Combined Effects of rTMS and Botulinum Toxin in Benign Essential Blepharospasm: A Novel Approach
Phase: NA
Conditions: Benign Essential Blepharospasm
Sponsor: University of Florida

Protocol Version: 1/5/15 
 
 
Title: Combined effects of rTMS and botulinum toxin in benign essential blepharospasm: A novel approach 
 
 
NCT02370875 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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BACKGROUND: 
 
Benign essential blepharospasm (BEB) is a focal dystonia characterized by excessive involuntary closure of the 
eyelids.1 BEB is a functionally disabling disorder with significant impact on the quality of life.2 Due to repeated 
involuntary closure of eyes, in severe cases, patients become functionally blind despite a normal visual acuity. 
Chemodenervation with botulinum neurotoxin (BoNT) injections administered every 12 weeks has emerged as 
an effective first-line therapy for the treatment of BEB. However, the treatment is purely symptomatic and does 
not modify the disease pathophysiology.3 Importantly, the clinical benefits are temporary with most patients 
reporting benefits lasting only about 8-10 weeks.4, 5 We conducted a retrospective analysis of BEB patients at our 
movement disorders center that has followed over 250 patients (manuscript submitted) and found that the average 
duration of benefits from BoNT injections was about 9.5 weeks which is consistent with other studies.   Thus 
BoNT therapy although a first-line therapy for BEB shows suboptimal benefits in many patients. Therefore, there 
is a clear merit in exploring other options that can potentiate and possibly prolong the effects of BoNT injections. 
 
 
rTMS refers to application of repetitious transcranial magnetic stimulation (TMS) pulses to a specific brain target 
at predefined stimulation parameters. We propose a novel approach of combining rTMS therapy with BoNT 
injections in BEB. The primary goal of this study is to compare the standard treatment with BoNT versus BoNT 
combined with a two week course of rTMS therapy. The central hypothesis is that rTMS therapy potentiates and 
prolongs the effects of BoNT therapy in BEB.  rTMS therapy has shown beneficial results in many neurological 
and psychiatric conditions.6,7 rTMS therapy is noninvasive and is FDA approved for treatment of medication 
refractory depression when delivered to the prefrontal cortex.8 In our study we will select the anterior cingulate 
cortex (ACC) as the target of stimulation. ACC has been proposed by many studies as the main sites of pathology 
in BEB. Anatomically in monkey studies, the ACC has been shown to have clear projections to the upper facial 
muscles.9 In BEB patients, PET study has shown there is an increased glucose uptake in the ACC.10,11 fMRI study 
has also shown an increased brain activity in the rostral ACC in relation to the eye-closure.12, 13 Kranz et al in 
collaboration with Dr Hallett’s lab tested the effects of rTMS of the ACC in BEB. So far to date this is the only 
rTMS study that is available for review in literature. These investigators found that a single session of low 
frequency rTMS delivered to the ACC had positive clinical benefits though lasting only for about one hour.14 
 
 
The fundamental mechanism of action for rTMS is modulation of brain excitability.15 rTMS at frequencies of 5-
Hz and higher has been found to transiently enhance the excitability,16  whereas rTMS at frequencies of 1-Hz and 
lower has been found to depress the cortical excitability.17 Many rTMS studies have also shown that repeated 
sessions of rTMS therapy results in cumulative persistent benefits that can last several weeks. For example, in a 
recent double blind randomized controlled study, low frequency rTMS delivered over eight weeks to Parkinson’s 
disease patients showed positive clinical benefits that lasted 12 weeks beyond the last rTMS session.18 In this 
proposal we plan to employ a two week course of rTMS therapy to achieve sustained benefits. With standard 
BoNT treatment, the peak-dose benefits are seen at about 4-6 weeks after the administration of injections. We 
plan to introduce rTMS during this peak-dose period (about 6 weeks after BoNT or T1). We will examine the 
effects of combined therapy at about 10 weeks after BoNT injections (T2) and at about 12 weeks after BoNT 
injections (T3). We will also measure the physiological effects at these time points.  We will use the blink reflex 
recovery (BRR) curve that reflects the brain stem excitability. An increased BRR indicates that there is increased 
excitability of facial motor neurons and bulbar interneurons. BRR has been shown to be increased in a significant 
proportion of patients with BEB.19,20 According to the animal model of blepharospasm, one of the underlying 
mechanisms for increased BRR is that a loss of dopamine-containing neurons in the substantia nigra pars 
compacta causes a decreased inhibition in the blink circuit.21 
 
