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April2013 Vol.50 Issue:      2 Table of Contents
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Pattern of Optical Coherence Tomography in Multiple Sclerosis

Dina Abdel Gawad Zamzam1, Ahmed Taha Ismail2, Amr Abdel Moneim1, Ahmed Elbassiouny1

Departments of Neurology1, Ophthalmology2; Ain Shams University; Egypt

 



ABSTRACT

Background: Optic neuritis (ON) is strongly associated with multiple sclerosis (MS). Optical coherence tomography (OCT) has the potential to provide a reliable means of capturing axonal deficits, which can be paired to tests of visual function to provide a structural functional paradigm of brain injury. Objective: We aimed to evaluate retinal nerve fibre layer (RNFL) and total macular volume (TMV) thickness in MS patients with and without optic neuritis, and to correlate our findings with clinical measures of disability and MRI findings. Methods: Forty patients with MS were recruited from the outpatient clinics and the Neurology Department at Ain Shams University hospitals, with age range 16-53 years, with and without optic neuritis and 16 age and sex matched healthy controls were enrolled in this study. All patients were subjected to history, clinical evaluation, extended disability status scale (EDSS) for disease severity, MRI brain with contrast, visual evoked potential (VEP) and high-resolution spectral-domain OCT to assess the RNFL and TMV of the optic nerve. The control group performed OCT. Results: RNFL and TMV thinning was significantly correlated with the MS group in all field sectors with and without ON, compared to the control group. No correlation was found between OCT and VEP among MS group. TMV was inversely correlated with MRI finding in contrast to RNFL, where no correlation was found. Conclusion: RNFL and TMV thickness was significantly decreased in MS with and without ON. In addition, there were significant differences in RNFL and TMV thickness within field quadrants. [Egypt J Neurol Psychiat Neurosurg.  2013; 50(2): 205-212]

 Key Words: Optical coherence tomography, Retinal nerve fibre layer, MS, Optic neuritis.

Correspondence to Dina Abdelgawad Zamzam. Department of Neurology and Psychiatry, Faculty of Medicine, Ain Shams University, Cairo, Egypt. e-mail: Dina.zamzam@hotmail.com.




INTRODUCTION

 

The most common ocular presentation in MS patients is optic neuritis (ON).  It is the initial clinical manifestation of MS in up to 20% of patients and occurs in more than 50% of patients over the course of the disease.1 Sequential involvement of the optic nerves is common. However, about one-third of optic neuritis patients present with a mildly swollen optic disc (papillitis); with rare association of haemorrhages or exudates.2 There is growing evidence of a relationship between retinal nerve fiber layer (RNFL) thinning; as detected by optical coherence tomography (OCT), and the pathophysiology of multiple sclerosis (MS).3 Involvement of the optic nerve and RNFL in MS can occur either in association with optic neuritis (ON) or as a result of subclinical axonal loss.4 Thus, optic nerve damage will result in some degree of RNFL loss, regardless of whether it occurs in the context of ON or not, and in spite of normal visual function. Furthermore, axonal loss is assumed to occur early in the course of the disease.4-6 Axonal loss is a key prognostic factor in MS and a primary target for neuroprotective treatment strategies. Accordingly, the

 

quantification of subtle axonal degeneration and its differentiation from axonal damage following acute optic neuritis will require enormous precision. This is to effectively monitor the disease processes responsible for disability in MS and thus monitor the impact of disease-modifying therapies

 

Aim of the Work

To evaluate retinal nerve fiber layer (RNFL) and total macular volume (TMV) thickness in MS patients with and without ON unilateral or bilateral and to correlate our findings with clinical measures of disability and MRI findings for disability in MS and thus monitor the impact of disease-modifying therapies.

 

SUBJECTS AND METHODS

 

This is a cross-sectional study of forty patients with multiple sclerosis were recruited from the Neurology Department Ain Shams University hospitals and sixteen age and sex matched healthy control subjects.

