years of age (Fig. 1). Since the assumption of prolonged P100 latency was set up to
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Fig. 1 Pattern reversal VEP responses of a MS-free subject demonstrated the normal P100 latency. The top and bottom trace were recorded from right and left eyes, respectively. Intra/ intersession of intraclass correlation coefficients of P100 latency were 0.86/0.84
mean ?2.5 SD, P100 latencies of C120 ms were regarded as prolonged latency. In this study, we selected the longer P100 latency of either eye from each patient to calculate base P100 latencies and amplitudes. Relative VEP interocular latencies and amplitudes were based on difference between P100 values of each eye. VEP patterns of all suspected MS patients (P100 latency, amplitude and interocular difference of both latency and amplitude) were analyzed along with the occurrence of subsequent CDMS using McDonald diagnostic criteria for MS-2005. Statistical analysis Statistical analyses were performed with SPSS software (version 11.5, SPSS Inc. Chicago, IL, USA). The Snellen best-corrected visual acuity (BCVA) was converted into logarithm of minimum angle of resolution (logMAR) unit for analysis. Means of parametric data were compared by a two-sample t test. Chisquare and the Fisher exact tests were applied for categorical data. A receiver operating characteristic curve (ROC curve) was used to define the threshold of P100 latency. Significance was set at p = 0.05 for all tests. Data were analyzed also for sensitivity—the probability of MS suspects developing MS with positive result of such tests, specificity—the probability of MS suspects developing MS with negative test
Doc Ophthalmol (2015) 130:25–30
27
result, positive predictive value (PPV)— the probability of MS suspects with positive test result developing MS, and negative predictive value (NPV)— the probability of MS suspects with negative test result not developing MS.
Results This study consisted of 35 MS suspects of whom 12 (34 %) developed CDMS (subsequent CDMS) within 2 years of the initial examination and 23 (66 %) did not and were classified as non-MS. None of subsequent MS was detected with optic neuritis; therefore, VEP was not indirectly used as a tool for final diagnosis of MS. Demographic characteristics, age, sex, and BCVA did not differ significantly between the two groups (Table 1). All patients in the subsequent CDMS group developed CDMS within 10.0 ± 6.32 (±SD) months (range 1–23 months) and were followed for 31.4 ± 7.82 months (range 24–40 months).
Non-MS patients were followed for a mean of 54.0 ± 6.37 months (range 48–71 months). P100 latencies in patients with subsequent CDMS were significantly longer than those in non-MS patients (p = 0.002), but P100 amplitude did not differ significantly (p = 0.24; Table 2). Seven patients had prolonged P100 latency (C120 ms; Fig. 2), and six patients (85.7 %) of these were finally diagnosed CDMS (Table 3). All patients in the subsequent MS group had P100 latencies longer than mean P100 latency. Six patients of these had latency between 103 and 120 ms. In the non-MS group, 12 patients had P100 latencies longer than 102 ms, while 11 patients had P100 latencies B102 ms. Only one patient in this group had prolonged P100 latency (C120 ms). There are not any differences of P100
Table 1 Demographics of patients with non- and subsequent multiple sclerosis (MS) Characteristic
Subsequent MS
Non-MS
P value
Number of patients (%)
12 (34 %)
23 (66 %)
–
Age (years)
34.0 ± 14.2 (16–52)
38.4 ± 15.5 (21–58)
0.42
3 (25 %)
6 (26.1 %)
1.00
9 (75 %) 0.10 ± 0.12 (0–0.3)
17 (73.9 %) 0.09 ± 0.12 (0–0.45)
0.98
Sex Male Female BCVA (log MAR)
BCVA best-corrected visual acuity
Fig. 2 Pattern reversal VEP responses of a subsequent CDMS demonstrated the prolonged P100 latency. The top and bottom trace were recorded from right and left eyes, respectively. Intra/ intersession of intraclass correlation coefficients of P100 latency were 0.86/0.84
Table 2 The P100 latency, amplitude and their interocular differences of visual evoked potentials in patients with non- and subsequent multiple sclerosis (MS) VEP
Subsequent MS
Non-MS
p value
Mean difference (95 % CI)
Latency (ms)
119.08 ± 15.72 (103–141)
103.48 ± 9.23 (87–130)
0.002*
15.60 (5.10, 26.10)
Amplitude (lV) Interocular latency difference (ms) Interocular amplitude difference (lV)
8.33 ± 2.74 (5.11–13.48)
9.83 ± 3.83 (4.35–13.80)
6.9792 ± 4.9537 (0–15.5) 0.9286 ± 0.8255 (0.19–2.80)
2.6703 ± 1.835 (0–7.0) 0.9125 ± 0.7309 (0.05–2.50)
0.24
1.49 (-4.03, 1.05)
0.001* 0.953
4.31 (1.97, 6.65) 0.02 (-0.54, 0.57)
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Table 3 The P100 latency of visual evoked potentials (VEP) in patients with non- and subsequent multiple sclerosis (MS) P100 latency of VEP (ms)
