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April2013 Vol.50 Issue:      2 Table of Contents
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Repetitive Transcranial Magnetic Stimulation Effect in Multiple Sclerosis Spasticity (Clinical and Electrophysiological evaluation): A preliminary Egyptian Study

Ann A. Abdelkader1, Hatem Samir2, Reem El-Hadidy1, Noha El-Sawy1

Departments of Clinical Neurophysiology1, Neurology2; Cairo University; Egypt 



ABSTRACT

Background: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique that induces cortical excitability changes at the stimulation and distant sites, leading to either facilitation or inhibition depending on the pulse frequency. These effects may outlast the train of stimulus duration, for minutes or even hours. Repetitive TMS may improve spasticity in multiple sclerosis (MS) especially that the current pharmacologic treatment of spasticity has side effects like sedation, weakness and cognitive disturbances. Hyperexcitability of the stretch reflex arc, secondary to lesion of the corticospinal tract, is considered a possible mechanism at the basis of spasticity. Objective: To investigate whether high and low frequency (rTMS) can modify MS spasticity assessed by clinical and electrophysiological scales. Methods: 21 relapsing-remitting (RRMS) patients with lower limb spasticity underwent (rTMS) of high (5Hz) and low (1Hz) frequency treatment protocols lasting 2weeks over the leg primary motor cortex. Spasticity was assessed using clinical scales (Tardieu and modified Ashworth scales) and neurophysiological H/M amplitude ratio of the soleus H reflex. Results: Our study showed that (5Hz) rTMS increased H/M amplitude ratio with significant improvement of the lower limb spasticity scales, while the (1Hz) rTMS sessions showed no improvement of H/M ratio as well as the spasticity scales. Conclusion: (5Hz) rTMS can contribute in improving the MS spasticity and hence improving quality of patients' life. [Egypt J Neurol Psychiat Neurosurg.  2013; 50(2): 157-162]

 Key Words: Repetitive transcranial stimulation, multiple sclerosis, spasticity, H/M ratio.  

Correspondence to Ann A. Abdelkader, Department of Clinical Neurophysiology, Egypt. Tel.: +201006063114. Email: ann.abdelkader@yahoo.com.





INTRODUCTION

 

Spasticity one of the three most common physical signs and symptoms experienced by MS patients, affects 60% of patients and tends to increase in severity as the disease progresses. Spasticity can significantly affect motor performance and the activities of daily living among people with MS, appropriate management should be implemented from the time of onset. Lower limbs are more commonly affected than upper limbs.1 Hyperexcitability of the stretch reflex arc, second­ary to corticospinal tract lesion, is considered a possible mechanism at the basis of spasticity.2

Different treatment methodologies were approached for spasticity as physical management followed by oral medication.3 When these interventions fail to improve function, more invasive treatments may be used. All anti-spastic medications produce adverse side  effects  like  muscle  weakness,  drowsiness, dizziness,

 

dry mouth, nausea, increased urinary frequency, light-headedness, and withdrawal effects.4 Invasive treatment involves, intrathecal baclofen pump, botulinum toxin injection, and surgical procedures. Limitations of intrathecal baclofen therapy include its cost, as well as the risk of complications, such as infection or pump dysfunction. The botulinum toxin type A can reduce focal spasticity in MS patients; however the clinical benefits from this reduction are clearer in the upper limb than in the lower limb.5 The disadvantages of botulinum injections include the need for repeat injections, being limited to treating focal not general spasticity, and the possibility of sensory damage.6

Repet­itive transcranial magnetic stimulation (rTMS) was introduced as a technique to improve spasticity in MS.7,8 It is a noninvasive technique that induces changes in corti­cal excitability at stimulation and distant sites, leading to facilitation or inhibition depending on the pulse frequency. These ef­fects may outlast the duration of the stim­uli trains for minutes to hours. Single session TMS applied over the primary motor cortex has been shown to modulate corticospinal tract excitabil­ity and the spinal H reflex.9,10

Purpose of the study is to investigate whether high and low frequency rTMS can modify spasticity assessed by the spinal H reflex (H/M ratio), MAS and Tardieu scales.

 

SUBJECTS AND METHODS

 

Twenty one patients (12 males and 9 females) with age ranged from 16-42 years were recruited from neurology department of Kasr El Aini, Cairo University Hospitals. All patients had remitting MS and spasticity affecting one or both lower limbs which were not responding to pharmacological treatments.

