The Optic Neuritis Treatment Trial (ONTT) compared three modes of treatment for acute unilateral optic neuritis: placebo, oral prednisone, or high-dose IVMP followed by oral prednisone [
Axonal and neuronal loss are increasingly recognized as the primary factors contributing to persistent deficits and disability in multiple sclerosis (MS) and optic neuritis [
ONTT patients underwent visual acuity, visual field, and contrast sensitivity testing at study entry then at the one-month, 6-month, 5-year, 10-year, and 15-year follow-up visits. EDSS assessments were performed at the 5-year, 10-year, and 15-year follow-up examinations. MRI was performed at baseline and at the five-year examination [
Serum derived from venous blood was drawn during follow-up examinations 5 years after patient enrollment into the treatment arm of the study. Serum was stored in a −80 freezer for 10 years. Serum was assayed for the presence of phosphorylated neurofilament heavy chain (pNF-H), using a recently described monoclonal antibody-based assay [
Optical coherence tomography (OCT) [
Pearson correlation analysis of data was performed using SPSS statistical software (Chicago, IL). The association of subject characteristics to pNF-H levels was studied with multiple regression. The pNF-H data were square root transformed to effect normality of distribution of residuals. Relationships between the square root of pNF-H were investigated within groups with Pearson correlation and the two-sample
We quantified pNF-H levels in the serum of 175 (44%) of the 397 patients, 87% of those initially entered into the ONTT, who returned for follow-up examinations 5 years after enrollment into the study. Their baseline characteristics are listed in Table
Baseline (recruitment) participant characteristics of ONTT subjects undergoing pNF-H testing.
Number | 175 |
Mean (SD) [range] age | 33.2 (6.8) [18,46] |
140 (80%) | |
Caucasian | 159 (91%) |
African-American | 15 (9%) |
Hispanic | 1 (1%) |
92 (53%) | |
None | 114 (65%) |
Possible | 35 (20%) |
Probable | 9 (5%) |
Definite | 17 (10%) |
Treatment group | |
IVMP | 63 (36%) |
Prednisone | 63 (36%) |
Placebo | 49 (28%) |
Bar plots of pNF-H concentration (nanograms per mL) in optic neuritis patients by treatment group (a) and between optic neuritis cases with or without MS at 5 years (b). Error bars = standard deviation.
Next, we investigated whether the increases in pNF-H levels of placebo and prednisone-treated patients relative to those who received IVMP, shown by the study to reduce the risk of developing MS for approximately 2 years [
Next, we compared baseline and 5-year measurements by randomized treatment assignment and 15-year follow-up with OCT (Table
Visual and clinical scores by treatment group and OCT.
Treatment group | IVMP | Placebo | Prednisone | Total | Total | ||||
