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April2014 Vol.51 Issue:      2 Table of Contents
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Radiologically Isolated Syndrome and its Possibility for Clinical Conversion to Multiple Sclerosis

  Wael A. Fadel, Wafik S. Bahnasy, Ehab A. El-Seidy, Yasser A. El-Heneedy,

Tarek M. El-Gammal, Khaled H. Rashed

Department of Neuropsychiatry, Tanta University; Egypt



ABSTRACT

Background: There is increasing incidence of abnormal MRI findings suggestive of multiple sclerosis (MS) in persons without MS symptoms, which is termed as radiologically isolated syndrome (RIS). These RIS people have increased incidence of clinical conversion to MS. Objective: To follow up a group of RIS persons both clinically and by some investigations to assess the possibility of conversion to MS. Methods: This study included 28 RIS patients who were followed up by clinical examination, brain and cervical MRI and visual evoked potential (VEP) for early detection of the development of clinical conversion to MS. Results: Six of 28 cases of RIS persons (21.4%) developed clinical manifestations of MS within 2 years follow up. Mean age of clinically converted cases were 22.6 years (SD±1.3), 5 patients were female, 2 patients had cervical MRI lesions, 4 patients had infratentorial MRI lesions and 4 patients had delayed P100 of VEP study. Conclusion: Patients with RIS are at high risk of developing clinical manifestations of MS especially those with baseline younger age, female sex, presence of periventicular high lesion number, cervical, infratentorial lesions and abnormally delayed VEP. [Egypt J Neurol Psychiat Neurosurg.  2014; 51(2): 229-234]

 

Key Words: Radiologically Isolated Syndrome, RIS, Multiple Sclerosis, MRI and Visual Evoked Potential, VEP.

Correspondence to Wafik S. Bahnasy, Department of Neuropsychiatry Tanta University, Egypt.Tel: +201060637106. Email: wafikbahnasy@gmail.com






INTRODUCTION

 

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS that affect over 2.5 million people worldwide and is the leading cause of serious neurological disabilities in young adults.1,2 The underlying pathogenic mechanisms of MS include inflammation, demyelination, and axonal loss, followed by chronic axonal degeneration later on.3 Laboratory and radiological assistance in the diagnosis of MS had been introduced since 1983 to avoid waiting for the occurrence of second clinical relapse.4

MRI has become increasingly available since its introduction in the early 1980s. Over 200 million MRI examinations had been performed by 2006 and the number of examinations continues to increase rapidly. With increasing availability, there has been an increase in the abnormal incidental findings and an increased awareness of MRI findings suggestive of MS in patients without typical MS symptoms.5,6 These MRI findings are termed radiologically isolated syndrome (RIS) which is defined as incidental MRI findings highly suggestive of MS in an asymptomatic patient lacking any history, symptoms, or signs of MS.6

Few case reports have been published on patients with asymptomatic demyelinating lesions with suspicion and final progression to clinically evident MS.7 There is increasing interest and research in RIS patients especially with the improvement in diagnosis and the advent of disease modifying treatment for MS.8 Studies have aimed to better understand disease cause and pathogenesis, to improve the accuracy of MS diagnostic criteria.9 Several studies suggest that short interval between radiological finding and first clinical manifestation within 2 years is of high indicator for long term disability.10

It is important to avoid over-estimation of the subcortical white matter lesions which can be caused by various disorders that may undergo dynamic radiological changes such as vasculitis and migraine.11,12

Aim of work: To follow up a group of RIS persons both clinically and by some investigations to assess the possibility of conversion to MS.

 

SUBJECTS AND METHODS

 

This study included 28 cases accidently diagnosed as RIS patients attending the outpatient neurology clinic of the neuropsychiatry department, Tanta university hospital and ordered to do brain or spinal cord MRI for various complaints from the first of January 2010 to the end of December 2012. The patients were followed up regularly for at least 2 years or until the patient developed clinical manifestations suggestive of MS.

Brain RIS were diagnosed according to Okuda and colleague 200913, who stated that brain RIS are incidentally identified MRI white matter anomalies which are (a) ovoid, well-circumscribed and homogeneous foci with or without involvement of the corpus callosum, (b) T2 hyperintensities measuring >3mm and fulfilling Barkhof criteria for dissemination in space, and (c) white matter anomalies not consistent with a vascular pattern. The criteria also included cases with (1) no historical accounts of remitting clinical symptoms consistent with neurologic dysfunction, (2) MRI anomalies do not account for clinically apparent impairments in social, occupational or generalized areas of functioning, and (3) MRI anomalies are not due to the direct physiologic effects of substances or a medical condition with exclusion of individuals with MRI phenotypes suggestive of leukoaraiosis or extensive white matter pathology lacking involvement of the corpus callosum.