The inclusion criteria: patients with relapsing-remitting MS established by clinical, laboratory, MRI criteria and matched the criteria of McDonald et al., with lower limb spasticity and Expanded Disability Status Scale (EDSS) scores between 3-5.5. Only patients in "remitting" phase were included.

We excluded patients with pacemaker, history of epilepsy, pregnant females and previous skull opening.

Assessment of spasticity of the lower limbs using Modified Ashworth (MAS), Tardieu scales, and soleus H reflex was done at the start and immediately after the end of treatment.

The patients were divided according to the rTMS frequency of the treatment protocol into two groups; Group A (comprised 12 patients), the stimulation protocols were 18 rTMS trains of 50 stimuli at high-frequency of (5 Hz) at 90% stimulator output (train duration 10s) separated by 40s pause delivered for a total of 900 pulses (total duration 15 minutes). Group B (9 patients) with usage of 1 train of 900 pulses at low frequency (1 Hz) with 90% stimulation intensity (total duration 15 minutes). Treatment was done for 2-weeks.11

A MagStim Rapid magnetic stimulator (Magstim Company, Whitland, Wales, UK), connected with a figure-of-eight coil with a diameter of 70 mm, was used to deliver rTMS over the scalp site corresponding to the leg area of primary motor cortex. The position of the coil was adjusted at the beginning of each experiment to find the optimal scalp position ("motor hot spot") which in general was 0-2 cm lateral to the vertex, tangentially to the subject's head surface, with the handle pointing posteriorly and positioned at 45° with respect to midsagittal axis. Using a figure-of-eight coil allows to stimulate selectively the leg area of the chosen hemisphere.

Soleus H reflex and compound muscle action potential (CMAP) were recorded with measuring of the maximum amplitudes of the H and M responses. The amplitudes were measured from baseline to peak, and H/M ratio was evaluated. These were done before and immediately after the rTMS protocol.

 

Statistical Analysis

Statistical analysis was conducted, using the mean, paired t-test, Chi-square and Linear Correlation Coefficient using SPSS V17.

 

RESULTS

 

All participants were subjected to clinical spasticity scales and neurophysiological assessment {H/M ratio} before and immediately after treatment.

 

In Group A: By comparing the before and after treatment results there was highly significant difference concerning muscle under stretch (P=0.000), and significant difference in Tardieu scale and H/M ratio (P=0.026, P=0.028 respectively) (Table 1).

 

In Group B: There was no significant difference between any of the used parameter before and after treatment.

 

By comparing the 2 groups before treatment, there were no significant differences in all used variables. While comparing the 2 groups after treatment, there was significant difference concerning muscle under stretch (P=0.024) while the other variables showed no significant differences (Table 2).

 

Correlations

·          Correlation between the MAS components, Tardieu scale and H/M ratio before treatment showed significant negative correlation between muscle under stretch and muscle strength (P=0.008), also significant negative correlation between Tardieu scale and muscle strength (P=0.041), while there was significant positive correlation between Tardieu scale and muscle under stretch (P=0.001). There was no significant correlation between H/M ratio and either of the mentioned variables. (Table 3).

·          Correlation between EDSS and each variable after treatment showed significant negative correlation between EDSS and muscle strength (P=0.009). While there was significant positive correlation between EDSS and muscle under stretch and Tardieu scale (P=0.036 and 0.015 respectively), however no significant correlation between EDSS and H/M ratio. Also there was no significant correlation between EDSS and all variables before treatment.


Table 1. Comparison between group (A) and group (B) regarding EDSS and each variable before and after treatment.

 

 

Group (A)

Group (B)

T-test

Mean±SD

t-value

P-value

EDSS

 

4.250±0.917

4.389±0.741

0.372

0.714

Ms under stretch

Before treatment

3.833±1.115

4.000±1.000

0.354

0.727

Ms strength

3.583±0.515

3.778±0.441

0.909

0.375

Tardieu scale

3.083±0.793

3.111±0.782

0.080

0.937

H/M ratio

0.538±0.355

0.372±0.246

-1.266

0.221

Ms under stretch

After treatment

2.917±0.996

4.000±1.000

2.462

0.024*

Ms strength

3.583±0.515

3.778±0.667

0.756

0.459

Tardieu scale

2.583±0.793

3.222±0.833

1.788

0.090

H/M ratio

0.388±0.241

0.393±0.270

0.043

0.966








EDSS Expanded Disability Status Scale, Ms muscle,

*Significant at P<0.05

 

Table 2. Comparison between the examined variables before and after treatment in the studied groups.

