Brain Excitability Changes in the Relapsing and Remitting Phases of Multiple Sclerosis: A Study with Transcranial Magnetic Stimulation

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1 Original Article Brain Excitability Changes in the Relapsing and Remitting Phases of Multiple Sclerosis: A Study with Transcranial Magnetic Stimulation Fawzia Gab Allah Elshehaby 1, Maha Hazem Ebrahim 1, Mohamed Abd Elsalam Mohamed 1, Walid Fouad Mohamed 2, Ahmed Esmael Ahmed 1 Department of Neurology, Mansoura University 1 ; Al-Azhar University 2 ; Egypt ABSTRACT Background: Multiple sclerosis (MS) is the most common disabling neurological disease in young adults characterized by recurrent relapses and/or progression. Multiple sclerosis was the first neurological disease in which transcranial magnetic stimulation (TMS) was used. Objective: The aim of this study is to assess the relationship between the level of cerebral excitability and clinical phase of MS (the relapsing and remitting phases of MS). Methods: Forty patients affected by relapsing-remitting (RR) MS were examined using single TMS in order to assess excitability changes in the hand motor cortex occurring during relapse and/or remission of the disease. The analyzed parameters were: motor threshold, amplitude of motor evoked potential (MEP), silent period (SP), and central motor conduction time (CMCT). Results: The analysis of variance exhibited a strong correlation (P<0.001) between the clinical phase and the type of excitability changes: relapsing patients showed increased threshold and reduced SP duration. By contrast, remitting patients showed a significant SP prolongation with normal motor thresholds. Conclusion: TMS is a highly sensitive non invasive technique recommended to evaluate conduction abnormalities and cortical excitability changes and in monitoring the course of the disease in relapsing-remitting MS. [Egypt J Neurol Psychiat Neurosurg. 2010; 47(4): ] Key Words: Multiple Sclerosis, Transcranial Magnetic Stimulation INTRODUCTION Two major forms of multiple sclerosis (MS) have been reported: relapsing-remitting MS (RRMS), which is the most frequent (85-90%), and primary progressive MS (PPMS). Most patients with MS have stable periods of variable duration (remission), although interrupted unpredictably by occurrence of relapse. Furthermore, RRMS patients later may develop secondary progressive MS (SPMS). About 10-15% of patients present with insidious disease onset and steady progression and therefore termed (PP) MS 3. Although magnetic resonance imaging (MRI) greatly improved the early diagnosis and the functional assessment of MS, evoked potentials still play an essential role in the clinical evaluation of the disease 4. The development of painless magnetic stimulation allowed several groups of studies in MS patients, most of which were focused on central motor conduction time (CMCT) measurements 2. Correspondence to Mohamed Abdelsalam, Department of Neurology, Mansoura University, Egypt. Tel.: [email protected] Studies with transcranial magnetic stimulation (TMS) have shown that, besides a significant prolongation of the CMCT, frequent abnormalities in MS patients are represented by both an increased threshold of MEP excitability and abnormal duration of central silent period (SP) 5. The aim of this study is to assess the relationship between the level of cerebral excitability and clinical phase of MS (the relapsing and remitting phases of MS). SUBJECTS AND METHODS The present study was conducted on 40 patients with clinically definite MS. The diagnosis of RR MS was established by clinical and MRI criteria, matched the criteria of Poser et al. 6 and McDonald et al. 4. Inclusion criteria were: Clinically definite diagnosis of RRMS with Expanded Disability Status Scale (EDSS) scores comprised between 0 (absence of neurological signs) and 3 (Moderate disability in 1 FS; or mild disability in 3-4 FS, though fully ambulatory), and a history of at least one clearly Egypt J Neurol Psychiat Neurosurg. October 2010 Vol 47 Issue 4 535