OCT at 15 yrs | Yes | No | Yes | No | Yes | No | Yes | No | Total |
18 | 45 | 15 | 34 | 18 | 45 | 51 | 124 | 175 | |
Mean ± SD LogMAR acuity | |||||||||
Affected eye | |||||||||
Baseline | 0.78 ± 0.65 | 0.66 ± 0.63 | 0.59 ± 0.71 | 0.67 ± 0.72 | 0.86 ± 0.67 | 0.86 ± 0.69 | 0.75 ± 0.67 | 0.74 ± 0.68 | 0.74 ± 0.68 |
Year 5 | −0.08 ± 0.14 | −0.06 ± 0.15 | −0.05 ± 0.11 | −0.02 ± 0.37 | −0.07 ± 0.16 | 0.01 ± 0.32 | −0.07 ± 0.14 | −0.03 ± 0.29 | −0.04 ± 0.25 |
Year 10 | −0.08 ± 0.10 | 0.01 ± 0.35 | −0.03 ± 0.09 | −0.07 ± 0.25 | −0.07 ± 0.11 | 0.06 ± 0.37 | −0.06 ± 0.10 | 0.01 ± 0.33 | −0.01 ± 0.28 |
Year 15 | −0.07 ± 0.11 | 0.06 ± 0.38 | −0.02 ± 0.10 | 0.04 ± 0.28 | −0.06 ± 0.10 | 0.11 ± 0.36 | −0.05 ± 0.11 | 0.07 ± 0.34 | 0.03 ± 0.29 |
Fellow eye | |||||||||
Baseline | −0.12 ± 0.07 | −0.12 ± 0.09 | −0.13 ± 0.10 | −0.08 ± 0.22 | −0.14 ± 0.08 | −0.14 ± 0.09 | −0.13 ± 0.08 | −0.12 ± 0.14 | −0.12 ± 0.12 |
Year 5 | −0.14 ± 0.14 | −0.12 ± 0.11 | −0.11 ± 0.10 | −0.08 ± 0.32 | −0.17 ± 0.09 | −0.07 ± 0.30 | −0.14 ± 0.12 | −0.09 ± 0.26 | −0.11 ± 0.22 |
Year 10 | −0.10 ± 0.15 | −0.07 ± 0.21 | −0.07 ± 0.11 | −0.15 ± 0.09 | −0.15 ± 0.08 | −0.05 ± 0.29 | −0.11 ± 0.12 | −0.08 ± 0.22 | −0.09 ± 0.19 |
Year 15 | −0.10 ± 0.15 | 0.01 ± 0.30 | −0.09 ± 0.09 | −0.04 ± 0.12 | −0.12 ± 0.09 | −0.01 ± 0.32 | −0.10 ± 0.11 | −0.01 ± 0.27 | −0.05 ± 0.23 |
Mean ± SD contrast sensitivity | |||||||||
Affected eye | |||||||||
Baseline | 7.8 ± 4.8 | 8.1 ± 4.6 | 8.6 ± 5.6 | 7.6 ± 5.1 | 7.4 ± 5.4 | 7.0 ± 4.9 | 7.9 ± 5.2 | 7.5 ± 4.8 | 7.6 ± 4.9 |
Year 5 | 14.3 ± 1.3 | 14.0 ± 1.5 | 13.9 ± 1.5 | 13.8 ± 2.8 | 14.8 ± 0.9 | 13.3 ± 3.0 | 14.4 ± 1.3 | 13.7 ± 2.5 | 13.9 ± 2.2 |
Year 10 | 11.6 ± 0.9 | 11.4 ± 2.2 | 11.3 ± 1.3 | 11.4 ± 2.4 | 11.8 ± 1.0 | 10.9 ± 2.5 | 11.6 ± 1.1 | 11.2 ± 2.4 | 11.3 ± 2.0 |
Year 15 | 11.6 ± 1.1 | 11.1 ± 2.7 | 11.3 ± 1.3 | 11.2 ± 2.7 | 11.5 ± 1.5 | 10.8 ± 2.9 | 11.5 ± 1.3 | 11.0 ± 2.8 | 11.2 ± 2.3 |
Fellow eye | |||||||||
Baseline | 15.2 ± 0.7 | 15.6 ± 0.6 | 14.9 ± 0.6 | 15.0 ± 1.3 | 15.4 ± 0.6 | 15.3 ± 0.8 | 15.2 ± 0.7 | 15.3 ± 0.9 | 15.3 ± 0.9 |
Year 5 | 15.3 ± 1.0 | 15.2 ± 0.7 | 15.1 ± 0.5 | 14.8 ± 2.1 | 15.7 ± 0.5 | 14.7 ± 2.6 | 15.4 ± 0.7 | 14.9 ± 2.0 | 15.1 ± 1.7 |
Year 10 | 12.2 ± 1.4 | 12.0 ± 1.2 | 12.3 ± 0.5 | 12.2 ± 0.9 | 12.2 ± 0.6 | 11.7 ± 2.3 | 12.3 ± 0.9 | 11.9 ± 1.6 | 12.0 ± 1.4 |
Year 15 | 12.1 ± 1.5 | 11.8 ± 1.8 | 12.5 ± 0.8 | 12.1 ± 1.0 | 12.5 ± 0.7 | 11.5 ± 2.7 | 12.4 ± 1.1 | 11.8 ± 2.0 | 12.0 ± 1.7 |
Mean ± SD mean deviation | |||||||||
Affected eye | |||||||||
Baseline | −22.0 ± 11.3 | −21.5 ± 9.9 | −19.2 ± 10.6 | −21.6 ± 10.0 | −23.4 ± 11.2 | −23.7 ± 10.2 | −21.7 ± 11.0 | −22.3 ± 10.0 | −22.1 ± 10.3 |
Year 5 | −2.0 ± 2.1 | −1.3 ± 4.0 | −5.1 ± 7.9 | −3.0 ± 8.1 | −1.5 ± 2.6 | −3.9 ± 7.4 | −2.7 ± 4.9 | −2.7 ± 6.6 | −2.7 ± 6.2 |
Year 10 | −1.3 ± 2.8 | −2.5 ± 5.1 | −5.0 ± 7.6 | −3.0 ± 6.9 | −1.5 ± 1.8 | −4.1 ± 7.3 | −2.5 ± 4.8 | −3.3 ± 6.5 | −3.0 ± 6.0 |