Cervical RIS were diagnosed according to Okuda and colleague 200913, who stated that cervical RIS are (a) focal or multifocal involvement of the spinal cord parenchyma with ovoid well-circumscribed lesions, (b) non-contiguous lesions involving more than 2 spinal segments. Imaging anomalies present in more than one MRI sequence, (c) no better explanation for observed abnormality.

We excluded patients aged more than 45 years, patients having cerebro-vascular risk factors, patients suspected to have collagenic disorders and patients having MRI contraindication or irregular follow up.

All patients were subjected to detailed medical history and thorough neurological examination, routine laboratory investigations, contrasted brain and/or cervical spinal cord MRI and VEP study through assessing of P 100. Follow up by repeated neurological examination and repeated MRI every 6 months or when clinical symptoms develop.

 

Statistical Analysis

Statistical analysis was performed using the Statistical Package for Social Sciences for Windows (SPSS Inc., Chicago, IL, USA, Version 16.0). The results were provided as percent of affected cases and also mean ± standard deviation. P value less than 0.05 was considered as statistically significant.

 

RESULTS

 

This study was conducted on 28 RIS patients. The ages of patients ranged from 19-34 years (26.4±1.6). Regarding patients' sex, eight cases were males and 20 cases were females.

The main indications for MRI were; 11 patients complained of headache, four patients had cervical pain, two patients had cranio-cerebral trauma, two patients had positional vertigo, two patients had mild cognitive symptoms, two patients had somatoform disorders, two patients complain of tinnitus, and three patients had dysthesia in the distribution of one trigeminal division (Table 1).

Neurological examination showed that two patients had temporal optic disc pallor, three had unsustained nystagmus, three had unilateral subjective trigeminal numbness and five had brisky reflexes. The remaining patients showed normal neurologic examination.

Regarding baseline MRI results, 27 patients (96%) had T2 hyperintense periventricular lesions; 16 patients (57%) had ≥ nine periventricular lesions and 11 patients (39%) had 3-9 periventricular lesions, five patients (17%) had juxta-cortical lesions, 13 patients (46%) had infratentorial lesions, and four patients (14%) had cervical spinal cord lesions. Regarding baseline VEP, 12 patients (42.9%) had delayed P100 (Table 2). The Delay ranged between 107-117 (111.3±2.4) (Table 2).

By the end of the research, six cases (21.4%) had developed clinical manifestations of MS 4 cases were presented by headache and two cases were presented by trigeminal dysthesia. Two cases developed MS within the first year of follow up and the remaining four cases developed MS within the second year. The mean duration for development of clinical manifestations was 1.3 years from the date of first MRI.

Regarding clinical follow up, out of six clinically converted patients; three cases (50%) developed optic neuritis, two cases (33.3%) developed long tract affection, two case (33.3%) developed cerebellar manifestations, two cases (33.3%) had brain stem manifestations and three cases (50%) had multifocal lesions. 

Clinically converted cases of RIS were more with younger age (22.6±1.3), female sex (83.3%) and presence of cervical (33.3%), infratentorial (66.7%) lesions and high number of supratentorial periventricular lesions. On the other hand, four out of clinically converted cases (66.7%) had delayed VEP at baseline (Table 3).

In follow up MRI studies, there were 10 patients showed radiological progression in the form of new FLAIR and T2 weighted hyperintense lesions and/or gadolinium enhanced lesions. These radiologically progressed cases were as follow; four patients with ≥9 periventricular lesion, one patient with juxta-cortical lesion, four patients with infra-tentorial lesions and three patients with spinal cord lesions. Follow up VEP study showed that four new cases (superadded to the 12 cases with delayed VEP at baseline examination) developed delayed P 100 in VEP; one of these patients was clinically converted to MS (Table 4 and Figure 1).

All clinically converted cases showed radiological progression. Five of them had silent MRI progression before the appearance of clinical manifestations. The sixth case showed radiological progression at the time of clinical conversion shortly before the time of first follow up.


 

Table 1. First Clinical presentation of RIS patients.

