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CROP - The Clinico-Radiologico-Ophthalmological Paradox in Multiple Sclerosis: Are Patterns of Retinal and MRI Changes Heterogeneous and Thus Not Predictable?

Aboulenein-Djamshidian F, Krššák M, Serbecic N, Rauschka H, Beutelspacher S, Kukurová IJ, Valkovič L, Khan A, Prayer D, Kristoferitsch W - PLoS ONE (2015)

Bottom Line: 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.Whether these changes are found in all MS patients, and if there is a correlation with clinical disease state, remains controversial.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, SMZ-Ost Donauspital, A-1220 Langobardenstrasse 122, Vienna, Austria.

ABSTRACT

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.

Show MeSH

Related in: MedlinePlus

white squares, RRMS without ON; black squares, RRMS with ON; white triangles, SPMS without ON; black triangles, SPMS with ON; black line, linear regression curve. Abbreviations: OD, oculus dexter (right eye); OS, oculus sinister (left eye); RNFL, retinal nerve fiber layer; NAA, N-acetyl-aspartate; Cho, choline; Cr, creatine; NAWM, normal appearing white matter; MIF, the maximum width of the anterior interhemispheric fissure; MSF, the maximum width of the Sylvian fissure; MFSS, the maximum frontal subarachnoid space; EDSS, expanded disability severity scale. a1-g8, linear regression curves for: a1, RNFL vs. NAA (right eye); a2, RNFL vs. NAA (left eye); a3, RNFL vs. Cho (right eye); a4, RNFL vs. Cho (left eye); a5, RNFL vs. Cr (right eye); a6, RNFL vs. Cr (left eye); a7, disease duration vs. NAA in the NAWM; a8, disease duration vs. Cho; b1, RNFL vs. lesion load (right eye); b2, RNFL vs. lesion load (left eye); b3, RNFL vs. lesion load per brain volume (right eye); b4, RNFL vs. lesion load per brain volume (left eye); b5, RNFL vs. lesion load along anterior right visual pathway (right eye); b6, RNFL vs. lesion load anterior right visual pathway (left eye); b7, RNFL vs. lesion load along anterior left visual pathway (right eye); b8, RNFL vs. lesion load anterior left visual pathway (left eye); c1, RNFL vs. lesion load along posterior right visual (right eye); c2, RNFL vs. lesion load along posterior left visual pathway (left eye); c3, RNFL vs. lesion load along posterior left visual (right eye); c4, RNFL vs. lesion load along posterior left visual pathway (left eye); c5, RNFL vs. Evan’s Index (right eye); c6, RNFL vs. Evan’s Index (left eye); c7, RNFL vs. Caudate Head Index (right eye); c8, RNFL vs. Caudate Head Index Index (left eye); d1, RNFL vs. Cella Media Index (right eye); d2, RNFL vs. Cella Media Index (left eye); d3, RNFL vs. Basal Cistern Index (right eye); d4, RNFL vs. Basal Cistern Index Index (left eye); d5, RNFL vs. the maximum width of the 3rd ventricle (right eye); d6, RNFL vs. the maximum width of the 3rd ventricle (left eye); d7, RNFL vs. the maximum of the 4th width ventricle (right eye); d8, RNFL vs. the maximum of the 4th width ventricle (left eye); e1, RNFL vs. MFSS (right eye); e2, RNFL vs. MFSS (left eye); e3, RNFL vs. MIF (right eye); e4, RNFL vs. MIF (left eye); e5, RNFL vs. MSF (right eye); e6, RNFL vs. MSF (left eye); e7, disease duration vs. Evan’s Index; e8, disease duration vs. Caudate Head Index; f1, disease duration vs. Cella Media Index; f2, disease duration vs. the maximum width of the 3rd ventricle; f3, disease duration vs. the maximum width of the 4th ventricle; f4, disease duration vs. MFSS; f5, disease duration vs. MIF; f6, disease duration vs. MSF; f7, disease duration vs. lesion load along both visual pathways; f8, disease duration vs. lesion load along the anterior right visual pathway; g1, disease duration vs. lesion load along the anterior left visual pathway; g2, disease duration vs. lesion load along the posterior right visual pathway; g3, disease duration vs. lesion load along the posterior left visual pathway; g4, disease duration vs. EDSS; g5, disease duration vs. RNFL (right eye); g6, disease duration vs. RNFL (left eye); g7, RNFL (right eye) vs. EDSS; g8, RNFL (right eye) vs. EDSS. Regression analyses demonstrated only weak correlations between the examined parameters a1-g8 of all 28 MS patients included in this study and associated subgroups (RRMS without ON, RRMS with ON, SPMS without ON, SPMS with ON). Of note, the plotted linear regression curves in a1 –g8 are calculated for the analysis of all included MS patient.