               Study included age range between 16-53 years and a definite diagnosis of multiple sclerosis according to McDonald’s criteria 20107, both sexes, MS patients with and without optic neuritis.

Age and sex matched 16 healthy controls and with a visual acuity of 20/30 or better, with neither ophthalmic, nor neurologic diseases or medical history of DM, HTN, renal or liver diseases, were recruited from the medical staff, and subjected for OCT.

The forty  MS patients were subjected to the following (a) detailed history taking and complete neurological examination, (b) level of disability from MS assessed with the Extended Disability Status Score (EDSS)8, duration was calculated as time since diagnosis in years, (c) MRI brain with contrast, (d) pattern reversal VEP for bilateral eyes, (e) visual acuity using Snellen test, and fundus examination, (f) participants underwent SD-OCT examination using the Heidelberg Engineering Spectralis. (Heidelberg Engineering, Heidelberg Germany). RNFL images were acquired by taking three circular 3.4 mm diameter scans, centered the mean of which was used to express RNFL thickness in four quadrants (temporal, superior, inferior and nasal). The thicknesses of the quadrants were automatically calculated by the OCT device software. Macular thickness maps were acquired by making six radial linear scans, centered on the fovea, and by construction of a map from these scans

We excluded (a) patients with a recent clinical diagnosis of optic neuritis (less than 6 months) prior to the study, (b) patients with a refractive error of ± ≥ 5.0 diopters with a history of eye disease that may impact significantly on OCT measures (particularly those reducing RNFL thickness such as glaucoma, anterior  ischemic optic neuropathy, high myopia, and congenital abnormalities of the optic nerves), or history of ocular surgery or penetrating trauma, (c) other neurological disease with possible ocular manifestations, (d) other medical diseases such as hypertension and diabetes mellitus, (e) visual acuity 20/20 (Snellen scale) or less in both eyes (because this would preclude some of the examinations), (f) contraindication to MRI.

 

Statistical Analysis

Quantitative data are presented as mean and standard deviation (SD). Categorical results are presented as numbers of cases and percentages. Quantitative variables were compared using student T-test or the Mann–Whitney U-test, depending on the distribution of data. Categorical variables were compared using the chi-square test or fisher exact test. Pearson’s correlation coefficient was used to assess the correlation between quantitative variables. The receiver operating characteristic (ROC) curve was used to evaluate the Sensitivity and specificity for quantitative diagnostic measures that categorize cases into one of two groups. A significance level of P <0.05 was used in all tests .All statistical procedures were carried out using SPSS version 15 for Windows (SPSS Inc, Chicago, IL, USA).

 

RESULTS

 

Forty hospital- based patients with clinically-definite MS (age 30.4±7.8) were enrolled in this study, 11 males and 29 females and 16 matched healthy controls 6 males and 10 females (age 29.4±21) were included. The forty MS patients have (80) eyes divided into two groups MS with optic neuritis (MS-ON) (31 eyes) and MS with no-optic neuritis (MS-NON) (49 eyes),

Retinal nerve fiber layer thickness and Total macular volume in the 2 groups of Multiple sclerosis patients with or without optic neuritis where compared to healthy controls.

Both groups MS with no optic neuritis (49 eyes) and MS with optic neuritis (31 eyes) showed high significance regarding reduction in RNFL compared to healthy controls  (mean 96.57 µm and 113.78 µm. respectively, P=0.0001 in MS-NON and in MS-ON (mean 90.7 µm) (P=0.0001)) with no significant difference between both groups (Figure 1). In contrast, no correlation was found between both groups of MS patients and healthy controls as regard TMV (Figure 2).

ROC Curve was used for differentiation of MS cases from controls with a cut-off point ≤102.5 µm with 84% specificity and 78% sensitivity for RNFL and TVM cut-off point was ≤257 mm3 with 78% specificity and 58% sensitivity (Tables 2 and 3).