In summary, BEB is a functionally disabling focal dystonia. BoNT therapy is suboptimal in many BEB patients. 
rTMS therapy is a promising noninvasive therapy and has shown positive benefits in BEB. rTMS therapy can be 

 
 
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easily combined with BoNT injections to enhance the effects of BoNT in BEB. We plan to collect pilot data on 
this novel approach in this one year application. The specific aims for the proposal are:  
 
Aim 1: Clinical impact of rTMS therapy in BEB.  
We will determine the clinical effects of 0.2 Hz rTMS therapy of the ACC when combined with BoNT injections 
in BEB. Comparisons will be drawn between the T1, T2 (about 10 weeks after BoNT) and T3 (about 12 weeks 
after BoNT) assessments in the clinical scoring of BEB symptoms and patient rating of quality of life. We 
hypothesize that in comparison to T1 assessment; there will be an increased control of BEB symptoms and patient 
rating of quality of life at T2 follow-up. These benefits will remain sustained at T3 follow-up though to a lesser 
extent.  
 
 
Aim 2: Physiological impact of rTMS therapy in BEB 
 
Aim 2a: We will determine the physiological effects of 0.2 Hz rTMS therapy of the ACC when combined with 
BoNT injections in BEB. We will record the time course of effects on BRR at T1, T2 and T3 assessments. We 
hypothesize that in comparison to T1 assessment, BRR will be reduced and reach physiological levels at T2 
follow-up. BRR will continue to remain at physiological levels at T3 follow-up though to a lesser extent than at 
T2. 
 
Aim 2b: We will determine if the effects of 0.2 Hz rTMS therapy on BRR will correlate with clinical scoring of 
BEB symptoms. We hypothesize that the change in BRR at T2 and T3 will show positive correlation with the 
improvement in BEB symptoms at these time points. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1:  
A shows the schedule for rTMS intervention and monitoring of clinical and physiological outcomes   
B shows the target in the brain for rTMS intervention 
A 
B 
rTMS will be delivered over the ACC with a figure-
of-eight coil. 

 
 
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METHODS 
 
Study design: We propose a blinded control study of real and sham rTMS with a goal of enrolling about eight 
subjects (age range 21–80 years) in each treatment arm and ten healthy control subjects for normative 
physiological data (total 26 16). Subjects diagnosed with blepharospasm or cranio-cervical dystonia who receive 
BoNT therapy at our center will be approached. The BoNT clinic at our center follows more than 250 subjects 
with dystonia. Subjects followed at our center regularly fill out a self-reported form to document if they have 
responded to BoNT and the duration of benefits perceived with BoNT therapy. We will enroll only those subjects 
who report experiencing positive benefits with BoNT but lasting about 10 weeks or less. We will exclude subjects 
if they report 1) pregnancy; 2) active seizure disorder; 3) significant cognitive impairment; 4) exposure to 
neuroleptics; and 5) presence of a metallic body such as pacemaker, implants, prosthesis, artificial limb or joint, 
shunt, metal rods and hearing aid.14 We will enroll about 10 healthy age and sex-matched subjects controls for 
normative electrophysiological data. Controls will be recruited through fliers placed across the campus. All 
controls will be examined by Dr. Wagle Shukla to ensure that they are neurologically healthy.  
 
