Clinical, Laboratory and Radiological Predictors of Outcome in Relapsing Remitting Multiple Sclerosis

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1 Ashraf A. Aboelsafa et al. Clinical, Laboratory and Radiological Predictors of Outcome in Relapsing Remitting Multiple Sclerosis Ashraf A. Aboelsafa, Ehab A. Elseidy, Ehab S. Mohammed Department of Neuropsychiatry, Tanta University ABSTRACT The process of inflammatory demyelination in patients with multiple sclerosis is characterized clinically by remissions and relapses which eventually lead to long term disability in most cases. Objective: To determine the clinical, laboratory and radiological predictors of outcome in patients with relapsing remitting multiple sclerosis (RRMS). Subjects & Methods: This study was carried out on 25 patients (14 females and 11 males) with relapsing remitting multiple sclerosis. All patients were subjected to clinical neurological examination, assessment of disability by the expanded Disability Status Scale (EDSS), determination of IgG in the cerebrospinal fluid (CSF) and gadoliniumenhanced magnetic resonance imaging (MRI). All patients received a high-dose intravenous methylprednisolone therapy course (IVMP) 1gram intravenous infusion daily for 5 days during relapse. Eleven patients received β-interferon while the other 14 patients did not, and served as the control group. Results: Patients with high EDSS were found to have a longer duration of symptoms. Patients with corpus callosum, infratentorial or spinal cord lesions were found to have higher EDSS. Patients received immunomodulating therapies were having a better outcome. Conclusion: Clinical predictors of favorable outcome in RRMS included female gender, younger age at onset, optic neuritis or sensory symptoms at onset, monosymptomatic relapse, longer duration between onset and first relapse, and receiving immunomodulation therapy. The radiological predictors of favorable outcome included less confluent lesions, and supratentorial lesions rather than infratentorial and spinal cord lesions on MRI. On the other side, high CSF IgG level was associated with unfavorable outcome. (Egypt J. Neurol. Psychiat. Neurosurg., 2006, 43(1): ) INTRODUCTION Multiple sclerosis is an autoimmune disease characterized by multifocal areas of inflammatory demyelination within the central nervous system (CNS) 1. It is an acute relapsing inflammatory disease of the CNS myelin, white matter tracts are affected including those of the cerebral hemispheres, infratentorium and spinal cord 2. It is the most common disabling neurological disease of young people 3, with a higher incidence in women than men 4. The age of onset is generally between 15 and 50 years with the majority of patients diagnosed during their third and fourth decades 5. There is a general agreement that environmental factors trigger an autoimmune response in genetically susceptible individuals with consequent initiation of the inflammatory demyelination process in the CNS 6. Clinically this process is characterized by relapses and remissions which eventually lead to long term disability in most cases. The original definition of benign case of MS is one where there is still no disability 10 years after disease onset 7. A definition that has been frequently used over the past years is minimal or no disability, equivalent to a score on the Expanded Disability Status Scale (EDSS) equal to or less than 3.0 (fully ambulatory), at least 10 years after disease onset 8. With the advent of MRI, the ability to confirm the diagnosis of MS has improved dramatically 9, and with its newer techniques, it yields important informations regarding the prognosis and treatment effects of MS