Year 15 | −1.0 ± 1.9 | −1.7 ± 5.7 | −5.1 ± 7.2 | −2.9 ± 6.9 | −1.6 ± 2.1 | −3.8 ± 6.6 | −2.4 ± 4.5 | −2.8 ± 6.4 | −2.7 ± 5.7 |
Fellow eye | |||||||||
Baseline | −2.1 ± 1.9 | −2.8 ± 1.9 | −2.7 ± 2.3 | −3.3 ± 3.5 | −3.6 ± 2.5 | −3.8 ± 4.6 | −2.8 ± 2.3 | −3.3 ± 3.5 | −3.1 ± 3.2 |
Year 5 | −1.1 ± 2.3 | −0.6 ± 1.9 | −1.8 ± 5.3 | −1.1 ± 5.1 | −0.1 ± 2.4 | −2.5 ± 6.5 | −1.0 ± 3.5 | −1.4 ± 4.9 | −1.3 ± 4.5 |
Year 10 | −0.7 ± 2.7 | −1.7 ± 4.6 | −1.7 ± 4.9 | −1.2 ± 2.7 | 0.0 ± 1.2 | −2.3 ± 7.1 | −0.8 ± 3.2 | −1.8 ± 5.3 | −1.5 ± 4.8 |
Year 15 | −0.3 ± 2.9 | −1.3 ± 5.5 | −2.0 ± 5.2 | −0.7 ± 2.4 | −0.2 ± 1.7 | −2.6 ± 5.0 | −0.8 ± 3.5 | −1.6 ± 4.6 | −1.3 ± 4.2 |
Baseline | 0 | 3 (7%) | 1 (7%) | 4 (12%) | 1 (6%) | 8 (18%) | 2 (4%) | 15 (12%) | 17 (10%) |
Year 5 | 4 (22%) | 14 (31%) | 3 (20%) | 20 (59%) | 3 (20%) | 6 (33%) | 13 (26%) | 59 (48%) | 72 (41%) |
Year 10 | 5 (28%) | 17 (38%) | 5 (33%) | 23 (68%) | 6 (33%) | 30 (67%) | 16 (31%) | 70 (57%) | 86 (49%) |
Year 15 | 6 (33%) | 20 (44%) | 7 (47%) | 23 (68%) | 7 (39%) | 32 (71%) | 20 (39%) | 75 (61%) | 95 (54%) |
MS characteristics.
Diagnosis of MS | All | |||||
Baseline, | Month 6, | Year 5, | Year 10, | Year 15, | ||
Mean (SD) EDSS | ||||||
Year 5 | 1.97 (1.59) | 1.77 (1.82) | 1.30 (0.98) | 0.71 (1.09)* | 0.22 (0.44)** | 1.28 (1.29) |
Year 10 | 2.79 (1.88) | 1.96 (1.96) | 2.42 (2.41) | 2.35 (2.13) | 0.78 (0.79)*** | 2.24 (2.14) |
Year 15 | 3.83 (1.90) | 2.55 (1.62) | 2.94 (2.46) | 2.96 (2.12) | 1.33 (1.36) | 2.84 (2.18) |
Year 5 mean (SD) sqrt pNFH | ||||||
IV | 0.29 (0.04) | 0.24 (0.11) | 0.25 (0.11) | 0.33 (0.09) | 0.22 (0.05) | 0.26 (0.09) |
Prednisone | 0.45 (0.13) | 0.36 (0.20) | 0.33 (0.16) | 0.31 (0.07) | 0.41 (0.36) | 0.37 (0.17) |
Placebo | 0.20 (0.13) | 0.21 (0.20) | 0.46 (0.34) | 0.30 (0.06) | 0.34 (0.11) | 0.36 (0.27) |
≥5 MRI lesions at baseline | 13 (77%) | 3 (30%) | 16 (42%) | 4 (29%) | 4 (57%) | 40 (47%) |
Year 15 mean (SD) RNFL | ||||||
Affected eye | 79.4 (4.6) | 70.0 (8.1) | 69.7 (19.8) | 65.0 (17.0) | 66.0 (25.5) | 69.3 (17.4) |
Fellow eye | 94.6 (3.8) | 74.2 (16.3) | 82.0 (19.0) | 97.3 (2.7) | 73.1 (24.5) | 82.6 (18.3) |
Difference | 15.2 (0.8) | 4.2 (8.5) | 12.4 (16.4) | 32.3 (15.1) | 7.1 (6.5) | 13.3 (14.7) |
Year 15 mean (SD) macular volume | ||||||
Affected eye | 7.1 (0.9) | 6.1 (0.7) | 6.0 (0.5) | 6.8 (0.5) | 6.2 (0.6) | 6.3 (0.6) |
Fellow eye | 7.6 (0.1) | 6.2 (0.8) | 6.6 (0.6) | 7.3 (0.9) | 6.7 (0.7) | 6.7 (0.7) |
Difference | 0.5 (0.8) | 0.1 (0.2) | 0.6 (0.5) | 0.5 (0.4) | 0.2 (0.2) | 0.4 (0.4) |
(a) A scatterplot shows the increasing pNF-H with worsening baseline visual acuity in the affected eyes with acute optic neuritis. (b) The scatterplot shows elevated serum pNF-H correlates with poorer contrast sensitivity at entry into the ONTT. (c) A scatterplot shows that higher pNF-H correlates with more severe visual field defects at baseline.