We will invite all eligible subjects to an introductory session. During this session the procedures outlined for the 
study will be explained in detail. We will then obtain an IRB approved informed consent. We will perform medical 
history and neurological examination using the NINDS Common Data Elements.  Each subject will be 
randomized to receive either real or sham stimulation. We will record the demographics and severity of BEB 
using the blepharospasm severity scale.22  The BEB subjects followed at our center are scheduled for BoNT 
treatment about every 12 weeks as per the standard of care. We will start rTMS therapy at about 6 weeks after 
they have received the BoNT injections. We have chosen this timeframe to coincide the rTMS therapy with the 
peak-dose effects of the BoNT injections. We will do our best to make sure that the patients are accompanied to 
the laboratory facility by a friend, relative, or spouse, or we will arrange transportation. Although the physician 
administering TMS will be aware of the status of the subject in terms of real TMS versus sham-TMS, this 
physician will play no role in any of the outcome measures, and will not be present during any of the outcome 
measure assessments. Similarly, the investigators who perform the outcome measures will not be present during 
any of the TMS sessions, and therefore will remain blinded to the status of the patients with respect to real-TMS 
versus sham-TMS.  
 
Outcome measures: The primary clinical outcome will be the percentage change in physician rating of BEB 
symptoms. We will record 5 minute videos of eye blinks for the eye blink rate, number of sustained blinks, and 
time of eye closure. These videos will be scored by a blinded rater. We will then use the Jankovic rating scale and 
blepharospasm disability index to rate the improvements. We have IRB approved consent to obtain videos of 
most patients presenting to our center but the ICF will include a video consent section.  The secondary outcome 
for the study will include the subjective rating by the patients. We will record blink reflex recovery (BRR) as the 
physiological outcome of rTMS. We will determine the time course effects of rTMS on physiological outcome. 
We will also determine if the physiological effects correlate with the clinical outcome measures.  
 
Clinical measures:  
 
Physician rating: We will score the eye blink rate, number of sustained blinks, and time of eye closure.  An eye 
blink will be defined as any visible, bilateral, and synchronous contraction of the orbicularis oculi (OO muscle), 
causing eyelid drop. Blink rate will be expressed as blinks per minute. Sustained spasms of the OO muscle will 
not be considered blinks and will be counted separately. The time (seconds) of eye closure whenever blinks cause 
prolonged eye closure (eyes shut > 2 seconds) will be recorded with a stopwatch.14  
 
Patient rating: We will administer the Craniocervical Dystonia Questionnaire Description for quality of life 
assessment. The Craniocervical Dystonia Questionnaire (CDQ-24) is a patient-rated health related quality of life 
(HR-QoL) measure for craniocervical dystonia. It was developed based on issues that are relevant to patients 
with BEB. It has been validated for use in clinical research. The CDQ-24 measures the impact of Craniocervical 

 
 
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Dystonia on 5 HR-QoL domains. It is composed of 24 items, forming 5 subscales: stigma, emotional well-
being, pain, activities of daily living, and social/ family life. Items are rated on a 5-point scale.23 Each item 
consists of five statements representing increasing severity of impairment, scored from 0 to 4. Subjects will be 
instructed to indicate how they have felt during the past two weeks because of dystonia by selecting one of the 
five statements for each item. Subjects will also rate their symptoms before and after stimulation using a 7-point 
nominal scale: 1) excellent, 2) very good, 3) good, 4) average, 5) slightly worse than usual, 6) bad or 7) very 
bad. 
 
Physiological Measure: 
 