2 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 43 (2) - July 2006 The aim of this study was to detect the clinical, laboratory and radiological predictors of outcome in patients with relapsing remitting multiple sclerosis. PATIENTS AND METHODS This study was carried out on 25 patients (14 females and 11 males) with definitive relapsing remitting multiple sclerosis according to the criteria of Poser et al. 11 (Table 1) recruited from Neuropsychiatry department, Tanta University Hospital. Inclusion criteria included: (1) Patients with RRMS of any age and sex (patients who have attacks of the disease with subsequent recovery and who have little or no residual neurological deficit between the attacks, two attacks are required for the classification of RRMS 12 ). The presence of relapse was confirmed in all patients. This was defined as a worsening of neurological impairment or the appearance of a new symptom or abnormality attributable to MS, lasting at least 24 hours, and preceded by stability for at least 1 month. The severity of the disease was scored using the EDSS 13. (2) All the investigations and baseline EDSS were of the second episode. All patients underwent studies on the same 1.5-tesla magnetic resonance imaging (MRI) unit (Signa Horizon SR 120; General Electric Medical Systems, Milwaukee, WI), using a standard head coil. Axial T1-weighted spin echo, axial T2- weighted spin echo, sagittal T1-weighted, and fluid attenuation inversion recovery - weighted images were obtained. In addition, the imaging protocol included axial and sagittal T1- and T2- weighted fast spin echo images for the spinal cord with a 4 mm thick sections and a 1 mm gap. Eleven patients received β-interferon and the other 14 did not afford it and served as the control group (who received only IVMP in the form of 1 gm intravenous methylprednisolone infusion daily for 5 days during each relapse). All patients were followed up at six months interval unless they had acute exacerbation. The EDSS was done during each visit. The patients were followed up for 3 years from the onset of the study. Patients were considered to have benign MS if they developed no disability or if their EDSS score was less than 3 after 10 years from the onset 14. The EDSS gives the most reliable assessment of any change in the clinical condition as well as treatment response. The difference of a single step on EDSS may not reflect a significantly important functional change, so at least 2 steps changes in the degree of disability or response to treatment is considered significant. The CSF IgG was measured by immunoturbidimetric method and readings above 16 mg/dl were considered high. Data were analyzed using Minitab Statistical Software Package version 12, Quantitative data were expressed as mean±sd; qualitative data were expressed as frequency and percent. For comparison of qualitative data Chi-square test was used. Unpaired t-test and paired t-test were used for comparison of means of independent and dependent groups respectively. For simultaneous comparison of more than two means, analysis of variance test (ANOVA) was used followed by the least significant difference test (LSD) as a post hoc procedure to locate the significant differences among the compared groups. The level of significance adopted was at p RESULTS Patients of the present study were 14 (56%) females and 11 (44%) males. The age at onset (in years) was 21.31±5.2 for patients with EDSS 3 while it was 26.45±4.6 for patients with EDSS > 3 (Table 2). Duration of symptoms (in years) was 2.67±1.1 for patients with EDSS 3 while it was 3.85±1.7 for patients with EDSS > 3 (Table 2). Duration between the onset and first relapse (in months) was 26.62±14.1 for patients with EDSS 3 while it was 14.85±9.2 for patients with EDSS > 3 (Table 2). 472

3 Ashraf A. Aboelsafa et al. There was a positive correlation between the EDSS and age at onset (in years) and with the duration of symptoms (in years) while that with the duration between onset and first relapse (in months) was a negative correlation. In the present study, patients with optic neuritis and predominantly sensory symptoms at onset showed significant reduction in EDSS, as shown in table (3). Table (4) showed a significant reduction in the EDSS score in monosymptomatic relapse (one system affection during attack) when compared to polysymptomatic relapse (multiple system affection during attack). In the present study, patients having high levels of CSF IgG showed a non-significantly higher EDSS score when compared to patients with normal CSF IgG levels (p>0.05), as shown in table (5). In the present study, patients with predominantly infratentorial and spinal lesions on MRI showed a higher EDSS score when compared to patients with predominantly supratentorial lesions at the onset, as shown in table (6). Also, patients with negative corpus callosum lesions on MRI showed a significantly lower EDSS score (p<0.05) when compared to patients with confluent lesions with corpus callosum atrophy and patients with focal lesion in the corpus callosum, as shown in table (7). Table (8) showed that patients received IVMP and β-interferon had a favorable outcome than patients received only IVMP. Table 1. The diagnostic criteria for relapsing remitting multiple sclerosis. Definite MS: Postpartum histopathological diagnosis. Clinically definite MS: 2 attacks and clinical evidence of separate lesions. 2 attacks and clinical evidence of 1 lesion and paraclinical evidence of another lesion. Laboratory supported definite MS: 2 attacks clinical evidence of 1 lesion and paraclinical evidence of another separate lesion and CSF findings (oligoclonal bands/elevated Ig). 1 attack clinical evidence of 2 separate lesions and CSF findings. 1 attack clinical evidence of 1 lesion and paraclinical evidence of another separate lesion and CSF findings. Clinically probable MS: At least 2 relapses with multifocal clinical findings. 1 exacerbation with multifocal clinical or monofocal clinical and additional mono-multifocal neurophysiological or neuroradiological findings. Laboratory supported probable MS: At least 2 relapses with monofocal clinical findings and elevated CSF Ig production with or without oligoclonal Ig bands. 1 exacerbation with multifocal clinical or monofocal neurophysiological or neuroradiological findings and elevated CSF Ig production with or without oligoclonal Ig bands. Clinically possible MS: Clinical, neurophysiological and neuroradiological findings with or without compatible CSF findings that are not sufficiently characteristic but so far no other suspected disease. 473

