Dystonia, Primary Cervical Dystonia
Conditions
Keywords
Botulinum Toxin, Transcranial Magnetic Stimulation
Brief summary
Primary cervical dystonia (PCD) is the most common form of focal dystonia. PCD is frequently reported as a source of disability, decreased quality of life, and social stigma. Botulinum toxin (BoNT) is the gold standard treatment for PCD. The average duration of benefits from BoNT injections was about 9.5 weeks and BoNT treatment is known to provide only pure symptomatic benefits and does not seem to modify the disease pathophysiology. The investigator plans to use repetitive transcranial magnetic stimulation (rTMS) therapy as an adjunctive therapy in combination with BoNT injections as a novel approach to treat PCD. The primary goal of this study is to compare standard treatment with BoNT versus BoNT combined with a two week course of rTMS.
Detailed description
rTMS refers to the application of transcranial magnetic stimulation (TMS) pulses to a specific target at predefined stimulation parameters. Repeated sessions of rTMS therapy have been demonstrated to induce cumulative persistent benefits that can last weeks after the conclusion of the rTMS sessions The central hypothesis of this study is that rTMS therapy in PCD can potentiate the effects of BoNT injections. With the current standard treatment, the peak-dose benefits seen with BoNT are seen at about 4-6 weeks after the administration of injections. The investigator will introduce a 1 week course of rTMS around 2-8 weeks before or after BoNT or T1). The investigator will examine the effects of combined therapy at 10 weeks after BoNT and 12 weeks after BoNT injections follow-up.
Interventions
DEVICENeuroStar TMS therapy
Application of repetitious transcranial magnetic stimulation (TMS) pulses using NeuroStar device to a specific brain target at predefined stimulation parameters.
DEVICESham NeuroStar TMS therapy
Same procedure as real rTMS without stimulating the cerebral cortex.
OTHERToronto Western Spasmodic Torticollis Rating Scale (TWSTRS)
All participants will receive a clinical assessment of dystonia severity by using the TWSTRS test.
OTHERCraniocervical Dystonia Questionnaire (CDQ-24)
All participants will fill out the Craniocervical Dystonia Questionnaire (CDQ-24) quality of life questionnaire.
All participants will have a measure of the cerebellar-brain inhibition(CBI) which will be conducted by using a TMS device determining the ability of the coil to activate the cerebellum.
PROCEDUREBotulinum toxin injections
All participants will receive Botulinum toxin(BoNT) injections as part of their standard of care
Sponsors
American Brain Foundation
Neuronetics
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of PCD in accordance with the Consensus Statement of the Movement Disorder Society * Subjects who report Botulinum Toxin benefits lasting 10 weeks or less only (suboptimal benefits with standard care)
Exclusion criteria
* Pregnancy * Active seizure disorder * Presence of a metallic body such as pacemaker, implants, metal rods and hearing aid.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dystonia Severity as Assessed by the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) | absolute value at 12 weeks | A clinical assessment of dystonia severity will be conducted at each study visit using the TWSTRS. The TWSTRS is a widely accepted composite rating scale for PCD with subscales for clinical severity, functional disability, and associated pain. The total score reported here can range 0-85, where a higher scores represent greater dystonia severity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| TMS Measure Referred to as Cerebellar Inhibition (CBI) | absolute value at 12 weeks | A measure of the cerebellar-brain inhibition(CBI) will be conducted using a TMS device determining the ability of the coil to activate the cerebellum. CBI is calculated by taking the mean of amplitudes of motor-evoked potentials (mV) in response to conditioned stimulation and dividing it by the mean of amplitudes of motor-evoked potentials (mV) in response to unconditioned stimulation (i.e., the control condition). Thus it is a measure of the degree of inhibition due to a conditioning stimulus, where \<1 indicates inhibition, =1 indicates no inhibition, and \>1 indicates not inhibition but excitation. As a ratio of amplitudes, it does not have units. |
| Craniocervical Dystonia Questionnaire | absolute value at 12 Weeks | The Craniocervical Dystonia Questionnaire (CDQ-24) is a patient-rated health related quality of life (HR-QoL) measure for craniocervical dystonia. 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. 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. The total score reported here can range from 0-96, with a higher score indicating a greater impact of dystonia on quality of life. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Real rTMS Stimulation Repetitive TMS will be delivered over each cerebellar hemisphere, using a NeuroStar TMS therapy system. The coil will be positioned 3 cm lateral to the inion on the line joining the inion and the external auditory meatus. The coil position will be marked on the skin. 900 pulses will be delivered consecutively to each side with a frequency of 1 Hz and at an intensity of 90% of the resting motor threshold (RMT) for a total duration of 15 min for each cerebellar hemisphere.
NeuroStar TMS therapy: Application of repetitious transcranial magnetic stimulation (TMS) pulses using NeuroStar device to a specific brain target at predefined stimulation parameters.
Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS): All participants will receive a clinical assessment of dystonia severity by using the TWSTRS test.
Craniocervical Dystonia Questionnaire (CDQ-24): All participants will fill out the Craniocervical Dystonia Questionnaire (CDQ-24) quality of life questionnaire.
Cerebellar-brain Inhibition (CBI): All participants will have a measure of the cerebellar-brain inhibition(CBI) which will be conducted by using a TMS device determining the ability of the coil to activate the cerebellum.
Botulinum toxin injections: All participants will receive Botulinum toxin(BoNT) injections as part of their standard of care | 5 |
| Sham rTMS Stimulation Patients will undergo the same procedure for identifying stimulus location used in patients receiving real rTMS. Simulated rTMS will be administered using sham NeuroStar TMS therapy system coil which produces discharge noise and vibration without stimulating the cerebral cortex. This technique has been suggested to provide more effective blinding compared to other methods use in previous controlled studies. In addition, this group will have the following performed: Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) test, Cerebellar-brain Inhibition (CBI) measurement, and Craniocervical Dystonia Questionnaire (CDQ-24) questionnaire to fill out.
Sham NeuroStar TMS therapy: Same procedure as real rTMS without stimulating the cerebral cortex.
Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS): All participants will receive a clinical assessment of dystonia severity by using the TWSTRS test.
Craniocervical Dystonia Questionnaire (CDQ-24): All participants will fill out the Craniocervical Dystonia Questionnaire (CDQ-24) quality of life questionnaire.
Cerebellar-brain Inhibition (CBI): All participants will have a measure of the cerebellar-brain inhibition(CBI) which will be conducted by using a TMS device determining the ability of the coil to activate the cerebellum.
Botulinum toxin injections: All participants will receive Botulinum toxin(BoNT) injections as part of their standard of care | 4 |
| Total | 9 |
Baseline characteristics
| Characteristic | Sham rTMS Stimulation | Total | Real rTMS Stimulation |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 9 Participants | 5 Participants |
| Age, Continuous | 59 years STANDARD_DEVIATION 6 | 60 years STANDARD_DEVIATION 6 | 61 years STANDARD_DEVIATION 6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 9 Participants | 5 Participants |
| Region of Enrollment United States | 4 participants | 9 participants | 5 participants |
| Sex: Female, Male Female | 3 Participants | 7 Participants | 4 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 4 |
| other Total, other adverse events | 2 / 5 | 1 / 4 |
| serious Total, serious adverse events | 0 / 5 | 0 / 4 |
Outcome results
Primary
Dystonia Severity as Assessed by the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)
A clinical assessment of dystonia severity will be conducted at each study visit using the TWSTRS. The TWSTRS is a widely accepted composite rating scale for PCD with subscales for clinical severity, functional disability, and associated pain. The total score reported here can range 0-85, where a higher scores represent greater dystonia severity.
Time frame: absolute value at 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Real rTMS Stimulation | Dystonia Severity as Assessed by the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) | 13 scores on a scale | Standard Deviation 6 |
| Sham rTMS Stimulation | Dystonia Severity as Assessed by the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) | 17 scores on a scale | Standard Deviation 8 |
Secondary
Craniocervical Dystonia Questionnaire
The Craniocervical Dystonia Questionnaire (CDQ-24) is a patient-rated health related quality of life (HR-QoL) measure for craniocervical dystonia. 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. 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. The total score reported here can range from 0-96, with a higher score indicating a greater impact of dystonia on quality of life.
Time frame: absolute value at 12 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Real rTMS Stimulation | Craniocervical Dystonia Questionnaire | 16 score on a scale | Standard Deviation 4 |
| Sham rTMS Stimulation | Craniocervical Dystonia Questionnaire | 18 score on a scale | Standard Deviation 6 |
Secondary
TMS Measure Referred to as Cerebellar Inhibition (CBI)
A measure of the cerebellar-brain inhibition(CBI) will be conducted using a TMS device determining the ability of the coil to activate the cerebellum. CBI is calculated by taking the mean of amplitudes of motor-evoked potentials (mV) in response to conditioned stimulation and dividing it by the mean of amplitudes of motor-evoked potentials (mV) in response to unconditioned stimulation (i.e., the control condition). Thus it is a measure of the degree of inhibition due to a conditioning stimulus, where \<1 indicates inhibition, =1 indicates no inhibition, and \>1 indicates not inhibition but excitation. As a ratio of amplitudes, it does not have units.
Time frame: absolute value at 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Real rTMS Stimulation | TMS Measure Referred to as Cerebellar Inhibition (CBI) | 0.7 ratio | Standard Deviation 0.2 |
| Sham rTMS Stimulation | TMS Measure Referred to as Cerebellar Inhibition (CBI) | 0.9 ratio | Standard Deviation 0.3 |