 

 

Number (28)

Percent

Headache

11

39.3%

Cervical pain

4

14.3%

Trigeminal dysthesia

3

10.7%

Cranio-cerebral trauma

2

7.14%

Vertigo

2

7.14%

Mild Cognitive impairment

2

7.14%

Somatoform disorder

2

7.14%

Tinnitus

2

7.14%

 

Table 2. Baseline MRI and VEP findings in RIS patients.

 

 

Number

Percent

≥ 9 periventricular lesion

16

57.1%

3 - 9 periventricular lesion

11

39.3%

Juxtacortical lesion

5

17.9%

Infratentorial lesion

13

46.4%

Spinal cord lesion

4

14.3%

Delayed P100 in visual evoked potential

12

42.5%

 

Table 3. Some demographic and baseline data of the clinically converted cases.

 

Age

Range

 

19 – 26

Mean ± SD

 

22.6 ± 1.3

Sex

Male

n

1

%

16.7%

Female

n

5

%

83.3%

MRI

Periventricular

n

6

%

100%

Juxt cortical lesion

n

1

%

16.7%

Infratentorial

n

4

%

66.7%

Spinal cord

n

2

%

33.3%

Visual Evoked Potential

Delayed

No

4

%

66.7%

Normal

No

2

%

33.3%

Table 4. Baseline versus follow up MRI and VEP Findings of RIS patients.

 

 

Baseline

Follow up

Number

%

Number

%

MRI Findings

 

≥ 9 periventricular lesion

16

57.1

20

71.4

3 - 9 periventricular lesion

11

39.3

8

28.5

Juxta cortical lesion

5

17.9

6

21.4

Infratentorial lesion

13

46.4

17

60.7

Cervical Spinal cord lesion

4

14.3

7

25

Gadolinium enhanced lesion

0

0

7

25

New T2 weighted lesion

0

0

8

28.5

Visual Evoked Potential

 

Delayed P 100

12

42.8

16

57.1

χ2

13.127

P-value

0.041*

*Significant at p<0.05

 

Figure 1. Brain MRI for a 23-year-old female with radiologically isolated syndrome showing

radiological progression (a) at time of baseline examination and (b) after 1 year follow up.

 

 


DISCUSSION

 

An asymptomatic period of unknown duration preceding the initial clinical presentation had been anticipated in MS for a long time.14,15 MRI can diagnose both dissemination in time and space of MS and thus help us for early diagnosis.15

In this study, 28 RIS persons had been followed up by clinical examinations contrasted MRI as well as VEP for 2 years to detect the incidence of clinical conversion among them.

Six persons (21.4%) out of followed up subjects had developed clinical manifestations of MS. These results are lower than that of Lebrun and colleague16 and Siva and colleague17, their incidence was 33% and 36% respectively. This difference may be due to longer duration of follow up among these studies.

Four from these clinically converted cases had headache as initial symptom and two cases had trigeminal dythesia. These data are in accordance with that of Liu and colleague.18 Current study showed that the mean duration for development of clinical conversion of MS was 1.3 years, which is shorter than that of Lebrun and colleague16 and Siva and colleague17, their results were 2.3 years and 2.4 years respectively. This difference is also due to longer duration of follow up in both studies.

The incidence of development of optic neuritis in clinically converted cases in this study is higher than that of Lebrun and colleague16 (50% versus 26% respectively). Long tract affection was also higher in this study when compared with that of Lebrun and colleague16 (33.3% versus 26% respectively). Regarding cerebellar manifestations, this study had higher incidence in clinically converted cases than that of Lebrun and colleague16 (33.3% against 24% respectively). Brain stem manifestation was also higher than that of Lebrun and colleague16 (33.3% against 21.7% respectively). This higher percent of each of the clinical conversion is due the development of multifocal manifestations in the studied cases.

Five out of the six clinically converted cases had silent radiological progression before the appearance of clinical manifestations and this result is in accordance with that of Okuda, and colleague13 as well as Morris and colleague. 19

In current study, the mean age of clinically converted cases was (22.6 ±1.3) and female sex was more liable (83.3%) which means that younger age and female sex are more liable for clinical conversion. These results are in harmony with that of Lebrun and colleague.16

Ten followed up cases showed radiological progression in periventricular, infratentorial and cervical spinal cord. All clinically converted cases were involved within those 10 patients. Liu and colleague18 concluded that approximately two-thirds of persons with RIS show radiological progression before the development of clinical manifestations. This difference is due to shorter duration of follow up in this study (2 years versus 5 years).

