CROP - The Clinico-Radiologico-Ophthalmological Paradox in Multiple Sclerosis: Are patterns of retinal and MRI changes heterogeneous and thus not predictable?

BACKGROUND: To date, no direct scientific evidence has been found linking tissue changes in multiple sclerosis (MS) patients, such as demyelination, axonal destruction or gliosis, with either steady progression and/or stepwise accumulation of focal CNS lesions. Tissue changes such as reduction of the retinal nerve fiber layer (RNFL) and the total macular volume (TMV), or brain- and spinal cord atrophy indicates an irreversible stage of tissue destruction. Whether these changes are found in all MS patients, and if there is a correlation with clinical disease state, remains controversial. The objective of our study was to determine, whether there was any correlation between the RNFL or TMV of patients with MS, and: (1) the lesion load along the visual pathways, (2) the ratios and absolute concentrations of metabolites in the normal-appearing white matter (NAWM), (3) standard brain atrophy indices, (4) disease activity or (5) disease duration.METHODS: 28 MS patients (RRMS, n = 23; secondary progressive MS (SPMS), n = 5) with moderately-high disease activity or long disease course were included in the study. We utilised: (1) magnetic resonance imaging (MRI) and (2) -spectroscopy (MRS), both operating at 3 Tesla, and (3) high-resolution spectral domain-OCT with locked reference images and eye tracking mode) to undertake the study.RESULTS: There was no consistency in the pattern of CNS metabolites, brain atrophy indices and the RNFL/TMV between individuals, which ranged from normal to markedly-reduced levels. Furthermore, there was no strict correlation between CNS metabolites, lesions along the visual pathways, atrophy indices, RNFL, TMV, disease duration or disability.CONCLUSIONS: Based on the findings of this study, we recommend that the concept of 'clinico-radiologico paradox' in multiple sclerosis be extended to CROP-'clinico-radiologico-ophthalmological paradox'. Furthermore, OCT data of MS patients should be interpreted with caution.</p

Brain atrophy indices in MS patients.

<p><b>CHI</b>, the caudate head index; <b>BCI</b>, the basal cistern index; <b>CMI</b>, the cella media index; <b>MIF</b>, the maximum width of the anterior interhemispheric fissure; <b>MSF</b>, the maximum width of the Sylvian fissure; and <b>MFSS</b>, the maximum frontal subarachnoid space.</p><p>Brain atrophy indices in MS patients.</p

Regression Analysis.

<p><u>Simple regression–linear model: Independent variable</u>, RNFL; <u>dependent variables</u>, NAA, N-acetyl-aspartate; Cho, choline; Cr, creatine; LL per BV, lesionload per Brain Volume, LL AR, lesion load along anterior right visual pathway; LL AL, lesion load along anterior left visual pathway; LL PR, load along posterior right visual pathway; LL PL, load along posterior left visual pathway; Evan’s Index; CHI; CMI; BCI; the maximum width of the 3^rd ventricle; the maximum width of the 4^th ventricle; MIF, the maximum width of the anterior interhemispheric fissure; MFSS, the maximum frontal subarachnoid space; MSF, the maximum width of the Sylvian fissure; DD, disease duration; EDSS, expanded disability severity scale. <b>1</b>^<b>st</b><b>row</b>: all right eyes (n = 28; with and without ON) of all included MS patient. <b>2</b>^<b>nd</b><b>row</b>: all left eyes (n = 28; with and without ON) of all included MS patient. <b>3</b>^<b>rd</b><b>row</b>: all right eyes of MS patients who never experienced an ON (neither on their right nor on their left eye; RRMS, n = 17, SPMS, n = 2; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142272#pone.0142272.t001" target="_blank">Table 1</a>). <b>4</b>^<b>th</b><b>row</b>: all left eyes of MS patients who never experienced an ON (neither on their left nor on their right eye; RRMS, n = 17, SPMS, n = 2; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142272#pone.0142272.t001" target="_blank">Table 1</a>). Patients are the same as in the 3^rd row. <b>5</b>^<b>th</b><b>row</b>: right eyes of 6 MS patients who experienced an ON on their right eyes (note, 4 out of 6 experienced ON on both eyes, 2 only on their right eyes; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142272#pone.0142272.t001" target="_blank">Table 1</a>). <b>6</b>^<b>th</b><b>row</b>: left eyes of 6 MS patients who experienced an ON on their left eyes (note, 4 out of 7 experienced ON on both eyes, 3 only on their left eyes <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142272#pone.0142272.t001" target="_blank">Table 1</a>). For each analysis the correlation coefficient (corr. coeff.), R-squared (percent), the standard error of estimate (STE of Est.) and the p-value (analysis of variance, ANOVA) is given. Since the p-value in the ANOVA table is less than 0.01, there is a statistically significant relationship between the maximum width of the 4^th ventricle and the RNFL (for all patients’ right eyes, n = 28, 1^st row and for all patient’s left eyes, who never experienced ON, n = 17, 4^th row) at 99% confidence level. However, the low correlation coefficient indicates that there is only a weak relationship between the variables. R-squared statistic indicates that the simple/linear regression explains only 24.92% (1^st row) or 28.68% (4^th row) of the variability of the independent variable. In all other analyses presented here (and performed for the six OCT-Sectors, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142272#sec006" target="_blank">material and methods</a> or <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142272#pone.0142272.t005" target="_blank">Table 5</a>) no statistically significant correlation could be found (data not shown).</p