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pone.0142272.g001: white squares, RRMS without ON; black squares, RRMS with ON; white triangles, SPMS without ON; black triangles, SPMS with ON; black line, linear regression curve. Abbreviations: OD, oculus dexter (right eye); OS, oculus sinister (left eye); RNFL, retinal nerve fiber layer; NAA, N-acetyl-aspartate; Cho, choline; Cr, creatine; NAWM, normal appearing white matter; MIF, the maximum width of the anterior interhemispheric fissure; MSF, the maximum width of the Sylvian fissure; MFSS, the maximum frontal subarachnoid space; EDSS, expanded disability severity scale. a1-g8, linear regression curves for: a1, RNFL vs. NAA (right eye); a2, RNFL vs. NAA (left eye); a3, RNFL vs. Cho (right eye); a4, RNFL vs. Cho (left eye); a5, RNFL vs. Cr (right eye); a6, RNFL vs. Cr (left eye); a7, disease duration vs. NAA in the NAWM; a8, disease duration vs. Cho; b1, RNFL vs. lesion load (right eye); b2, RNFL vs. lesion load (left eye); b3, RNFL vs. lesion load per brain volume (right eye); b4, RNFL vs. lesion load per brain volume (left eye); b5, RNFL vs. lesion load along anterior right visual pathway (right eye); b6, RNFL vs. lesion load anterior right visual pathway (left eye); b7, RNFL vs. lesion load along anterior left visual pathway (right eye); b8, RNFL vs. lesion load anterior left visual pathway (left eye); c1, RNFL vs. lesion load along posterior right visual (right eye); c2, RNFL vs. lesion load along posterior left visual pathway (left eye); c3, RNFL vs. lesion load along posterior left visual (right eye); c4, RNFL vs. lesion load along posterior left visual pathway (left eye); c5, RNFL vs. Evan’s Index (right eye); c6, RNFL vs. Evan’s Index (left eye); c7, RNFL vs. Caudate Head Index (right eye); c8, RNFL vs. Caudate Head Index Index (left eye); d1, RNFL vs. Cella Media Index (right eye); d2, RNFL vs. Cella Media Index (left eye); d3, RNFL vs. Basal Cistern Index (right eye); d4, RNFL vs. Basal Cistern Index Index (left eye); d5, RNFL vs. the maximum width of the 3rd ventricle (right eye); d6, RNFL vs. the maximum width of the 3rd ventricle (left eye); d7, RNFL vs. the maximum of the 4th width ventricle (right eye); d8, RNFL vs. the maximum of the 4th width ventricle (left eye); e1, RNFL vs. MFSS (right eye); e2, RNFL vs. MFSS (left eye); e3, RNFL vs. MIF (right eye); e4, RNFL vs. MIF (left eye); e5, RNFL vs. MSF (right eye); e6, RNFL vs. MSF (left eye); e7, disease duration vs. Evan’s Index; e8, disease duration vs. Caudate Head Index; f1, disease duration vs. Cella Media Index; f2, disease duration vs. the maximum width of the 3rd ventricle; f3, disease duration vs. the maximum width of the 4th ventricle; f4, disease duration vs. MFSS; f5, disease duration vs. MIF; f6, disease duration vs. MSF; f7, disease duration vs. lesion load along both visual pathways; f8, disease duration vs. lesion load along the anterior right visual pathway; g1, disease duration vs. lesion load along the anterior left visual pathway; g2, disease duration vs. lesion load along the posterior right visual pathway; g3, disease duration vs. lesion load along the posterior left visual pathway; g4, disease duration vs. EDSS; g5, disease duration vs. RNFL (right eye); g6, disease duration vs. RNFL (left eye); g7, RNFL (right eye) vs. EDSS; g8, RNFL (right eye) vs. EDSS. Regression analyses demonstrated only weak correlations between the examined parameters a1-g8 of all 28 MS patients included in this study and associated subgroups (RRMS without ON, RRMS with ON, SPMS without ON, SPMS with ON). Of note, the plotted linear regression curves in a1 –g8 are calculated for the analysis of all included MS patient.