Retinal nerve fiber layer and Total macular volume in multiple sclerosis group compared to MRI lesions. MS patients having RNFL ≤ 102.5 (62 eyes) correlated to MRI brain lesion load (number of T2 lesion and enhanced lesions). Also, there is correlation between MS patients having TMV less than or equal 257 (46 eyes) in relation to MRI lesion load (number of T2 lesion and enhanced lesions) (table 4). In our study, there was no significant correlation between MS patients (62 eyes) having RNFL ≤ 102.5 and MRI lesions (P=0.383). While there was significant inverse correlation with TMV (46 eyes having TMV ≤ 257) and MRI brain lesion load (P=0.007).

We compared total MS patients (80 eyes) to the healthy controls as regard RNFL and TMV in four quadrant of fields (temporal, superior, inferior and nasal). The results showed that there is significant thinning in RNFL most evident in the temporal quadrant (mean thickness 57.94 µm, in MS group compared to 80.94 µm in HC group) followed by inferior quadrant compared to the HC (P=0.001) (Figure 3). While TMV was significantly reduced in the temporal and nasal sectors (P=0.013, 0.037 respectively) (Figure 4).

Regarding RNFL thickness in four quadrants of field we compared the two groups of MS patients with or without optic neuritis with healthy controls. There was a highly significant correlation in the inferior, superior and nasal quadrants among patients no optic neuritis (P=0.0001) while all quadrant of fields are highly correlated in the group of patient with optic neuritis. TMV was significantly correlated with the inferior quadrant of field MS patient with no optic neuritis (P= 0.048) and highly correlated with the temporal and inferior sectors in patients with optic neuritis.

The values of RNFL and TMV did not correlate with neither EDSS of patients nor the duration of illness, or the visual evoked potential results (demyelinating and axonal).


 

 

Table 1. Demographic data of Multiple sclerosis group.

 

MS GROUP (n= 40)

Mean

±SD

Minimum

Maximum

Median

Age ( in year)

30.4

7.8

16.0

53.0

29

Duration of disease ( In year)

6.3

4.8

1.0

23.0

5

EDSS

3.3

1.8

0.0

7.5

3

Gender

Male (n %)

11

27.5%

 

 

 

Female (n %)

29

72.5%

 

 

 

Family History

Negative (n %)

38

95.0%

 

 

 

Positive (n %)

2

5.0%

 

 

 

Optic Neuritis

(n=80 eyes)

No (n %)

49

61.3%

 

 

 

Yes (n %)

31

38.8%

 

 

 

MS Multiple sclerosis, EDSS Extended disability status scale

 

 

 

HC healthy control, MS-ON multiple sclerosis with optic neuritis, MS-NON multiple sclerosis without optic neuritis, RNFL Retinal nerve fiber layer

 

Figure 1. Comparison between Multiple sclerosis with optic neuritis and Multiple sclerosis

without optic neuritis and healthy controls as regard Retinal nerve fiber layer (RNFL).

 

HC healthy control, MS-NON multiple sclerosis without optic neuritis, MS-ON multiple sclerosis with optic neuritis, TMV total macular volume

 

Figure 2. Comparison between Multiple sclerosis with optic neuritis and multiple sclerosis without optic neuritis and healthy controls as regard Total macular volume.

 

Table 2. Receiver operating characteristic curve for differentiation of Multiple sclerosis cases from controls using retinal nerve fibre layer.

 

 

Cu-off

AUC

95% CI

Sensitivity

Specificity

PPV

NPV

P

RNFL

(µm)

≤102.5

0.47

0.875

0.810-0.939

78%

84%

92.5%

60%

0.001*

RNFL Retinal nerve fiber layer

*Significant at P<0.01

 

Table 3. Receiver operating characteristic curve for differentiation of multiple sclerosis cases from controls using total macular volume.