2 relapse. While, patients with: pacemaker, history of epilepsy, neurosurgical interference and presence of metallic foreign body were excluded. Patients were pooled in two separate groups: relapsing and remitting. Relapsing patients were suffering from a new symptom or a recrudescence of an old one; this was combined either with a new lesion taking gadolinium or by an old lesion with contrast enhancement. Patients with a stable condition in the past 3 months, both on clinical grounds and MRI, were defined as remitting. Transcranial Magnetic Stimulation (TMS) was performed for both groups relapsing and remitting. TMS with single pulses was performed using a regular round coil connected with a Magstim 200 magnetic stimulator. The coil was held tangentially to the scalp region overlying the right or left central sulcus on the hot spot for eliciting threshold motor responses in the contralateral hand target muscles. We compared patients single shock TMS data with those of an age-matched control population of 20 healthy volunteers (12 females, 8 males) aged years. Statistical analysis: The collected data were computed and analyzed using the following statistical rules: Mean and standard deviation (Mean±SD) was done for quantitative data (frequency & proportion). One way ANOVA test was done to compare between groups. P values considered statistically significant if p < Statistical package SPSS for Microsoft Windows was used. RESULTS This study included 24 female patients (60% of patients) and 16 male patients (40% of patients). The age of the studied patients ranged from years. The studied patients were classified according to age into three categories: category I (17-35 years) includes 7 males (17.5%) and 26 females (47.5%), while, category II (36-50 years) includes 7 males (17.5%), and 5 females (12.5%) and category III (> 50 years) includes only 2 males (5%) (Table 1). The frequency of functional systems affected in patients with relapsing remitting MS (Table 2) was pyramidal affection (90%); bowel or bladder affection (42.5%); cerebellar affection, (40%); sensory affection, (72.5%); visual affection, (50%); brainstem affection, (42.5%); and cognitive affection, (40%) (Table 2). More disability on EDSS was noticed with relapsing phase of MS compared with remitting course (2.35±0.69 versus 1.32±0.60) (Table 3). Relapsing patients showed increased threshold when compared to both control subjects (P<0.001) and remitting MS patients (P<0.001) (In relapsing patients 64.2±6.3 versus 37.1±2.8 in control group). Also, relapsing patients showed prolonged CMCT when compared to both control subjects (P<0.001) and remitting MS patients (P<0.001) (In relapsing patients 11.9±2.3 versus 5.9±0.69 in control group). There was a significant statistical difference in mean amplitude value amongst the different groups compared separately. In relapsing group mean amplitude value was less than remitting and control groups (2.48±0.42 versus 3.3±0.62 in remitting group and 3.6±0.63 in control group). Regarding SP was decreased in relapsing MS patients (P, 0:01) when compared to both control subjects and remitting patients (91.95±13.37 m/sec in relapsing group versus 143±20.8 m/sec in remitting patients and 113.2±10.5 m/sec in control group) (Table 4). Figures (1), (2), and (3) showing TMS in male patient aged 23 year presented by relapsing course of multiple sclerosis: Showing prolonged CMCT (Figure 1), low Amplitude (Figure 2) and decreased SP (Figure 3). Table 1. Age and sex distribution in studied patients with multiple sclerosis. Age group Males Females Total No. % No. % No. % I (17-35 Y) II (36-50 Y) III (> 50 Y) Total Egypt J Neurol Psychiat Neurosurg. October 2010 Vol 47 Issue 4

3 Tables 2. Frequency of functional systems involvement in patients with relapsing remitting multiple sclerosis. Functional systems Affected Not affected Frequency Percent Frequency Percent Pyramidal system Cerebellar Brainstem Sensory system Bowel and bladder Visual Mental and mood affection Table 3. Relationship between EDSS and course of disease in studied patients with multiple sclerosis. Course EDSS Duration (Years) Mean Y Relapsing SD n 18 Mean Y Remitting SD n 22 Mean Y Total SD N 40 EDSS expanded disability status scale, SD standard deviation Table 4. Showing comparison of TMS in relapsing multiple sclerosis patients and remitting multiple sclerosis patients groups versus control group. Relapsing group Remitting group Control group Mean SD Mean SD Mean SD Excitability Threshold CMCT Amplitude S P SD standard deviation F (variance ratio): one way ANOVA (Analysis of Variance) F (variance ratio) F = P < (**) F = P < (**) F = P < 0.01 (**) F (= P < (**) Figure 1. Transcranial magnetic stimulation in a 23 years male patient presenting with relapsing course of multiple sclerosis showing prolonged CMCT (central motor conduction time). CMCT (central motor conduction time) = T1 (Total cranial conduction) T2 (Cervical conduction) = 11.6 M/S Egypt J Neurol Psychiat Neurosurg. October 2010 Vol 47 Issue 4 537