Blink reflex recover: We will record surface EMG recordings for both eyes separately from the orbicularis oculi 
(OO) muscle using Ag-AgCl surface electrodes. The EMG signals will be amplified using D360 amplifiers 
(Digitimer, Welwyn, UK), band pass filtered (5–2,500 Hz), analog-to-digital-converted using a 1401 AD 
converter (CED, Cambridge, UK) at a sample rate of 5,000 Hz, and will be collected on a computer. Electrical 
stimulation will be applied to the supraorbital nerve in the supraorbital notch with a bipolar stimulating electrode 
and a constant current generator (Digitimer). Single and paired electrical stimuli (conditioning and test) will be 
delivered and EMG amplitudes will be recorded from the OO muscle. All stimuli will be 0.2 msec in duration 
and stimulus intensity will be set at 3 times the R2 threshold (lowest intensity that gives an R2 response in at least 
5 out of 10 trials). Subjects will be studied at rest, with eyes gently closed. The blink reflex in response to paired 
stimulation will be assessed at multiple inter stimulus intervals of about 200 msec (6 trials of test and paired 
stimulus each, pseudo randomized.). Pairs of stimuli will be separated by varying time intervals of 20–40 seconds 
to minimize habituation. Trials with excessive EMG artifact will be rejected online. Data will be analyzed offline 
using Signal software (Cambridge Electronic Design, UK). The raw blink recordings will be DC-corrected, 
rectified, and averaged. The onset latency and duration of R1 and R2 responses will be determined by manual 
cursor marking of the beginning and end of responses. Peak amplitude of R2 will be calculated within a window 
from 30 to 60 msec to avoid stimulation artifacts. We will obtain R2 recovery values by dividing the size of R2-
test [R2T] by the size of conditioning response [R2C]. 19 
 
rTMS therapy:  
 
Real stimulation: rTMS will be delivered over each anterior cingulate cortex, using a figure-of-eight coil 
connected to a Magstim machine (Magstim Company, Dyfed, UK). We will apply rTMS with 0.2 Hz frequency 
to the ACC. We will deliver 180 stimuli (around 15 min) with a stimulator output of 100% active motor threshold 
(AMT). AMT will be assessed at the tibialis anterior muscle with the figure-of-eight coil. The AMT will be 
defined as the lowest stimulation intensity required to evoke a 150 μV potential in the target muscle. To determine 
the stimulation site for ACC, the figure-of-eight/double cone coil will be placed over Fz and then moved over the 
midline of the brain in 0.5-cm steps anteriorly, until the point of maximum motor evoked potential in the 
orbicularis oculi (OO) muscle (with a latency of 6–8 msec) is reached (about 3.5 cm medial and 5.5 cm anterior 
to motor cortex).14 The coil position will be marked on the skin. Constant coil position will be continuously 
monitored during the experiment. These rTMS sessions will be repeated on a daily basis over 10 days. During 
rTMS, all patients will wear ear plugs in order to protect the ears from the acoustic artefact associated with the 
discharge of the stimulation coil. 
 
Sham Stimulation: During sham rTMS, subjects will undergo the same procedure for identifying stimulus 
location as used in patients receiving real rTMS. Sham rTMS will be administered using the same Magstim coil 
as used in real stimulation. This coil will be placed on the patient’s head in an identical manner however will not 
be connected to the Magstim device. Instead another coil will be connected to provide stimulation sound. In each 
stimulation condition, the Magstim will be placed behind the patient and not visible to him or her. Placebo sham 
coil which produces discharge noise and vibration similar to a real coil without stimulating the cerebral cortex. 
During rTMS, all patients will continue to wear ear plugs as instructed during the real stimulation sessions. 

 
 
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Safety of rTMS: Repetitive TMS can have undesired side effects. Guidelines for the safe use of rTMS were 
formulated at the 1st International Workshop on the Safety of TMS.24  These were adopted by the International 
Federation for Clinical Neurophysiology and subsequently updated.25 The proposed study will use TMS 
parameters well within the published safety guidelines. We will conduct careful monitoring of the participants 
and follow all recommended precautions for the application of TMS.  Subjects will have a urine pregnancy test 
done on the first day of the scheduled rTMS visit before rTMS is done.   
There will be a potential for direct benefit if the study stimulation helps subject’s blepharospasm symptoms. Risks 
include a neck ache or headache. The study procedure may also cause the nearby scalp muscles to twitch.  
Although TMS has been used for over 20 years, there is a possibility of unknown risks due to TMS. 
 