 

 

Cut-off

AUC

95% CI

Sensitivity

Specificity

PPV

NPV

P

TMV

(mm3)

≤257

0.47

0.637

0.519-.755

58%

72%

83.6%

40.3%

0.024*

TMV Total macular volume

*Significant at P<0.01

 

Table 4. Correlations between Retinal nerve fiber layer ≤102.5 and Total macular volume ≤ 257 and MRI brain among Multiple sclerosis patients.

 

MS

(n= 62 eyes)

 

MRI number of T2 Lesion

MRI number of enhanced Lesion

RNFL (µm)

R

-0.119

-0.113

P

0.358

0.383

MS

(n= 46 eyes)

 

MRI number of T2 Lesion

MRI number of enhanced Lesion

TMV (mm3)

R

-0.392

-0.393

P

0.007

0.007

MS multiple sclerosis, RNFL retinal nerve fiber layer, TMV total macular volume

 

 

Figure 3. Retinal nerve fiber layer (RNFL) thinning was highly correlated with

the temporal sector in the Multiple sclerosis group

 

 

 

Figure 4. Total macular volume (TMV) thinning was correlated with the

temporal sector in the Multiple sclerosis group

Table 5. Correlations between field measurements and TMV and RNFL among MS-NON versus MS-ON cases.

 

MS -NON

(n=49 eyes)

 

TMV

RNFL

Temporal

R

0.107

0.297

P

0.462

0.038*

Superior

R

0.098

0.794

P

0.503

0.0001**

Inferior

R

0.284

0.838

P

0.048*

0.0001

Nasal

R

0.186

0.647

P

0.200

0.0001**

MS –ON

(n=31 eyes)

 

TMV

RNFL

Temporal

R

0.459

0.624

P

0.009**

0.0001**

Superior

R

0.277

0.892

P

0.131

0.0001**

Inferior

R

0.486

0.956

P

0.006**

0.0001**

Nasal

R

0.250

0.755

P

0.174

0.0001**

MS-NON multiple sclerosis without optic neuritis, MS-ON multiple sclerosis with optic neuritis, RNFL Retinal nerve fiber layer, TMV total macular volume

 

 

 

MS-NON multiple sclerosis without optic neuritis, MS-ON multiple sclerosis with optic neuritis

 

Figure 5. Correlations between field measurements and TMV and RNFL among MS-NON versus MS-ON.


DISCUSSION

 

Multiple sclerosis is the most common demyelinating disorder of the central nervous system.9 Almost half the patients present with ocular findings as the initial manifestation of the disease. There are numerous neuro-ophthalmic findings in MS, ranging from subclinical to disabling visual deficit.

In Comparing RNFL thickness among MS patients (80 eyes) and HC (32 eyes), RNFL was greatly reduced in MS group compared to HC group  and thinning of RNFL was also correlated with MS-NON and in MS-ON compared to HC group. There was no significant difference in RNFL between MS-ON and MS-NON. Also no correlations, was found as regard TMV in both groups .In agreement to our findings, studies have shown that OCT-measured RNFL values are reduced in patients with MS with and without a history of ON. However, RNFL atrophy tends to be greater in ON-affected eyes6, 10. This was in agreement with Timm and colleagues11, who found pronounced thinning of RNFL and TMV in both MS-ON and MS-NON eyes when compared to HC eyes. However, in our study no correlation was found as regard TMV possibly because of the small number of the sample. Comparing the disease severity using EDSS and RNFL thickness among MS group, EDSS and disease duration, no correlation was found. Sepulcre and colleagues12 found an inverse correlation between RNFL thickness and neurologic disability measured by the EDSS score (thinner RNFL correlated with worse disability). Another study found the same inverse correlation between RNFL thickness and disease duration or EDSS in a population of 52 MS patients who were not receiving any immune-modulating therapy13. However, in contrast to their results, disease duration and EDSS were not correlated in our study possibly the small number of our sample that may explain these inconsistent findings.