4 Figure 2. Transcranial magnetic stimulation in a 23 years male patient presenting with relapsing course of multiple sclerosis showing low Amplitude (2.03mV). Figure 3. Transcranial magnetic stimulation in a 23 years male patient presenting with relapsing course of multiple sclerosis showing decreased SP Silent period (84 M/S). DISCUSSION In studied patients group there were 16 males with percentage of 40%, while females were 24 representing 60 % of patients. Age range years: mean 32±9.1 and these match the results of Preeti et al. 7, who studied thirty patients of MS, 17 females, 13 males (age range years; mean 30.4±10.8). Studied patients were classified according to age into three categories: category I (17-35 years) includes 7 males (17.5%) and 26 females (47.5%), while, category II (36-50 years) includes 7 males (17.5%), and 5 females (12.5 %) and category III (> 50 years) includes only 2 males (5 %) (Table 1). This is in accordance with the study of Sluder et al., 2002 who found that the range of age incidence in MS patients most commonly presents in individuals who were 20 to 40 years of age, with the average age of onset being 30 years of age 8. Regarding the frequency of functional system affection (Table 2): The most common was the pyramidal system (90% of patients), followed by sensory affection (72.5%), while the least of functional system shown to be affected is the mental system as only sixteen patients (40 %). In accordance with our results the study of Syal et al. (1999) who, found that during the course of illness, the pyramidal involvement was the most common sign in 87% of patients followed by sensory involvement in 65%of patients 9. Regarding the relation between Expanded Disability Status Scale (EDSS) and course of studied groups (Table 3), more disability on EDSS was noticed with relapsing phase of MS compared with remitting phase (2.35±0.69 versus 1.32±0.60). This is in agree with the study of Garaci et al. (2007) who, found statistically significant differences in EDSS when comparing relapsing and remitting patients 10. Also, Claire et al.,2008 found a significant increase in mean EDSS score during relapse compared to prerelapse (p<0.0001) of 1.45 EDSS points (median 1.5) and a significant improvement in mean EDSS score of 0.95 points post-relapse (remission) compared to during relapse (p<0.0001) 11. In this study the CMCT in the relapsing group was 11.9±2.3 ms while, in the remitting group was 7.08±1.19 ms and in the control group was 5.9±0.69 ms (P<0.001) so, there is a significant statistical prolongation of CMCT in relapsing group when compared to both control subjects and remitting MS patients (Table 4). Most studies of hand muscle MEPs reported CMCT abnormalities in about 75% of patients with definite MS, along with amplitude reduction of responses 12,13. Other parameters can be of importance to assess the function of corticospinal pathways (beside central motor conduction measurements), such as motor threshold (MT) and SP measurements. MT reflects the global excitability of fast conducting corticospinal pathways, including large pyramidal neurons, but also cortical interneurons and spinal motoneurons. While, SP is thought to represent GABA-B receptor-mediated inhibition of cortical excitability, in addition to spinal inhibitory mechanisms 14. In this study the MT in the relapsing group was 64.2±6.3 % while, in the remitting group was 50.7±4.6 % and in the control group was 37.1±2.8 % (P<0.001). So, there is a significant statistical increase of MT in relapsing group when compared to both control subjects and remitting MS patients (Table 4). In a population of MS patients, average 538 Egypt J Neurol Psychiat Neurosurg. October 2010 Vol 47 Issue 4