OCT signal strengths ranged from 5 to 10 in both fellow and affected eyes, with 44 (86%) and 47 (92%) having signal strength greater or equal to 7. Table
OCT data RNFL and macular volumes.
IVMP | Placebo | Prednisone | Total | |
---|---|---|---|---|
Signal strength | ||||
Affected eye | 8.2 ± 1.2 | 8.2 ± 1.2 | 7.9 ± 1.5 | 8.1 ± 1.3 |
Fellow eye | 8.1 ± 1.8 | 8.5 ± 1.1 | 8.4 ± 1.2 | 8.3 ± 1.4 |
Year 15 mean (SD) RNFL | ||||
Affected eye | 80.9 ± 18.1 | 71.3 ± 22.7 | 78.2 ± 17.1 | 77.1 ± 19.3 |
Fellow eye | 95.2 ± 16.7 | 87.1 ± 18.1 | 94.5 ± 18.5 | 92.6 ± 17.8 |
Difference (AF-FE) | −14.3 ± 17.3 | −15.8 ± 22.4 | −16.3 ± 15.9 | −15.5 ± 18.2 |
| .003 | .016 | <.001 | <.001 |
Year 15 mean (SD) macular volume | ||||
Affected eye | 6.3 ± 0.5 | 6.5 ± 0.7 | 6.4 ± 0.5 | 6.4 ± 0.6 |
Fellow eye | 6.7 ± 0.5 | 6.9 ± 0.8 | 7.0 ± 0.6 | 6.9 ± 0.7 |
Difference | −0.4 ± 0.5 | −0.4 ± 0.5 | −0.7 ± 0.6 | −0.5 ± 0.6 |
| .005 | .010 | <.001 | <.001 |
We found a significant correlation of baseline visual acuity loss to a reduction in total macular volume in the subset of 51 patients that had their RNFL and macular volumes thickness measured with Stratus OCT at the 15-year follow-up visit. Table
Correlations of clinical profile to OCT and pNF-H.
Measurement | Visit | Statistic | Study eye RNFL thickness | Study eye total macular volume | Square root pNFH |
---|---|---|---|---|---|
EDSS | Year 5 | −0.28 | −0.28 | 0.15 | |
.048 | .057 | .291 | |||
50 | 47 | 50 | |||
Year 10 | −0.38 | −0.11 | 0.02 | ||
.008 | .473 | .901 | |||
49 | 46 | 49 | |||
Year 15 | −0.23 | 0.07 | 0.03 | ||
.107 | .641 | .841 | |||
51 | 48 | 51 | |||
LogMAR study eye acuity | Baseline | −0.09 | −0.29 | 0.44 | |
.512 | .046 | .001 | |||
51 | 48 | 51 | |||
Month 1 | −0.44 | −0.41 | 0.13 | ||
.002 | .005 | .364 | |||
48 | 45 | 48 | |||
Month 6 | −0.35 | −0.22 | −0.11 | ||
.011 | .132 | .442 | |||
51 | 48 | 51 | |||
Year 5 | −0.27 | −0.26 | −0.18 | ||
.060 | .074 | .206 | |||
51 | 48 | 51 | |||
Year 10 | −0.52 | −0.30 | −0.08 | ||
<.001 | .040 | .565 | |||
50 | 47 | 50 | |||
Year 15 | −0.48 | −0.36 | 0.00 | ||
<.001 | .011 | .974 | |||
51 | 48 | 51 | |||
Sensitivity study eye contrast | Baseline | 0.18 | 0.23 | −0.37 | |
.207 | .121 | .007 | |||
51 | 48 | 51 | |||
Month 1 | 0.54 | 0.42 | −0.17 | ||
<.001 | .004 | .256 | |||
48 | 45 | 48 | |||
Month 6 | 0.54 | 0.44 | −0.12 | ||
<.001 | .002 | .419 | |||
51 | 48 | 51 | |||
Year 5 | 0.45 | 0.37 | −0.04 | ||
.001 | .010 | .759 | |||
50 | 47 | 50 | |||
Year 10 | 0.52 | 0.43 | 0.01 | ||
<.001 | .003 | .964 | |||
49 | 46 | 49 | |||
Year 15 | 0.58 | 0.52 | −0.06 | ||
<.001 | <.001 | .685 | |||
51 | 48 | 51 | |||
Study eye visual field mean deviation | Baseline | 0.24 | 0.30 | −0.29 | |
.095 | .036 | .038 | |||
51 | 48 | 51 | |||
Month 1 | 0.56 | 0.46 | −0.11 | ||
<.001 | .001 | .462 | |||
48 | 45 | 48 | |||
Month 6 | 0.55 | 0.34 | 0.08 | ||
<.001 | .019 | .593 | |||
51 | 48 | 51 | |||
Year 5 | 0.48 | 0.32 | 0.06 | ||
<.001 | .029 | .650 | |||
51 | 48 | 51 | |||
Year 10 | 0.57 | 0.40 | 0.10 | ||
<.001 | .006 | .512 | |||
50 | 47 | 50 | |||
Year 15 | 0.55 | 0.30 | 0.05 | ||
<.001 | .041 | .730 | |||
51 | 48 | 51 |
Looking at the OCT findings by treatment group, we found no significant difference of mean IVMP RNFL = 81