Magnetic resonance image findings are considered the most sensitive and reliable markers for assessing inflammatory and axonal pathology in patients with multiple sclerosis. In our study, there was no significant correlation between MS patients (62 eyes) having RNFL ≤ 102.5 and MRI lesions. While there was significant inverse correlation with TMV (46 eyes having TMV ≤ 257) and MRI brain lesion load (the less TMV the more lesion in MRI brain). In a study by Costello and colleagues14, they found no association between RNFL values and MRI status in ON patients which correlates with our findings.

When comparing RNFL and TMV Field measurements in MS group, and HC, we found RNFL thinning was highly correlated with MS group in all field sectors compared to the healthy control and most evident in the temporal quadrant. RNFL thickness was reduced in the inferior, superior and nasal quadrant among MS patient with no optic neuritis, while it was markedly reduced in all quadrants in patient with optic neuritis, TMV was significant correlated with inferior quadrant in MS-ON while it was highly correlated to the temporal sector in patient with ON. These results were in agreement with many other studies12,14,15, which showed thinning of RNFL and TMV correlated with the temporal, superior and inferior field sectors.

In comparing RNFL and TMV and VEP in MS group. No significant correlation was found with VEP findings both axonal and demyelinating lesions in MS group. VEPs are not typically necessary for patients with clear clinical evidence of ON.  However, VEPs may be a valuable tool for assessing subclinical lesions.

 

Conclusion

(i) Optical coherence tomography confirms the presence of optic disc affection of patient with optic neuritis showing axonal atrophy developing at least six months after the event of optic neuritis in the form of reduction of the RNFL thickness. (ii) The RNFL thickness can be used to detect visual disability. (iii) OCT can detect subclinical axonal loss in patients with no optic neuritis having normal visual acuity and visual fields. (iv) The temporal quadrant is the most vulnerable to the disease process. (v) Reduced temporal thickness is often the only sign that may differentiate multiple sclerosis patients from healthy subjects.

 

[Disclosure: Authors report no conflict of interest]

 

REFERENCES

 

1.        Jacobs DA, Galetta SL. Multiple sclerosis and the visual system. Ophthalmol Clin North Am. 2004; 17(3): 265-73.

2.        Nilsson P, Larsson EM, Maly-Sundgren P, Perfekt R, Sandberq-Wollheim M. Predicting the outcome of optic neuritis: Evaluation of risk factors after 30 years of follow-up. J Neurol. 2005; 252(4): 396-402.

3.        Trip SA, Schlottmann PG, Jones SJ, Li WY, Garway-Heath DF, Thompson AJ, et al. Optic nerve atrophy and retinal nerve fibre layer thinning following optic neuritis. Evidence that axonal loss is a substrate of MRI-detected atrophy. Neuroimag. 2006; 31: 286-93.

4.        Sergott RC, Frohman E, Glanzman R, Al-Sabbagh A; OCT in MS Expert Panel. The role of optical coherence tomography in multiple sclerosis: expert panel consensus. J Neurol Sci. 2007; 263: 3-14.

5.        Albrecht P, Frohlich R, Hartung HP, Kieseier BC, Methner A. Optical coherence tomography measures axonal loss in multiple sclerosis independently of optic neuritis. J Neurol. 2007; 254: 1595-6.

6.        Pueyo V, Ara JR, Almarcegui C, Martin J, Güerri N, García E, et al.  Sub-clinical atrophy of the retinal nerve fiber layer in multiple sclerosis. Acta Ophthalmol. 2010; 88: 748-752.

7.        Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis 2010 Revisions to the McDonald criteria. Ann Neurol. 2011; 69(2): 292-302.

8.         Kurtzke JF.  Rating  neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983; 33(11):1444-52. 

9.        Wang J, Cheng H, Hu YS, Tang RA, Frishman LJ. The photopic negative response of the flash Electroretinogram in multiple sclerosis. Invest Ophthalmol Vis Sci. 2012; 53(3): 1315-23.

10.     Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004; 364(9451): 2106-12.