 

 

Groups

Before treatment Mean±SD

After treatment

Mean±SD

t-value

P-value

Ms under stretch

A

3.833±1.115

2.917±0.996

6.167

0.000**

B

4.000±1.000

4.000±1.000

0.000

1.000

Ms strength

A

3.583±0.515

3.583±0.515

0.000

1.000

B

3.778±0.441

3.778±0.667

0.000

1.000

Tardieu scale

A

3.083±0.793

2.583±0.793

2.569

0.026*

B

3.111±0.782

3.222±0.833

-1.000

0.347

H/M ratio

A

0.538±0.355

0.388±0.241

2.538

0.028*

B

0.372±0.247

0.393±0.270

-1.972

0.084

MAS

A

7.417±0.900

6.500±0.798

6.167

0.000**

B

7.778±0.833

7.778±0.667

0.000

1.000

Ms muscle

*Significant at P<0.05 **Significant at P<0.01

 

Table 3. Correlation between the EDSS and each variable before and after treatment.

 

 

 

EDSS

R

P-value

Ms under stretch

Before treatment

0.180

0.434

Ms strength

-0.416

0.060

Tardieu scale

0.226

0.324

H/M ratio

-0.123

0.595

Ms under stretch

After treatment

0.460

0.036*

Ms strength

-0.557

0.009**

Tardieu scale

0.525

0.015*

H/M ratio

-0.069

0.766

Ms muscle

*Significant at P<0.05 **Significant at P<0.01

 

 


DISCUSSION

 

Our patients were diagnosed as relapsing-remitting MS patients with spas­ticity affecting predominantly one lower limb. Their EDSS scores were 3-5.5, which was one of the inclusion criteria. This range allowed the patients to be ambulant to come regularly to receive their rTMS sessions more easily than higher scores at which the patient was going to be handicapped.

All participants were subjected to clinical spasticity scales and neurophysiological assessment (H reflex and H/M ratio) before and immediately after treatment.

The H/M ratio of the soleus muscle is considered a reliable well established electrophysiological technique for measurement of spasticity. Several studies12-14 have found that the reflexes, when measured in resting individuals, are larger in a population of spastic individuals as compared to an age-matched population of healthy persons. In the present study the mean baseline score of this ratio was 0.467 which was used as a reference result to be compared with the post treatment results.

Our patients were divided into two groups according to the rTMS frequency protocol. In group A high-frequency (5 Hz) rTMS protocol was used, while in group B we used low-frequency (1 Hz) rTMS protocol. Evaluation of our cases before treatment reported no statistically significant difference between both groups as regard age, EDSS, muscle under stretch, muscle strength, Tardieu Scale, or H/M ratio (P>0.05). On the other hand the comparison after treatment between groups A and B could reveal a statistical significant difference particularly as regard the muscle under stretch score and the Tardieu scale score with a lower score for group A. These findings could project the light on the value of the high frequency rTMS treatment protocol over the low frequency in improving the degree of spasticity. Our findings could be correlated with those of Nielsen etal15, Centonze etal.11, Mori et al.16 and Verhaagen etal.8, who reported similar findings. They explained their observations by the point that these might be mediated through corticospinal projections to local inhibitory interneurons of the spinal cord. The point that the pyramidal tract has widespread terminations in the spinal gray matter, there by controlling motor neurons through monosynaptic but also non mono-synaptic connections, involving local interneurons and sensory afferents. Huang et al.17 proved that interaction be­tween corticospinal projections and spinal inter­neurons has been documented in physiologic and pathologic conditions. In particular, corticospi­nal tract activation is supposed to modulate changes in the presynaptic control on la sensory afferents mediating stretch reflex, whereas it seems not to involve disynaptic reciprocal inhibi­tion18,19. Mori et al.16  have demonstrated that spastic MS patients cannot exert normal control over the mechanisms that are involved in setting the agonist and antagonist stretch reflex size and gain in relation to voluntary contraction. Therefore, it is possible that in our study, the observed beneficial effects of rTMS on spasticity may be mediated, at least in part, by long-lasting modulation of complex spinal circuits such as the one involved in presynaptic inhibition.