(a) A barplot of OCT RNFL thickness at 15 years in a subset of 51 patients shows no significant difference of mean RNFL with treatment of optic neuritis patients with MS or clinically isolated optic neuritis patients without MS. (b) A scatterplot of RNFL thickness difference of the fellow eye (FE) minus the study eye (SE) RNFLFEmSE correlated to serum pNF-H levels in the IVMP group.
Lastly, we found no statistical correlation of pNF-H levels to recovery of visual acuity at 6 months or RNFL thickness at 15 years in patients with or without MS. However, RNFL thickness differences of fellow eye (FE) minus study eye (SE) RNFLFEmSE correlated to pNF-H levels in the IV methylprednisolone group (
We have shown here that serum pNF-H levels measured 5 years after acute optic neuritis correlate with baseline visual function. Next, early follow-up visual function correlates with RNFL and macular volumes measured at 15 years. Lastly, pNF-H levels at year 5 do not correlate with RNFL and macular volumes in the affected eye, but they do correlate with the difference between study and fellow eyes at least in the IVMP group.
Our findings of increased pNF-H levels with more severe baseline visual deficits are consistent with axonal transection by inflammatory cells that is believed to contribute to the loss of axons [
While we found no correlation of pNF-H to clinical measures of visual function at the very late time points, and pNF-H was not associated with study eye RNFL even in the IVMP group, the difference between fellow eye and study eye RNFL thickness correlated with pNF-H levels in the IVMP group. This finding validates pNF-H as a biomarker of suppression of axonal loss by high-dose methylprednisolone, now standard therapy for acute optic neuritis and MS exacerbations. Since no difference in serum pNF-H concentration between clinically isolated optic neuritis and MS patients were detected, it is unlikely that brain lesions outside the optic nerve contributed to the differences in pNF-H between the IV methylprednisolone and the other two treatment groups. We also excluded brain lesions in clinically isolated optic neuritis and multiple sclerosis patients detected on T2-weighted MRI as a cause for the differences in pNF-H between the treatment groups.
Consistent with our observations in ONTT patients, elevation of serum pNF-H has also been found in another disease that affects the optic nerve, Lebers’ hereditary optic neuropathy (LHON) [
Despite the OCT and pNF-H correlation data supporting a long-term benefit of treatment with IVMP, its effect on visual parameters and neurologic or MRI lesions was virtually nil. For month 1, month 6, year 5, year 10, and year 15, treatment had very little affect on outcome variables of acuity, contrast sensitivity, visual field mean deviation, EDSS score, or MRI lesions [
Corticosteroids have been shown to suppress axonal loss in the optic nerves of animals with experimental autoimmune encephalomyelitis (EAE) [
Serum samples used in the analyses were provided by the ONTT study Group. Mabel Wilson edited the paper. This Study supported by R01EY07982. Gerry Shaw holds equity in EnCor Biotechnology Inc., a company commercializing antibodies and the ELISA assay used in this study, and may benefit by receiving royalties or equity growth.