4 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 43 (2) - July 2006 Table 2. Comparison of patients with good prognosis versus bad prognosis. Patients with EDSS 3 (n=17) Patients with EDSS > 3 (n=8) Gender (Female : Male) 12 : 5 2 : 6 <0.05* Age at onset (in years) ± ± 4.6 <0.05* Duration of symptoms (in years) 2.67 ± ± 1.7 <0.05* Duration between onset and first relapse (in months) ± ± 9.2 <0.05* * = significant. Table 3. The relation between the predominant clinical manifestation and the EDSS. Optic neuritis Predominantly Predominantly (n=10) sensory (n=8) motor (n=7) F EDSS at the onset (mean±sd) 4.15± ± ± (p>0.05) EDSS at the end of the study 2.23± ± ±1.7 Paired t-test p <0.05* <0.05* >0.05 * = significant. Table 4. The effect of monosymptomatic versus polysymptomatic relapse on EDSS. Monosymptomatic relapse (n=10) Polysymptomatic relapse (n=15) EDSS (mean±sd) 3.1 ± ± 1.5 t 2.82 p <0.05* * = significant. Table 5. The relation between CSF IgG levels and the EDSS. High CSF IgG (n=16) Normal CSF IgG (n=9) EDSS (mean±sd) 5.1± ±1.3 t 1.67 p >0.05 p Table 6. The relation between the site of MRI lesions and the EDSS. Predominantly supratentorial [1] (n=10) Predominantly infratentorial [2] (n=8) Predominantl y spinal [3] (n=7) EDSS at the onset 3.89 ± ± ± * EDSS at the end of the 2.23 ± ± ± * study * = significant. LSD = least significant difference. F LSD All groups are different [1] = [2] [2] = [3] [1] < [3] 474

5 Ashraf A. Aboelsafa et al. Table 7. The effect of corpus callosum lesion in MRI on the EDSS. Focal corpus callosum lesion [1] (n=9) Confluent lesions with corpus callosum atrophy [2] (n=8) Negative corpus callosum lesion [3] (n=8) EDSS 4.78 ± ± ± * [1] = [2] < [3] * = significant. LSD = least significant difference. Table 8. The effect of therapy on the EDSS. β-interferon + IVMP IVMP only (n=11) (n=14) t p EDSS at the onset 4.78 ± ± >0.05 EDSS at the end of the study 2.07 ± ± <0.05* Number of relapse per year 0.69 ± ± <0.05* * = significant. F LSD DISCUSSION Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, with a highly variable clinical course and prognosis. A small fraction of MS patients, about 10%, do well for more than 20 years and can live many years without restriction of daily living and work, and have a benign course of the disease. Early identification of these patients is important in the counseling of newly diagnosed patients, designing and interpreting clinical trials and in considering the immunomodulatory treatment 15. The clinical outcome of MS is a continuum between non-progressive and rapidly aggressive (progressive) disease. Patients with longstanding, apparently benign relapsing remitting MS can develop a progressive and disabling disease. Many patients during long-term follow-up of years show disease progression beyond EDSS score of 3. After 10 years from disease onset, approximately 40% have a benign course. After 20 years, the benign group is less than 20%. Benign MS seems therefore to be a temporary condition 16. Because of the highly unpredictable course of MS, demographic and clinical features, such as gender, age of onset, initial course, symptoms at onset, interval between attacks, attack frequency and rate of progression in the early phase of the disease have been studied to define possible predictors of outcome 17. The conclusions from these studies have somewhat varied, but this may be related to differences in study design 18. In our study, there was a positive correlation between the age at onset, and the duration of symptoms on one side and the EDSS score on the other side, while that with the duration between onset and first relapse was a negative one. This is consistent with Bernardie et al. 19, who found that younger patients and a longer duration to first relapse predict a favorable outcome. Also in the present study, most of the patients were females and most of the patients with EDSS score 3 were females. This is in agreement with Hawkin and McDonnel 16, Moreau and Confavreux 17 and with Myhr et al. 18, who observed that the patients with benign MS were predominantly females and younger age at onset. However, Wang et al. 20 showed no significant difference between sex of patients and the EDSS score. Also, Verjans et al. 21, Confavreux et al. 22 and Riise et al. 23 found no significant effect of sex on the prognosis in MS patients. 475