This study showed that, cases with baseline cervical RIS have higher incidence of radiological progression and clinical conversion. Okuda and colleague20 suggested that the presence of asymptomatic spinal cord lesions place subjects with RIS at substantial risk for clinical conversion. In addition, Liu and colleague18 stated that cervical cord lesions are important predictors of clinical conversion of RIS.

Regarding baseline VEP study, 12 patients (42.9%) had delayed VEP, which is in accordance with that of Lebrun and colleague21 and Tereza and colleague22 but lower than that of Lebrun and colleague.(64%)16 This higher incidence of delayed VEP in Lebrun and colleague16 may be due to number differences of studied cases.

Follow up VEP study showed that there were new four cases of RIS had delayed P100. Five out of 6 clinically converted patients were involved within those 16 cases with delayed P100. This means that abnormal VEP is an important predictor for clinical conversion of RIS to MS, which is in harmony with that of Lebrun and colleague.16

 

Conclusion

Patients with RIS are at high risk of developing clinical manifestations of MS especially those with baseline younger age, female sex, presence of periventricular high lesion number, cervical or infratentorial lesions and abnormally delayed VEP.

 

[Disclosure: Authors report no conflict of interest]

 

REFERENCES

 

1.        Confavreux C, Vukusic S. The clinical epidemiology of multiple sclerosis. Neuroimag. Clin N Am. 2008; 18:589-622.

2.        Weiner HL. The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease? Ann Neurol. 2009; 65:239-48.

3.        Koblet G, Berg J, Lindgren P, Kerrigan J, Russel N, Nixon R. Cost and quality of multiple sclerosis in United Kingdom. Eur J Health Econ. 2006; 7:96-104.

4.        Palace J.  Making the diagnosis of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2001; 71: ii3-8.

5.        McDonalds WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001; 50:121-7.

6.        Morris Z, Whiteley WN, Longstreth WT Jr, Weber F, Lee YC, Tsushima Y, et al. Incidental findings on brain magnetic resonance imaging: Systematic review and meta-analysis. BMJ. 2009; 339: b3016-21.

7.        Okuda DT, Mowry EM, Beheshtian A, Carbetree EC, Goodin DS, Waubant E, et al. Incidental MRI anomalies suggestive of multiple sclerosis: The radiologically isolated syndrome. Neurology. 2009; 72:800-5. Erratum: Neurology. 2009; 73:1714-20.

8.        Hakiki B, Goretti B, Portaccio E, Zipoli V, Amato MP. ‘Subclinical MS”: follow-up of four cases. Eur J Neurol. 2008; 15(8):858-61.

9.        Tintore M. Rationale for early intervention in with immunomodulatory treatments. J Neurol. 2008; 255 suppl 1:37-43.

10.     De Stefano N, Stromillo ML, Rossi F, Battaglini M, Giorgio A, Portaccio E, et al. Improving the characterization of radiologically isolated syndrome suggestive of multiple sclerosis. PLoS ONE. 2011; 6:e19452.

11.     Kurne A, Isikay IC, Karlioguz K, Kalyoncu U, Aydin OF, Calguneri M, et al. A clinically isolated syndrome: a challenging entity: multiple sclerosis or colagen tissue disorder: clue for differentiation. J Neurol. 2008; 255:1625-35.

12.     Rocca MA, Ceccarelli A, Falini A, Colombo B, Totorella P, Bernasconi L, et al. Brain Grey matter changes in migraine patients withT2 visible lesions: a 3T MRI study. Stroke. 2006; 37:1765-70.

13.     Okuda DT. Unanticipated demyelinating pathology of the CNS. Nat Rev Neurol. 2009; 5:591-97.

14.     Engeil T. A clinical patho-anatomical study of clinical silent multiple sclerosis. Acta Neurol Scand. 1989; 79:428-30.

15.     Miller D, Barkhof F, Montalban X, Thompson A, Filippi M. Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis and prognosis. Lancet Neurol. 2005; 4:281-8.

16.     Lebrun C, Bensa C, Debouverie M, Wiertevski S, Brassat D, de Seze J, et al. Association between clinical conversion to multiple sclerosis in radiologically isolated syndromes in magnetic resonance imaging, cerebrospinal fluid and visual evoked potential: follow up of 70 patients. Arch Neurology. 2009; 66:841-6.