Non-MS Subsequent MS
B102
103–120
C120
11
11
1
0
6
6
latency from 103 to 120 ms in both non-MS and subsequent MS. The calculated predictive values of CDMS are shown in Table 4. P100 latency C120 provided low sensitivity (50 %) but high specificity (95.7 %) while P100 latency [102 provided high sensitivity (100 %) but low specificity (47.8 %). Interocular latency differences were significantly higher in patients with subsequent CDMS than nonMS (p = 0.001). In contrast, interocular amplitude differences did not differ significantly between the two groups (p = 0.953, Table 2). An interocular latency difference of 3.5 ms (0.5 of our normal population SD) predicted the majority of subsequent CDMS patients (Table 4). The majority of patients (83 %) with subsequent MS had at least one MS-like brain lesion, while those with non-MS had lesions in only 4 of 21 (19 %) patients. These three of four patients had been followed-up over 5 years (61, 64, and 71 months), while one patient was diagnosed with systemic lupus
erythematosus in 4 years. The presence of MRIdetected brain lesions was significantly associated with developing CDMS (p = 0.001) and hence highly predictive (Table 4). The presence of spinal lesions was not significantly associated with developing CDMS (p = 0.741) with 58 % of patients (7 of 12) with subsequent MS and 52 % with non-MS (11 of 21) exhibiting spinal lesions. Predictability of MS from P100 latency values [102 ms performed best with 100 % sensitivity and NPV while the specificity and PPV were not high; however, a brain MRI lesion provided generally high predictive values (Table 4). The combination of a P100 latency[102 ms and an interocular latency difference [3.5 ms associated significantly with the eventual development of CDMS (p = 0.001; Table 5). Greater significance was found by combining a P100 latency [102 ms with the presence of brain MRI lesions (p \ 0.001). Interestingly, combining P100 latency, interocular latency difference, and brain MRI lesion frequency was equally associated with subsequent CDMS (p \ 0.001) and demonstrated high specificity and PPV (100 %; Table 5). However, the results of the average P100 latencies were not different from those of the longer P100 latencies, and the predictive values were also not different even when combined with interocular latency difference and brain MRI lesion (data not shown).
Table 4 Predictive values of paraclinical tests in diagnosed clinically definite multiple sclerosis (CDMS) Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
p value
P 100 latency C120 ms
50
95.7
85.7
78
0.001
P 100 latency [102 ms
100
47.8
50
100
0.001
Interocular latency difference [3.5 ms
75
52.5
45
80
0.001
brain MRI C1 lesion
83.3
81
71.4
89.5
0.001
PPV positive predictive value and NPV negative predictive value
Table 5 Predictive values of combined paraclinical tests in diagnosed clinically definite multiple sclerosis (CDMS) Combined tests
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
p value
1?2
75
78.3
64.3
85.7
p \ 0.001
1?3
83.3
95.7
90.9
91.7
p \ 0.001
1?2?3
58.3
100
100
82.1
p \ 0.001
PPV positive predictive value and NPV negative predictive value (1 = P100 latency [102 ms, 2 = Interocular latency [3.5 ms, 3 = brain MRI C1 lesion)
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Discussion In previous studies, paraclinical tests for diagnosis of MS consisted of MRI, evoked potentials, and CSF oligoclonal banding and showed that an abnormal brain MRI was strongly suggestive for MS [2–5]. Among multimodal evoked potentials, VEP has the greatest predictive value, which demonstrated clinically that silent lesions occur more frequently than somatosensory and auditory EPs as reported in numerous studies [3–7]. Despite previous reports that multifocal VEP is better performance than conventional VEP in diagnosed optic neuritis, but multifocal VEP takes a long time and less available [9, 10]. Conventional VEP is usually more sensitive to optic nerve demyelination than routine MRI but is not sensitive in the diagnosis of CDMS [3, 11]. An association between abnormal VEP and an increased risk of CDMS has been established [7, 8]. Prolonged latency of VEP was determined when the test value was longer than 2.5–3 SD of the norm, or interocular latency difference was more than 6–7 ms (83 %) [3, 11, 12]. In MS suspects with no evidence of optic neuritis, an abnormal latency of VEP could unveil some demyelination of the optic nerve and provide some suggestion of MS development. However, the sensitivity and specificity of VEP in anticipation of MS development varied between 25–83 and 63–87.8 %, respectively [8]. Difference between these studies may be due to variations in patient populations, diagnostic criteria, and VEP techniques and criteria for abnormalities. The