Data Safety Monitoring Plan 
 
The principal investigator monitors the patient safety and data collection of each study visit.  If she feels there is 
possible harm to subject safety or the possibility of, any harm due to something new that was learned during the 
study, she will convene a multi-disciplinary committee of at least 2 health professionals to perform a thorough 
review of the study details. 
 
Patient Stipends  
 
Payments for mileage reimbursement will be paid to study subjects with blepharospasm. If a hotel visit is required, 
the study team will make the hotel arrangements for the subjects and the cost will be pre-paid. 
 
Control subjects will be paid a flat rate of $20 or can be paid for mileage, whichever is greater. If you are paid 
more than $75, we will need to collect your social security number. 
 
SAMPLE SIZE, EXPECTED OUTCOME AND STATISTICAL ANALYSIS:  With an expected difference 
of 30% in the primary outcome measure14 between before (T0) and after rTMS therapy (T1), a standard deviation 
of 20%, type I error of 5% and power of 80%, the necessary sample size for each group has been determined. In 
this one year pilot study we propose to enroll a total of 16 BEB subjects with eight subjects in each treatment arm 
and 16 healthy controls for normative physiological data. Descriptive statistics will be used for the demographic 
data. Data will be presented as mean (SD) unless otherwise indicated. We will examine each of the dependent 
measure separately. These include the eye blink rate, number of sustained blinks, the time of eye closure, patient 
rating of blepharospasm and the BRR cycle. For Aim 1 and Aim2a, each dependent measure will be examined 
using the following statistical approach.  We will conduct a mixed model analysis using time and stimulation arm 
as repeated factors adjusted for baseline values, and subjects as the random factor. The model will include 2 
within-subject factors: treatment (2 levels: active vs sham) and time (3 levels: T1, T1, and T3).  If the interaction 
effects between stimulation arm and time are found as non-significant, they will be dropped. In case of significant 
main effects, post hoc pairwise comparisons will be corrected using Fisher least significant difference procedure 
in accordance with the closed test principle; i.e., post hoc comparisons will be declared non-significant if the 
global p value of the main effect (testing equality of all 2 stimulation arms simultaneously) are non-significant, 
but will be carried out without further correction in case of a significant global main effect. SPSS version 15.0 
for Windows will be used for statistical computations. The 2-tailed significance level will be set at 0.05. For Aim 
2b, we will use Spearman correlation test to determine the relation between the change in BRR and change in 
clinical scores at T2 compared to T1 and at T3 compared to T1. 
 
 
POTENTIAL PROBLEMS 
 

 
 
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1. Subjects may not meet the criteria, may not tolerate the rTMS therapy or drop out of the study. We will 
factor in these considerations during recruitment. We propose a sample size of eight subjects in each 
treatment arm (total 16). We have an IRB approved database of patients followed at our center. In order 
to meet our target sample, while conducting the retrospective analysis we preemptively identified the BEB 
subjects that receive suboptimal benefits (36 subjects). 
2. Quality assurance (QA) on the Magstim machine will be constantly monitored. 
3. Quality of EMG recordings: The EMG recordings (Delsys, Inc., Boston, Massachusetts) are reliable with 
high signal-to-noise ratio. We will reduce the noise of the EMG signals by cleaning and lightly abrading 
the skin. 
 
The University of Florida nor the Principal Investigator hold a patent or license for any material, object or process 
used in this study.  There is no license pending or under consideration or is there any intention to file a patent 
application at a later date.  
 
Computer-based files will only be made available to personnel involved in the study through the use of access 
privileges, passwords and encryption.  Passwords and encryption are used to ensure that the electronic data is 
secure and housed in a locked room.   
 
References  
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Report from the BEBRF international workshop. Neurology 2008;71:1275-1282.  
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4. Ainsworth JR, Kraft SP. Long-term changes in duration of relief with botulinum toxin treatment of essential 
blepharospasm and hemifacial spasm. Ophthalmology 1995;102:2036-2040.  
5. Streitova H, Bares M. Long-term therapy of benign essential blepharospasm and facial hemispasm with 
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more than 15 years. Acta Neurol Belg 2014.  

 
 
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