17.     Siva A, Saip S, Altinatas A, Jacob A, Keegan BM, Kantarci OH. Multiple sclerosis risk in radiologically uncovered asymptomatic possible inflammatory demyelinating disease. Mult Scler. 2009; 15:918-27.

18.     Liu SKullnat JBourdette DSimon JKraemerDFMurchisonCet al. Prevalence of brain magnetic resonance imaging meeting Barkhof and McDonald criteria for dissemination in space among headache patients. Mult Scler. 2013; 19(8): 1101-5.

19.     Morris Z, Whiteley WN, Longstreth WT, Weber F, Lee YC, Tsushima Y, et al. Incidental findings in on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ. 2009; 339:b3016.  

20.     Okuda DTMowry EMCree BACrabtree ECGoodin DSWaubant E, et al. Asymptomatic spinal cord lesions predict disease progression in radiologically isolated syndrome. Neurology. 2011; 76(8):686-92.

21.     Lebrun C, Le Page E, Kantarci O, Siva A, Pelletier D, Okuda DT, et al. Impact of pregnancy on conversion to clinically isolated syndrome in a radiologically isolated syndrome cohort. Mult Scler. 2012; 18:271-80.

22.     %87 Gabelić T, Radmilović M, Posavec V, Skvorc A, Bošković M, Adamec I, %87et al. Differences in oligoclonal bands and visual evoked potentials in patients with radiologically and clinically isolated syndrome. Acta Neurologica Belgica. 2013; 113:13-7.


 

الملخص العربى

 

المتلازمة المعزولة راديولوجيا واحتماليه تحولها لمرض التصلب المتناثر

 

التغيرات المبكرة في أشعه الرنين المغناطيسي على المخ والنخاع الشوكي قبل ظهور الأعراض السريريه لمرض التصلب المتناثر أدي الى عمل كثير من الأبحاث لمحاوله التشخيص المبكر للمرض.

الهدف من البحث: أجرى هذا البحث لمتابعه الأشخاص الذين تم تشخيصهم المتلازمة المعزولة راديولوجيا وذلك بأشعة الرنين المغناطيسي الخاص بهم عن طريق الصدفة حيث أشتكى هؤلاء الأشخاص من الصداع أو آلام بالرقبة أو الوجه أو اصطدام بالرأس أو أعراض نفس جسدية أو دوار. هذه الأعراض لا تمثل أعراض مرض التصلب المتناثر.

الحالات وطرق البحث: شمل البحث 28 شخص وقد تم تحديد البؤر المرضية بأفلام الأشعة الخاصة بهم والتى هى مشابه لمرض التصلب المتناثر. تم متابعه المشاركين فى البحث كل 6 أشهر لمدة عامين من خلال الفحص السريري العصبى وذلك لتشخيص أية أعراض سريرية للمرض بصوره مبكرة. تم عمل أشعه بالرنين المغناطيسى بصبغه الجادولينيم على المخ والنخاع الشوكي كل ستة أشهر وكذلك الجهد المثار البصري لجميع المشاركين.

النتائج: أظهر البحث أن هناك 6 مرضى ظهر عليهم الأعراض السريريه لمرض التصلب المتناثر وذلك بواقع حالتان خلال السنة الأولى وأربعة حالات خلال السنة الثانية.هناك 10 حالات ظهر عليهم تغيرات جديدة اشعاعية بالرنين المغناطيسى وقد تضمنوا المرضى المتحولين إكلينيكيا. 12 حالة لديها إضطراب بالجهد المثار البصري عند بداية البحث وقد زادت الى 16 حالة مع المتابعة. متوسط عمر المرضى المتحولين إكلينيكيا 22 سنة, 5 منهم من الإناث. هناك 4 حالات بها بؤر مرضية إشعاعية بالأنسجة تحت المخيمة بجزع المخ وكذلك 2 بالنخاع الشوكي العنقي. الجهد المثار البصري أظهر أن هناك 5 من المرضى المتحولين إكلينيكيا لديهم تأخير فى ال. P100 الخاصة بالجهد المثار البصرى.

الاستنتاج: مرضى المتلازمة المعزولة راديولوجيا أكثر عرضه لحدوث مرض التصلب المتناثر وخاصة المرضى صغار السن من الإناث والذين لديهم أعراض إشعاعية بجزع المخ والنخاع الشوكي، هذا بالإضافة الى اضطراب بالجهد المثا


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