Evaluating the H/M ratio which is the electrophysiological correlate for spasticity, we reported no statistically significant difference between group A and B either before or after treatment.  On the other hand the validity of the H/M ratio as a reflection for spasticity was quite evident in the higher frequency (A group) when comparing the ratios before and after treatment, as we reported statistical significant decrease in the after treatment values compared to before treatment. The value of high frequency was clearly previously proved before by many investigators18,19,11,20,14 as they reported significant reduction of the H/M amplitude ratio of the soleus H reflex in spastic MS patients even after single sessions of TMS. The authors concluded that the 5 Hz decreased the H/M amplitude ratio and increased corticospinal excitability. As regard the low frequency many studeis18,19,11,8 found out that one Hz rTMS over the leg primary motor cortex could increase the H/M amplitude ratio of the soleus H reflex and that signify the inhibitory effect of the low frequency rTMS when applied over the motor cortex.

Once more the value of high frequency stimulation was evidenced in our work as we reported significant improvement in the MAS (muscle under stretch) and Tardieu scales after treatment. On the other hand no improvement was seen regarding the muscle strength. Our observations might reflect the value of high frequency rTMS on improving spasticity with no effect on the power of the affected limb. Similar results were reported by many studies18,19,11.

The insignificant role of the 1 Hz (low frequency) rTMS previously reported by several authors18,19,11,8 were once again verified in our study, as we reported no statistical significant difference of the Tardieu scale, muscle under stretch, muscle strength and the MAS. From these observations we concluded that the low-frequency rTMS has no outcome either on the clin­ical or the electrophysiological evaluation.

Quartarone et al.19 documented that the lasting inhibitory after-effects of 1 Hz rTMS and facilitatory after-effects following high-frequency rTMS were found on motor corticospinal output in healthy subjects, with a neurophysiologic substrate that remains unclear. Various mechanisms should be considered including synaptic changes resembling experimental long term depression (LTD) and long term potentiation (LTP) mechanisms, as well as shifts in network excitability, activation of feedback loops, activity-dependent metaplasticity. In the present study we failed to document this inhibitory effect of the low frequency as we reported no statistically significant difference between before and after treatment using the 1 Hz stimulation.

From the present work it’s quite expected before treatment to have negative correlation between the muscle under stretch and muscle strength, as when spasticity decreases the range of power of the muscles will increase. In addition there was a negative correlation between the Tardieu scale and muscle strength, as the higher the Tardieu scale score the lesser the muscle strength. In the same time we reported significant positive correlation between the Tardieu scale and muscle under stretch, and that means the more the spasticity the worse is the Tardieu scale and the more the disability of the patient.

In group A correlating the EDSS with the muscle strength, muscle under stretch and Tardieu scale after treatment revealed a significant negative correlation with the muscle strength, as the lesser the EDSS the better is the muscle strength, and that means the reduction of the EDSS might reflect an improvement of the outcome. In the mean time there was a positive correlation between the EDSS and the muscle under stretch and Tardieu scale. This signifies the importance of the score of the EDSS as an inclusion criterion, as an increase of the score of the EDSS denotes more spasticity and disability.

Our treatment protocol for the two groups lasted for 2-weeks, supported by Wassermann et al.21, Kobayashi et al.22 and Centonze et al.11 as they reported significant improvement of lower limb spasticity observed when rTMS applications were repeated during a 2-week period. This could be explained by the cumulative plastic changes that can be produced by rTMS23,24. It is possible that clinical benefit emerged in our patients after repeated sessions of rTMS due to long-lasting modulation of spinal circuits, presumably through LTD-like mecha­nisms as Nielsen and Sinkjaer25 previously reported.

We concluded that high frequency (5 Hz) rTMS may improve spasticity in MS and contribute to evolution of new treatment modalities which focus on promoting plastic changes in spinal cord circuits.

 

[Disclosure: Authors report no conflict of interest]

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3.        Haselkorn JK, Loomis S. Multiple Sclerosis and Spasticity. Phsy Med Rehab Clinics North Am. 2005; 16: 467–81.

4.        Chou R, Peterson K, Helfand M. Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review. J Pain Symptom Manage. 2004; 28: 140–75.