present study revealed a direct association between VEP latency and development of MS in MS suspects and confirmed that a prolonged latency can identify a clinically silent lesion of the optic nerve [2]. Furthermore, some studies also showed a decease in VEP amplitude in MS patients without optic nerve diseases [13] in contrast to the results of the present study. Since the assumption of prolonged P100 latency was set up to mean ?2.5 SD, P100 latencies of C120 ms were regarded as prolonged latency. At this threshold (mean ?2.5SD), the present study found seven patients qualified as prolonged P100 latency with 6 (85.7 %) finally diagnosed CDMS. The calculated predictive value of CDMS resulted in a sensitivity of 50 %, specificity of 95.7 %, PPV of 85.7 %, and NPV of 78 %. This outcome was similar to previous studies that found the incidence of CDMS
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detection was rather low [11, 14]. As we knew, early diagnosis and early treatment of CDMS would be decreased long-term disability. If we used mean P100 latency for screening CDMS, the results allowed high sensitivity and NPV (100 %) but only low specificity and PPV (47.8 and 50 %) to predict the development of CDMS. It implied that MS suspects with P100 latency ([102 ms) would have a chance to develop MS of 50 %, and patients with latency \102 ms will not develop MS. There are not any differences of P100 latency from 103 to 120 ms in both non-MS and subsequent MS. In this study, VEP was not indirectly used as a tool for final diagnosis of MS. The diagnosis of MS was made by neurologists based on McDonald diagnostic criteria for MS-2005. For only the interocular latency difference, the predictive value was not suggestive. And for the brain MRI lesion, though the sensitivity was not the best (83.3 %), the PPV and specificity were rather good (71.4 and 81 %). It was still signified as being worth as in other previous reports. We have randomized combining the paraclinical tests together and the result turned out best when all three paraclinical tests (P100 latency more than 102 ms, interocular latency difference more than 3.5 ms, at least 1MS-like lesion on brain MRI) were met. The specificity and PPV reached to 100 %. An early diagnosis of MS is important as early treatment could reduce long-term disability. From the present study, only patients with P100 latency [102 ms developed CDMS. Thus, we propose to use mean P100 latency as the primary screening test for MS. We did not denote to use over mean P100 latency as prolonged latency for diagnosis CDMS. This high sensitivity test would increase the probability of identifying patients that could develop CDMS. However, mean P100 latency has a shortcoming in that it provides a low specificity. Therefore, we recommend merging the other two paraclinical tests (interocular latency difference and MS-like lesion on brain MRI) to improve the accuracy of CDMS prediction in MS suspects. In this study, the mean BCVA (log MAR) in both groups were about 0.10 (6/7.5). Most patients’ visual acuity was 6/6–6/7.5. Only one patient in subsequent MS was 6/12 and one in non-MS was 6/18. The cause of mild reduced visual acuity was mild cataract. However, these mild cataracts were not affecting the VEP results [15]. Every patient with subsequent
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CDMS had developed CDMS within 24 months while our follow-up time of non-MS was assigned C48 months. We have presumed that the other nonMS would not eventually turn to CDMS. This study might be limited by a small number of patients and the retrospective, possibly dated, McDonald diagnostic criteria for MS-2005. The predictive validity of VEP in MS suspects should be further confirmed in prospective studies and with multivariate analysis; however, in prospective study, the probability of patients having MS would be greatly reduced, thus reducing PPV, NPV, and sensitivity. The cost-effectiveness between VEP and the MRI then would be evaluated. Moreover, the threshold of P100 latency might then be verified for the best predictive value.
Conclusion The P100 latency of VEP is beneficial for predicting the development of MS in potential MS patients. MS Suspects with P100 latency longer than mean of MSfree subjects are more likely to develop MS. In the early stage of MS, VEP latency combined with MRI is recommended to the accuracy of MS prediction. Acknowledgments We would like to thank Ms. Julaporn Pooliam, MS.C for the statistical calculations ,and Dr. William Beamish in reviewing of this manuscript. Conflict of interest The authors declare that there is no conflict of interest. Ethical standard Hospital.
The Institutional Review Board of Siriraj
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