11.     Oberwahrenbrock T,  Schippling S, Ringelstein M, Kaufhold F,  Zimmermann H,  Keser N, et al. Retinal Damage in Multiple Sclerosis Disease Subtypes Measured by High-Resolution Optical Coherence Tomography. Mult Scler Int. 2012; 2012: 530305. doi:  10.1155/2012/530305.

12.     Sepulcre J, Murie-Fernandez M, Salinas-Alaman A, Garcia-Layana A, Bejarano B, Villoslada P. Diagnostic accuracy of retinal abnormalities in predicting disease activity in MS. Neurology. 2007; 68: 1488-94.

13.     Spain RI, Maltenfort M, Sergott RC, Leist TP. Thickness of retinal nerve fiber layer correlates with disease duration in parallel with corticospinal tract dysfunction in untreated multiple sclerosis. J Rehabil Res Dev. 2009; 46: 633-42. 

14.     Costello F, Hodge W, Pan YI. Exploring the Association between Retinal Nerve Fiber Layer Thickness, and Initial Magnetic Resonance Imaging findings in patients with Acute Optic Neuritis.  Mult Scler Int. 2011; 2011: 289785. doi: 10.1155/2011/289785

15.     Lamirel C, Newman NJ, Biousse V. Optical Coherence Tomography (OCT) in Optic Neuritis and Multiple Sclerosis. Rev Neurol (Paris). 2010; 166(12): 978-86.


 

 

الملخص العربي

 

نمط مرض التصلب المتناثر فى التصوير المقطعي للتماسك البصري

 

           يرتبط التهاب العصب البصري بمرض التصلب المتناثر، ويملك التصوير المقطعي للتماسك البصري القدرة على توفير وسيلة لالتقاط الضرر بالمحاور العصبية والتي يمكن إضافتها لاختبارات الوظائف البصرية النموذج الهيكلي التشريحي الوظيفي للإصابة المخية.

 

الأهداف: تهدف هذه الدراسة إلى تقييم سمك طبقة الألياف العصبية بالشبكية والحجم الكلي للبقعة الصفراء لمرض التصلب المتناثر سواء كانوا يعانون أم لا من التهاب العصب البصري في إحدى أو كلتا العينين ومقاربة هذه النتائج بالمقاييس الإكلينيكية لمعدلات الإعاقة ونتائج الرنين المغناطيسي.

الموضوع وطريقة البحث: تمت الدراسة على أربعون من مرضى التصلب المتناثر المترددون على مستشفيات جامعة عين شمس، احدى عشر رجال وتسع وعشرون  نساء، تراوحت أعمارهم بين السادسة عشر والثالثة والخمسون سواء أكانوا يعانون أم لا من التهاب العصب البصري بالإضافة لمجموعة ضابطة تتكون من سنة عشر أصحاء المتماثلين في العمر والجنس، تم فحص جميع الحالات بواسطة التاريخ المرضي، مقياس حالة الإعاقة الممتد لقياس شدة المرض، رنين مغناطيسي على المخ بالصبغة، الموجات المستفزة للعصب البصري والتصوير المقطعي للتماسك البصري عالي الدقة لقياس سمك طبقة الألياف العصبية بالشبكية والحجم الكلي للبقعة الصفراء.

النتائج:

1.    انخفاض سمك طبقة الألياف العصبية بالشبكية والحجم الكلي للبقعة الصفراء في جميع قطاعات مرض التصلب المتناثر سواء أكانوا يعانون أم لا من التهاب العصب البصري مقارنة بالمجموعة الضابطة.

2.    عدم وجود ارتباط عكسي بين الحجم الكلي للبقعة الصفراء ونتائج الرنين المغناطيسي بعكس سمك طبقة الألياف العصبية بالشبكية التي لم تثمر أي نتائج ذات دلالة إحصائية واضحة.

3.    ختاماً، انخفاظ سمك طبقة الألياف العصبية بالشبكية والحجم الكلي للبقعة الصفراء في مرض التصلب المتناثر سواء في وجود التهاب العصب البصري أو عدمه.

4.       



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