Mentions: Neither the RNFL nor TMV was found to correlate strictly with: (1) brain metabolites in the NAWM (NAA, Cho and Cr) or (2) the various brain atrophy indices and lesion load in the visual pathways. Evan’s ratio, CHI, CMI, BCI were found to be within normal range in all 28 patients even though global brain atrophy was detectable on MRI. This may suggest that these indices were not applicable to the brain atrophy seen in the MS patients in this study (Table 3). The atrophy detected in MS patients seemed to be described better by other parameters such as the maximum width of 3rd and 4th ventricles, MIF, MSF and MFSS (see results and Table 1, patient 1, 24 and 25, Fig 1). Usually the whole brain volume and white and grey matter volume/fractions are determined in MRT studies of MS patients to detect even mild brain atrophy. Also in most of our included MS patients there could at least a mild brain atrophy be detected by inspection of his/her MRI by a skilled radiologist and or neurologist. Interestingly, also in those MS patients with marked brain atrophy also the RNFL or TMV were not significantly reduced (this applies also for the further 2 years follow-up [38; 39]). However, we state clearly that the brain atrophy indices—we have used here—have potential methodological limitations and basically do not correlate strictly with disease course or clinical progression in all MS patients as this has been shown for so many other MRI parameters before [1].


CROP - The Clinico-Radiologico-Ophthalmological Paradox in Multiple Sclerosis: Are Patterns of Retinal and MRI Changes Heterogeneous and Thus Not Predictable?

Aboulenein-Djamshidian F, Krššák M, Serbecic N, Rauschka H, Beutelspacher S, Kukurová IJ, Valkovič L, Khan A, Prayer D, Kristoferitsch W - PLoS ONE (2015)

