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]

 

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