6 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 43 (2) - July 2006 In the present study, there was a significant reduction in the EDSS score in patients with optic neuritis and sensory symptoms at the onset. This is in agreement with Hawkin and McDonnel 16, Moreau and Confavreux 17 and with Myhr et al. 18, who found that the presentation with optic neuritis and or sensory symptoms correlates with favorable course in MS patients. In the present study, it was found that patients with monosymptomatic relapse (one system affection) had a better outcome than patients with polysymptomstic relapse (multiple system affection). Regarding the laboratory predictors of outcome in our study, patients with high CSF IgG had a non-significantly higher EDSS score than patients with normal CSF IgG. This is consistent with that found by Confavreux et al. 22, who concluded that the constituents of CSF had no prognostic value in MS. However, this is in contrary with that concluded by Izquierdo et al. 24, who confirmed that intrathecal IgG levels do not correlate with the presence of more attacks in the following years, but IgG index can be a good marker of further progression of the disease. Patients with IgG index above 1.0 could have an increased risk of progression and must be considered as candidates to be treated as soon as possible with immuno-modulator agents. They mentioned that IgG index must be included as a surrogate marker of disease activity in prospective studies of MS with other clinical and paraclinical predictors and must be considered as marker of disease activity. Regarding the radiological predictors of outcome in the present study, patients with supratentorial lesions on MRI had a better prognosis than those with infratentorial and spinal lesions. This matches with that obtained by David 25, who said that most the lesions leading to disability in MS are in the spinal cord or posterior fossa. Also in a previous study done by Filippi et al. 26, there was a higher load of posterior fossa lesions in patients with progressive disease compared to benign MS. It was found also in the present study that patients with negative corpus callosum lesions on MRI had a favorable outcome than patients with corpus callosum lesions. Moreover, more confluent lesions with corpus callosum atrophy yields an unfavorable outcome than focal corpus callosum lesion. Previous studies (27&28) found that patients with MS are more likely to develop loss in the corpus callosum and spinal cord than matched normal control individuals. Moreover, linear measures of the third ventricle diameter, lateral ventricle diameter and brain width together with midsagittal area of the corpus callosum were used as atrophy surrogates which is correlated with worsening disability in MS patients 29,30. It was found, in the present study that patients received β-interferon and IVMP had a better EDSS score than patients received IVMP only. There was also a significant reduction in the relapse rate per year in patients received β- interferon and IVMP than patients received IVMP only. This is in accordance with that obtained by Patty et al. 12 and Adams et al. 31, who found a significant reduction in relapse rate in patients receiving β-interferon. They concluded that β- interferon is shown to slow the progression of disability when given to RRMS, also β-interferon reduces the number of new T2-weighted MRI lesions as well as the number and volume of gadolinium-enhanced lesions. This is also in accordance with Söderström 32, who found that treatment with interferon-beta-1a is beneficial in reducing the development of clinically definite MS. In conclusion, the present study concluded that the clinical predictors of favorable outcome in patients with relapsing remitting multiple sclerosis include female gender, younger age at onset, optic neuritis and sensory symptoms at onset, longer duration between onset and first relapse, monosymptomatic relapse and receiving immunomodulating therapies. The radiological predictors of favorable outcome include less confluent lesions, and supratentorial lesions rather than infratentorial and spinal cord lesions on MRI. 476

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