white squares, RRMS without ON; black squares, RRMS with ON; white triangles, SPMS without ON; black triangles, SPMS with ON; black line, linear regression curve. Abbreviations: OD, oculus dexter (right eye); OS, oculus sinister (left eye); RNFL, retinal nerve fiber layer; NAA, N-acetyl-aspartate; Cho, choline; Cr, creatine; NAWM, normal appearing white matter; MIF, the maximum width of the anterior interhemispheric fissure; MSF, the maximum width of the Sylvian fissure; MFSS, the maximum frontal subarachnoid space; EDSS, expanded disability severity scale. a1-g8, linear regression curves for: a1, RNFL vs. NAA (right eye); a2, RNFL vs. NAA (left eye); a3, RNFL vs. Cho (right eye); a4, RNFL vs. Cho (left eye); a5, RNFL vs. Cr (right eye); a6, RNFL vs. Cr (left eye); a7, disease duration vs. NAA in the NAWM; a8, disease duration vs. Cho; b1, RNFL vs. lesion load (right eye); b2, RNFL vs. lesion load (left eye); b3, RNFL vs. lesion load per brain volume (right eye); b4, RNFL vs. lesion load per brain volume (left eye); b5, RNFL vs. lesion load along anterior right visual pathway (right eye); b6, RNFL vs. lesion load anterior right visual pathway (left eye); b7, RNFL vs. lesion load along anterior left visual pathway (right eye); b8, RNFL vs. lesion load anterior left visual pathway (left eye); c1, RNFL vs. lesion load along posterior right visual (right eye); c2, RNFL vs. lesion load along posterior left visual pathway (left eye); c3, RNFL vs. lesion load along posterior left visual (right eye); c4, RNFL vs. lesion load along posterior left visual pathway (left eye); c5, RNFL vs. Evan’s Index (right eye); c6, RNFL vs. Evan’s Index (left eye); c7, RNFL vs. Caudate Head Index (right eye); c8, RNFL vs. Caudate Head Index Index (left eye); d1, RNFL vs. Cella Media Index (right eye); d2, RNFL vs. Cella Media Index (left eye); d3, RNFL vs. Basal Cistern Index (right eye); d4, RNFL vs. Basal Cistern Index Index (left eye); d5, RNFL vs. the maximum width of the 3rd ventricle (right eye); d6, RNFL vs. the maximum width of the 3rd ventricle (left eye); d7, RNFL vs. the maximum of the 4th width ventricle (right eye); d8, RNFL vs. the maximum of the 4th width ventricle (left eye); e1, RNFL vs. MFSS (right eye); e2, RNFL vs. MFSS (left eye); e3, RNFL vs. MIF (right eye); e4, RNFL vs. MIF (left eye); e5, RNFL vs. MSF (right eye); e6, RNFL vs. MSF (left eye); e7, disease duration vs. Evan’s Index; e8, disease duration vs. Caudate Head Index; f1, disease duration vs. Cella Media Index; f2, disease duration vs. the maximum width of the 3rd ventricle; f3, disease duration vs. the maximum width of the 4th ventricle; f4, disease duration vs. MFSS; f5, disease duration vs. MIF; f6, disease duration vs. MSF; f7, disease duration vs. lesion load along both visual pathways; f8, disease duration vs. lesion load along the anterior right visual pathway; g1, disease duration vs. lesion load along the anterior left visual pathway; g2, disease duration vs. lesion load along the posterior right visual pathway; g3, disease duration vs. lesion load along the posterior left visual pathway; g4, disease duration vs. EDSS; g5, disease duration vs. RNFL (right eye); g6, disease duration vs. RNFL (left eye); g7, RNFL (right eye) vs. EDSS; g8, RNFL (right eye) vs. EDSS. Regression analyses demonstrated only weak correlations between the examined parameters a1-g8 of all 28 MS patients included in this study and associated subgroups (RRMS without ON, RRMS with ON, SPMS without ON, SPMS with ON). Of note, the plotted linear regression curves in a1 –g8 are calculated for the analysis of all included MS patient.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4643899&req=5