5 motor thresholds in resting or pre-activated hand muscles were moderately increased 15,16. Similarly MT changes were observed in the study of Fierro et al., 2002 who reported that the stimulus threshold of MS patients was higher in respect to controls. MT is a measure of cortico-cortical excitability of pyramidal neurons but SP is a useful index of cortical inhibitory activity. They found an increase of MT in 38% of their sample and a decrease of SP in 52% of the examined muscles 17. As regard the SP (Table 4) it was decreased in relapsing MS patients (P, 0:01) when compared to both control subjects and remitting patients (91.95±13.37 m/sec in relapsing group versus 143±20.8 m/sec in remitting patients and 113.2±10.5 m/sec in control group). Also, Cengiz et al., 2003 evaluated CMCT and the duration of SP in 58 patients with definite MS and 31 controls in order to determine the importance of CMCT and SP in patients with multiple sclerosis (MS). Prolonged CMCT latency was shown in 75.2% of patients and SP decreases in 69% of patients 18. This study revealed a significant statistical difference in mean amplitude value amongst the different groups compared separately. In relapsing group mean amplitude value was less than remitting and control groups (2.48±0.42 mv versus 3.3±0.62 mv in remitting group and 3.6±0.63 mv in control group) (Table 4). These results are in agree with Andrea et al., 2007 who used Motor Evoked Potentials (MEPs), elicited by transcranial magnetic stimulation, for assessing a motor pathways dysfunction in a 32 Relapsing Remitting MS patients and 20 healthy individuals with similar height and age distribution 19. [Disclosure: Authors report no conflict of interest] REFERENCES 1. Berger T, Reindl M. Multiple sclerosis: Disease biomarkers as indicated by pathophysiology.j Neurol Sci. 2007; 259: Alain MN. Magnetic stimulation in MS & peripheral neuropathies. In: Alvaro PL, Nick JD, John R, Eric MW, Basant KP, editors. Handbook of transcranial magnetic stimulation. London: Arnold; p Steinman L. Multiple sclerosis: a two stage disease. Nat Immunol. 2001; 2: Ian McDonald 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: Petajan JH, White AT. Motor-evoked potentials in response to fatiguing grip exercise in multiple sclerosis patients. Clin Neurophysiol. 2000; 111: Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983; 13: Sahota P, Prabhakar S, Lal V, Khurana D, Das CP, Singh P. Transcranial magnetic stimulation: Role in the evaluation of disability in multiple sclerosis. Neurol India. 2005; 53: Sluder JA, Newhouse P, Fain D. Pediatric and adolescent multiple sclerosis. Adolesc Med State Art Rev. 2002; 13(3): Syal P, Prabhakar S, Thussu A, Sehgal S, Khandelwal N. Clinical profile of multiple sclerosis in north-west India. Neurol India. 1999; 47: Garaci FG, Colangelo V, Ludovici A, Gaudiello F, Marziali S, Centonze D, et al. A Diffusion Longitudinal MR Imaging Study in Normal Appearing White Matter in Untreated Relapsing- Remitting Multiple Sclerosis. AJNR Am J Neuroradiol. 2007; 28: Hirst C, Ingram G, Pearson O, Pickersgill T, Scolding N, Robertson N. Contribution of relapses to disability in multiple sclerosis. J Neurol. 2008; 255: Hess CW, Mills KR, Murray NMF, Schriefer TN. Magnetic brain stimulation: central motor conduction studies in multiple sclerosis. Ann Neurol. 1987; 22: Ingram DA, Swash M. Central motor conduction is abnormal in motor neurone disease. J Neurol Neurosurg Psychiatry. 1987; 50: Kimberley TJ, Borich MR, Prochaska KD, Mundfrom SL, Perkins AE, Poepping JM. Poepping. Establishing the definition and inter-rater reliability of cortical silent period calculation in subjects with focal hand dystonia and healthy controls. Neurosci Lett 2009; 464: Caramia MD, Cicinelli P, Paradiso C, Mariorenzi R, Zarola F, Bernardi G, Rossini P M. 'Excitability' changes of muscular responses to magnetic brain stimulation in patients with central motor disorders. Electroencephalogr Clin Neurophysiol. 1991; 81: Sheean LG, Murray NMF, Rothwell JC, Miller DH, Thompson AJ. An electrophysiological study of the mechanism of fatigue in multiple sclerosis. Brain. 1997; 120: Fierro B, Salemi G, Brighina F, Buffa D, Conte S, La Bua V, et al. A transcranial magnetic stimulation study evaluating methylprednisolone treatment in multiple sclerosis. Acta Neurol Scand. 2002; 105: Tataroglu C, Genc A, Idiman E, Cakmur R, Idiman F. Cortical silent period and motor evoked potentials in patients with multiple sclerosis. Clin Neurol Neurosurg. 2003;105: Gagliardo A, Galli F, Grippo A, Amantini A, Egypt J Neurol Psychiat Neurosurg. October 2010 Vol 47 Issue 4 539

6 Martinelli C, Amato MP, et al. Motor evoked potentials in multiple sclerosis patients without الملخص العربي walking limitation: amplitude vs. conduction time abnormalities. J Neurol. 2007; 254 (2): دراست التغير فى اإلثارة المخيت فى طىر االنتكاست وطىر المهادنت للتصلباث المتناثرة بالجهاز العصبى باستخذام جهاز المنبه المغناطيسى لقشرة المخ EDSS) - ± (EDSS) Egypt J Neurol Psychiat Neurosurg. October 2010 Vol 47 Issue 4