5.        Sun SF, Hsu CW, Hwang CW. Application of combined botulinum toxin type A and modified constraintinduced movement therapy for an individual with chronic upper-extremity spasticity after stroke. Phys Ther. 2006; 86: 1387–97.

6.        Sheean G. Botulinum toxin treatment of adult spasticity: a benefit-risk assessment. Drug Safe. 2006; 29: 31–48.

7.        Rizzu MA, Hadjimichael OC, Preiningerova J, Vollmer TL. Prevalence and treatment of spasticity reported by multiple sclerosis patients. Mult Scler. 2004; 10: 589-95.

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9.        Romero JR, Anschel D, Sparing R. Subtbreshold low frequency repetitive transcranial magnetic stimulation selectively decreases facil­itation in the motor cortex. Clin Neurophysiol. 2002; 113:101-7.

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14.     Paes F, Machado S, Arias-Carrión O, Velasques B, Teixeira S, Budde H, et al. The value of repetitive transcranial magnetic stimulation (rTMS) for the treatment of anxiety disorders: an integrative review. CNS Neurol Disord Drug Targets. 2011 Aug;10(5):610-20.

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16.     Mori F, Koch G, Foti C, Bernardi G, Centonze D. The use of repetitive transcranial magnetic stimulation (rTMS) for the treatment of spasticity. Prog Brain Res. 2009; 175:429-39.

17.     Huang YZ, Edwards MJ, Bhatia KP, Rothwell JC. One-Hz repetitive transcranial magnetic stimulation of the premotor cortex alters recipro­cal inhibition in DYT1 dystonia. Mov Disord. 2004; 19:54-9.

18.     Perez MA, Lungholt BK, Nielsen JB. Short-term adaptations in spinal cord circuits evoked by repetitive transcranial magnetic stimulation: possible underlying mechanisms. Exp Brain Res. 2005; 162: 202-12.

19.     Quartarone A, Bagnato S, Rizzo V. Distinct changes in cortical and spinal excitability following high-frequency repetitive TMS to the human motor cortex. Exp Brain Res. 2005; 161:114-24.

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23.     Baumer T, Lange R, Liepert J. Repeated premotor rTMS lead to cumulative changes of motor cortex excitability in humans. Neuroimage. 2003; 20: 550-60.

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الملخص العربي

 

يعتبر التيبس أكثر الأعراض شيوعاً في مرضى التصلب المتناثر، وتعتبر الأطراف السفلية أكثر تأثراً بصفة عامة. ويصاحب العلاج الدوائى آثار جانبية مثل الشعور بالخدر والضعف بالإضافة إلى إضطرابات إدراكية.

يساعد التنبيه المغناطيسى المتكرر عبر المخ على إحداث تغييرات في إثارة القشرة المخية عند موقع التحفيز وفي المواقع البعيدة، يؤدى إلى المنع أَو التسهيل اعتمادا على تردد النبض. التنبيه المغناطيسى المتكرر قد يحسن التيبس. قد تدوم هذه التأثيرات أطول من مدة المحفزات، لدقائق  حتى ساعات.

أجريت الدراسة على 21 مريض  (12 ذكر و9 إناث) يعانون من التيبس الناتج عن التصلب المتناثر بشكل خاص على طرف سفلى واحد. أعمارهم من 16-42 سنة. يتراوح مقياس العجز الموسع بين 3-5.5. كل المشاركون خضعوا للعلاج بالتنبيه المغناطيسى المتكرر عبر المخ لمدة أسبوعين  وقسموا المرضي إلى مجموعتين. 

المجموعة (أ): إستعملنَ تذبذب عالي (5 هيرتز).

المجموعة (ب): إستعملنا تردد منخفض (هيرتز 1).

خضعت جميع الحالات لمقياس أشوورث المعدل ومقياس تارديو والتقييم الكهروفسيولوجىH/M ratio) ) في بداية الأسبوعين وعند نهاية العلاج. نتحرى في دراستنا عن دور التردد العالى والمنخفض للتنبيه المغناطيسى فى علاج التيبس الناتج عن التصلب المتناثر وتقييم الحالات إكلينيكيا وفسيولوجيا.

أثبتت نتائجنا أن جلسات التنبيه المغناطيسى المتكرر تردد 5/هيرتز حسن مقياس أشوورث المعدل وميزان تارديو والتقييم الكهروفسيولوجى ولم يستطع تردد 1 هيرتز تحسينة.

 



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