pone.0142272.g001: white squares, RRMS without ON; black squares, RRMS with ON; white triangles, SPMS without ON; black triangles, SPMS with ON; black line, linear regression curve. Abbreviations: OD, oculus dexter (right eye); OS, oculus sinister (left eye); RNFL, retinal nerve fiber layer; NAA, N-acetyl-aspartate; Cho, choline; Cr, creatine; NAWM, normal appearing white matter; MIF, the maximum width of the anterior interhemispheric fissure; MSF, the maximum width of the Sylvian fissure; MFSS, the maximum frontal subarachnoid space; EDSS, expanded disability severity scale. a1-g8, linear regression curves for: a1, RNFL vs. NAA (right eye); a2, RNFL vs. NAA (left eye); a3, RNFL vs. Cho (right eye); a4, RNFL vs. Cho (left eye); a5, RNFL vs. Cr (right eye); a6, RNFL vs. Cr (left eye); a7, disease duration vs. NAA in the NAWM; a8, disease duration vs. Cho; b1, RNFL vs. lesion load (right eye); b2, RNFL vs. lesion load (left eye); b3, RNFL vs. lesion load per brain volume (right eye); b4, RNFL vs. lesion load per brain volume (left eye); b5, RNFL vs. lesion load along anterior right visual pathway (right eye); b6, RNFL vs. lesion load anterior right visual pathway (left eye); b7, RNFL vs. lesion load along anterior left visual pathway (right eye); b8, RNFL vs. lesion load anterior left visual pathway (left eye); c1, RNFL vs. lesion load along posterior right visual (right eye); c2, RNFL vs. lesion load along posterior left visual pathway (left eye); c3, RNFL vs. lesion load along posterior left visual (right eye); c4, RNFL vs. lesion load along posterior left visual pathway (left eye); c5, RNFL vs. Evan’s Index (right eye); c6, RNFL vs. Evan’s Index (left eye); c7, RNFL vs. Caudate Head Index (right eye); c8, RNFL vs. Caudate Head Index Index (left eye); d1, RNFL vs. Cella Media Index (right eye); d2, RNFL vs. Cella Media Index (left eye); d3, RNFL vs. Basal Cistern Index (right eye); d4, RNFL vs. Basal Cistern Index Index (left eye); d5, RNFL vs. the maximum width of the 3rd ventricle (right eye); d6, RNFL vs. the maximum width of the 3rd ventricle (left eye); d7, RNFL vs. the maximum of the 4th width ventricle (right eye); d8, RNFL vs. the maximum of the 4th width ventricle (left eye); e1, RNFL vs. MFSS (right eye); e2, RNFL vs. MFSS (left eye); e3, RNFL vs. MIF (right eye); e4, RNFL vs. MIF (left eye); e5, RNFL vs. MSF (right eye); e6, RNFL vs. MSF (left eye); e7, disease duration vs. Evan’s Index; e8, disease duration vs. Caudate Head Index; f1, disease duration vs. Cella Media Index; f2, disease duration vs. the maximum width of the 3rd ventricle; f3, disease duration vs. the maximum width of the 4th ventricle; f4, disease duration vs. MFSS; f5, disease duration vs. MIF; f6, disease duration vs. MSF; f7, disease duration vs. lesion load along both visual pathways; f8, disease duration vs. lesion load along the anterior right visual pathway; g1, disease duration vs. lesion load along the anterior left visual pathway; g2, disease duration vs. lesion load along the posterior right visual pathway; g3, disease duration vs. lesion load along the posterior left visual pathway; g4, disease duration vs. EDSS; g5, disease duration vs. RNFL (right eye); g6, disease duration vs. RNFL (left eye); g7, RNFL (right eye) vs. EDSS; g8, RNFL (right eye) vs. EDSS. Regression analyses demonstrated only weak correlations between the examined parameters a1-g8 of all 28 MS patients included in this study and associated subgroups (RRMS without ON, RRMS with ON, SPMS without ON, SPMS with ON). Of note, the plotted linear regression curves in a1 –g8 are calculated for the analysis of all included MS patient.
Mentions: Neither the RNFL nor TMV was found to correlate strictly with: (1) brain metabolites in the NAWM (NAA, Cho and Cr) or (2) the various brain atrophy indices and lesion load in the visual pathways. Evan’s ratio, CHI, CMI, BCI were found to be within normal range in all 28 patients even though global brain atrophy was detectable on MRI. This may suggest that these indices were not applicable to the brain atrophy seen in the MS patients in this study (Table 3). The atrophy detected in MS patients seemed to be described better by other parameters such as the maximum width of 3rd and 4th ventricles, MIF, MSF and MFSS (see results and Table 1, patient 1, 24 and 25, Fig 1). Usually the whole brain volume and white and grey matter volume/fractions are determined in MRT studies of MS patients to detect even mild brain atrophy. Also in most of our included MS patients there could at least a mild brain atrophy be detected by inspection of his/her MRI by a skilled radiologist and or neurologist. Interestingly, also in those MS patients with marked brain atrophy also the RNFL or TMV were not significantly reduced (this applies also for the further 2 years follow-up [38; 39]). However, we state clearly that the brain atrophy indices—we have used here—have potential methodological limitations and basically do not correlate strictly with disease course or clinical progression in all MS patients as this has been shown for so many other MRI parameters before [1].

Bottom Line: 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.Whether these changes are found in all MS patients, and if there is a correlation with clinical disease state, remains controversial.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, SMZ-Ost Donauspital, A-1220 Langobardenstrasse 122, Vienna, Austria.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus