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October2013 Vol.50 Issue:      4 Table of Contents
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Can Repetitive Transcranial Magnetic Stimulation Help On-Freezers with Parkinson’s Disease?

Mohamed S. El-Tamawy1,  Hatem S. Shehata1, Nevin M. Shalaby1,

Amani Nawito2,  Eman H. Esmail1

Departments of Neurology1, Clinical Neurophysiology Unit2, Cairo University;



ABSTRACT

Background: Freezing of gait (FOG) or “motor block” is experienced in about 30% of Parkinson’s disease (PD) patients within 5 years, and nearly in 60% after 10 years. Treatment of “Off” time FOG is relatively straight forward, but “On-freezing” is a difficult to treat scenario. Objective: This study evaluated the efficacy and safety of repetitive transcranial magnetic stimulation (rTMS) in management of “on-freezing” in patients with advanced PD. Methods: Sixteen Egyptian patients received 12 rTMS sessions over 4 weeks (either real or sham) using figure-of-8-shaped coil over the leg area of motor cortex contralaterally to the more affected side in addition to rehabilitation program involving specific gait training techniques. Primary efficacy variables were frequency of freezing episodes, FOG questionnaire (FOG Q) short form (SF), motor section and total score of unified PD rating scale (UPDRS), secondary outcomes were gait variables (Cadence, number of falls, stride length, stride time and turn time), and on-time. Patients were followed for 3 months. Results: There was improvement of FOG Q (SF), together with significant decrease in number of falls and widened stride length in patients receiving real rTMS. The total score of UPDRS and other gait variables were not significantly change. Dopaminergic drugs dosages were not reduced. No adverse effects were recorded apart from mild and transient headaches. Conclusion: rTMS may have a positive effect in on-freezers with advanced PD with subsequent decrease of number of falls. [Egypt J Neurol Psychiat Neurosurg.  2013; 50(4): 355-360]

Key Words: Parkinson’s disease, On freezing, repetitive transcranial magnetic stimulation (rTMS).

Correspondence to Hatem Samir Shehata, Department of Neurology, Cairo University, Egypt.

Tel.: +201227312131   Email: samirhatem@hotmail.com




 

 


INTRODUCTION

 

Freezing of gait (FOG) or "motor block" is one of the most disabling symptoms of Parkinson’s disease (PD); that involves a sudden and brief interruption or difficult initiation of gait despite the intention to walk”1. Its prevalence ranges from 7% in early PD to 60% of late cases2. It impairs mobility and quality of life (QoL), in addition to increase the risk of falls in PD patients with their consequences3,4.

In a study of 71 patients with PD, who were suffering from FOG, all of them had off-freezing; while; only 35% had on-freezing5. The true on-freezing is a resistant to treat situation; and it may be aggravated by increasing its dose whether or not there are associated FOG in the Off state6.

Freezing behavior is not limited to gait but can occur in speech and upper limb movement, suggesting its pathophysiology may not be simply a damage in neuronal centers involved in normal gait7,8.

 

Hashimoto 9 emphasized the role of the medial frontoparietal dysfunction as a key player for FOG; being a higher center for locomotion in humans. Moreover; the Diffusion Tensor imaging (DTI) on vascular parkinsonism (VP) supported the curcial role of dysfunction of motor circuits in frontal lobes in the pathogenesis of gait apraxia in VP10,11. Though most cases of FOG respond to dopaminergic agents; yet, this response can be transitory and partial. So extra-nigral non dopamenergic (serotonergic, glutamenergic, noradrenergic, and cholinergic) mechanisms are likely to be involved in the pathophysiology underling this phenomenon12,13.

Magnetic stimulation -when delivered in series or train of pulses (repetitive TMS, rTMS) can modify neuronal activity through plastic changes in motor cortical networks, including long term potentiation (LTP), long term depression (LTD), modulation of neurotransmitters or gene induction14,15.

Several studies have demonstrated the therapeutic effect of rTMS of motor cortex on motor symptoms of PD; however, less data are available regarding its particular efficacy in FOG in PD16-20.

The present study aims at evaluating the effectiveness of rTMS in management of “On-freezing” in patients with advanced PD.

 

SUBJECTS AND METHODS

 

This study was designed as a double blinded, placebo controlled study, comparing the effect of real versus sham rTMS on resistant FOG during” On state” in medicated PD patients. Both patients and investigators conducting follow up examination were blinded to the technique used being real or sham. All patients were naïve to rTMS. The study enrolled sixteen non-demented PD patients with on- FOG. They were enrolled from June 2011 to January 2013. All patients had MRI brain and thyroid function tests before being enrolled and they all fulfilled the UK Parkinson’s disease brain bank criteria for IPD21. None of them had serious medical illness, implanted devices, or history of seizures.  All patients provided a written informed consent. The study was carried out in the Neurology department and clinical neurophysiology unit, Kasr Al-Aini School of medicine, Cairo, Egypt, and was approved by the Medical Ethical Committee, Cairo University.

Demographic information and full history were obtained from each participant. Patients had baseline medical assessment including, mini mental state examination (MMSE), unified Parkinson disease rating scale (UPDRS), modified Hoehn and Yahr scale to assess for severity, freezing of gait questionnaire (short form) [FOG Q (SF)] , Five Times Sit to Stand Test (FTSTS) to assess gross fall risk in individuals with PD (falls that are not related to freezing). One month before receiving magnetic stimulation; patients were required to provide daily schedule to record: On-time freezing episodes, number of falls, time and types of freezing. Dosages of dopaminergic medications were recorded. Patients were then randomly assigned to either real or sham rTMS stimulation via a computer generated program and were followed up for 3 months and were reassessed in the “On state”. The primary efficacy variables were: frequency of freezing episodes, FOG Q (SF), and falling, freezing, and walking subscores, and total score of UPDRS III, and the secondary outcomes were gait variables (cadence, stride length, stride time and turn time), as well as dosage of L-Dopa drugs received.

Stimulation technique: Repetitive TMS was delivered to the scalp over the site corresponding to the leg area of primary motor cortex contralateral to the more affected side using a Magstim rapid2 machine and a figure-of- 8- shaped coil.  Each patient had 12 sessions over 4 weeks. The session comprised of ten trains of 50 stimuli each delivered at 1 Hz with 20 seconds intervals between the trains. The stimulus intensity was set at 90% of the motor threshold (MT)22. The procedure was conducted with the patients in the “On-state”.

For real TMS the coil was held tangentially to the patient's head surface and position of the coil was adjusted to find the optimal scalp position and the location of stimulation was marked. For sham TMS the figure of eight coil was rotated away from the scalp so that its lateral edge was touching the scalp. The sham subjects went through the same procedures as the real TMS subjects up to the point of the coil position.

Patients had rehabilitation program including: enhancing of motor relearning, helping tricks including gait manipulations (visual cueing), and weight shift method, and treadmill training (30 minutes).

 

Statistical Methods

Data was analyzed by Microsoft Office 2003 (excel) and Statistical Package for Social Science (SPSS) version 16. Parametric data was expressed as range, and mean±SD, and non parametric data was expressed as number and percentage of the total. Comparing the mean±SD of 2 groups was done using paired and unpaired student’s t test. P value < 0.05 was considered significant.

 

RESULTS

 

The study included 16 patients (11 males, 5 females). The demographic and clinical data are shown in Table (1).

 

Primary Efficacy Measures:

Primary outcomes were evident after 3 months from starting rTMS sessions. Freezing episodes statistically decreased in patients subjected to the active rTMS stimulation relative to the placebo arm. FOG Q showed marked improvement after the sessions  (Figure 1), together with improvement of UPDRS “falling; freezing; and walking” subscorers, however, the latter did not  reach statistical significance, while the total UPDRS score was not affected (Table 2).

 

Secondary efficacy measures:

Regarding gait variables; significant decrease in turn time was detected (Figure 2); whereas, cadence, stride length and stride time were not affected. The L-dopa dose was not reduced. No serious adverse events were detected. Only 3  patients reported mild transient headaches; one patient received real rTMS and the other two were on the placebo arm.


Table 1. Demographic and clinical characteristics of the studied sample.

 

 N = 16

Range

Mean ±SD

 Age (years)

58–74

67±7.32

MMSE

25–30

28.57±1.61

L-Dopa Dose (mg)

400-750

565.6±111.1

Modified Hoehn & Yahr

2.5–4

3.1±0.56

 Off UPDRS

63–98

81.2±11.06

On UPDRS

19–34

25.33±8.54

FOG–Q

12–22

16.3±5.5

Freezing episodes /day

3–63

21.71±17.61

Turn Time (sec)

5-10

7.18± 1.6

MMSE: Mini-Mental State Examination; UPDRS: unified Parkinson’s disease rating scale; FOG Q: freezing of gait questionnaire.

 

 

 

 

Figure 1. Comparing FOG Q score between patients on the active and the  placebo arms.

 

Table 2. Comparing primary efficacy outcomes between patients on the active and the placebo arms.

 

Efficacy Outcome

Active arm

Placebo arm

P Value

Primary Measures (Mean±SD/Mode)

Freezing episodes/day

11.87±6.81

30±16.81

0.013*

FOG Q

10±3.42

20±4.63

0.001**

UPDRS (Mode)

Falling

1

4

0.009**

Freezing

1

4

0.001**

Walking

2

3

0.09

*Significant at p<0.05 ** Significant at p<0.01

 

 

Figure 2. Comparing Turn Time between the active and placebo arms.

 

 


DISCUSSION

 

It is well known that the patients with PD show several disturbances in their movement, particularity in the gait and in the repetitive and rhythmic upper limb movements23. Pascual-Leone and colleagues24 reported an improvement in motor performance during 5 Hz rTMS to the motor cortex in patients with PD. However, a real efficacy of rTMS on motor cortex in PD is controversial  since subsequent studies, using figure-of-eight coil17,19,25, or using a circular coil16,20,26, show various results. 

These different results could be due to the different methodologies used in the TM stimulation technique such as the shape of coil, the stimulus intensity, frequency and number of pulses27.

In our study, improvement of gait freezing in patients receiving real rTMS evidenced by FOG Q (SF), together with significant decrease in freezing episodes; number of falls; and widened stride length was detected relative to the sham group. The total score of UPDRS and other gait variables were not significantly changed. No adverse events were recorded apart from mild and transient headaches. These findings agree with Ameli and colleagues28, whose data suggested an improvement of hypokinetic gait in PD after 1Hz rTMS. However, this was contradictory to the results of Filipović and colleaugues29, where 1Hz TMS were delivered over the motor cortex for four consecutive days. Neither total Motor Scale scores nor subscores for axial symptoms, rigidity, bradykinesia, and tremor showed any significant difference. Arias and colleagues22, who used a similar protocol to this study, found  only the total and motor section of the UPDRS and the turn time during gait to be affected by the stimulation and this improvement was equally displayed in both real and sham group and concluded that the protocol of stimulation used has no therapeutic value. Shirota and colleagues30, found that 1-Hz rTMS over the supplementary motor area (SMA) was effective for motor symptoms as monitored by the UPDRS. Higher frequencies were also used like in a double-blind placebo-controlled study31; 25 Hz rTMS over eight  sessions were performed over a 4-week period on the motor and dorsolateral prefrontal cortices. The authors concluded their protocol had a cumulative benefit for improving gait.

Elahi and colleagues32 evaluated the effects of rTMS on motor signs in PD. Ten randomized, controlled clinical trials (n=275 patients) were included in the meta-analysis. The authors concluded that the results of the systematic review showed that high-frequency rTMS is a promising treatment of motor symptoms in PD and  low frequency effects were not significant. There were several limitations of this systematic review. First, the study outcomes were not uniformly reported. Second, there were considerable differences in the rTMS protocol. Moreover, the analyzed studies also varied in patient selection criteria, demographics, and duration of follow-up and stages of PD.

A large, randomized controlled trial with appropriate follow-up will be useful to further define role of TMS in the treatment of PD. Future studies are also needed to clarify the optimal stimulation parameters, how the different stages of PD affect the response to rTMS, and the effects of rTMS on other aspects of the disease such as gait, cognition, and memory.

 

[Disclosure: Authors report no conflict of interest]

 

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الملخص العربى

 

هل بامكان التنبيه المغناطيسى المتكرر عبر المخ مساعدة مرضى الباركنسون المتقدم

الذين يعانون من تجمد المشي تحت العلاج؟

 

تهدف الدراسة لتقييم كفاءة و سلامة التنبيه المغناطيسى المتكرر عبر المخ في التعامل مع ظاهرة تجمد المشي تحت العلاج عند مرضي الباركنسون المتقدم ،و قد أجريت هذه الدراسة علي 16 مريضا مصريا اجري لهم 12 جلسة تنبيه المغناطيسى المتكرر عبر المخ (إما تنبيها حقيقيا أو زائفا) خلال 4 أسابيع علي  منطقة القشرة المخية الخاصة بالساق في الناحية المعاكسة للساق الأكثر تأثرا، ذلك بالإضافة  إلى برنامج إعادة تأهيل، وقد أظهرت النتائج تحسن معاملFOG Q (SF)  ومعدل التجمد وكذلك انخفاض عدد مرات السقوط واتساع الخطوة وتقليص زمن الالتفاف في المرضى  الذين اجري لهم التنبيه الحقيقي في حين لم تتأثر مقياسUPDRS والمعاملات الأخرى للخطوات، ولم تسجل أي أثار جانبية عدا حالات من الصداع الطفيف المؤقت، وأوضحت النتائج أن التنبيه المغناطيسى المتكرر عبر المخ له تأثير ايجابي علي تجمد المشي تحت العلاج في مرضى الباركنسون المتقدم.

 



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