Clinical data.

<p><b>ON</b>, <b>optic neuritis;</b></p><p><b>*</b>, relapses treated with high dose steroid pulse therapy; no included patient had an ON within 12 months prior to the beginning of the study;</p><p><b>GLAT</b>, glatiramer-acetate 20mg subcutaneous once daily; <b>MITOX</b>, mitoxantrone; <b>IFN(a)</b>, interferon beta 1a intramuscularly once per week; <b>IFN(b)</b>, interferon beta 1a (44μg) subcutaneous trice per week; <b>IFN(c)</b>, interferon beta 1b (250μg) subcutaneous alternate day. Most importantly, the disease activity remained high in further follow-up with a median observation period of 22 ± 0.5 months [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142272#pone.0142272.ref033" target="_blank">33</a>]. However, no significant reduction of either the RNFL or the TMV could be found in follow-up [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142272#pone.0142272.ref033" target="_blank">33</a>; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142272#pone.0142272.ref036" target="_blank">36</a>].</p><p>¹, discontinued (48mg mitoxantrone per m² body surface); <b>none</b>, neither specific immunomodulatory or immunsuppressive therapy, drug holiday;</p><p>², drug withdrawal 12 months before OCT examination;</p><p>³, drug withdrawal 6 months before OCT examination;</p><p>⁴, drug withdrawal 20 months before OCT examination;</p><p>⁵, high titres of anti-interferon autoantibodies, drug withdrawal 14 months before OCT examination;</p><p>⁶, mitoxantrone cumulative dose 96mg per m² body surface, drug withdrawal 10 months before OCT examination;</p><p>⁷, mitoxantrone cumulative dose 92mg per m² body surface, drug withdrawal 10 months before OCT examination;</p><p>⁸, mitoxantrone cumulative dose 92mg per m² body surface, drug withdrawal 26 months before OCT examination;</p><p>⁹, mitoxantrone cumulative dose 108mg per m² body surface, drug withdrawal 27 months before 1^st OCT examination.</p><p>Clinical data.</p

Metabolites in NAWM and lesion load in the visual pathways in MS patients.

<p><b>Metabolites</b>, N-Acetyl-Aspartate (NAA), Choline (Cho) and creatine (Cr) given in mM; <b>lesion load in the visual pathways</b>, here given as ratio of lesion volume in the visual pathways (AD, right anterior; AS, left anterior; PD, right posterior; PS, left posterior and total lesion volume) to total brain volume.</p><p>Metabolites in NAWM and lesion load in the visual pathways in MS patients.</p

RNFL in MS patients.

<p><b>Retinal sectors: OD</b>, right eye; <b>OS</b>, left eye; <b>G</b>, global; <b>S</b>, superior; <b>I</b>, inferior; <b>T</b>, temporal; <b>TS</b>, temporal superior; <b>TI</b>, temporal inferior; <b>N</b>, nasal; <b>NS</b>, nasal superior; <b>NI</b>, nasal inferior. All values are given in μm.</p><p>RNFL in MS patients.</p