Multiple Sclerosis
Conditions
Brief summary
The purpose of this research study is to: 1. Determine whether deep brain stimulation (DBS) with two leads (very thin coiled wires) placed unilaterally (on one side of the brain) is beneficial to patients with multiple sclerosis (MS) tremor. 2. Compare the two different locations of the DBS lead placement in effectiveness for treatment of muscle tremors that do not respond to treatment with medication caused by multiple sclerosis. 3. Evaluate any side effects that may result from the two DBS leads.
Detailed description
Surgical treatment of disabling multiple sclerosis (MS) tremor that does not respond to medication has proven difficult. To date, there have been no prospective blinded studies to evaluate efficacy of surgical treatments for these tremors. Based on prior data, this study will examine the use of 2 DBS electrodes on the same side of the brain in the thalamus region (one at an area referred to as the ventralis intermedius nucleus/ventralis oralis posterior nucleus border, or VIM, and one at a region called the ventralis oralis anterior nucleus/ventralis oralis posterior nucleus border, or VO) for treatment of MS tremor. This study will test the effectiveness of VIM combined with, and independent of, VO DBS, and characterize safety, benefits and side effects of this procedure for treatment of MS-related tremors.
Interventions
DEVICEDeep Brain Stimulation
Use of two ipsilateral thalamic Deep Brain Stimulation electrodes (one at the ventralis intermedius nucleus/ventralis oralis posterior nucleus border or VIM and one at the ventralis oralis anterior nucleus/ventralis oralis posterior nucleus border or VO) for treatment of disabling and medication refractory tremor secondary to head trauma or multiple sclerosis.
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Medtronic
University of Florida
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
* The patient must have an unequivocal diagnosis of Multiple Sclerosis (MS) resulting in disabling tremor as indicated by a score of at least 3 on the Tremor Rating Scale (TRS) baseline global assessments by the examiner and the patient. * The patient must have a history of an unsatisfactory response to medical management. Any patient will need to have tried and failed at least one drug from at least three of the four following medication classes: anticholinergics, muscle relaxants, benzodiazepines, and beta blockers. Alternatively, a patient may also qualify if tremor-suppressing medications are contraindicated due to a coexisting medical condition or drug allergy. * The MS patient must have disabling and medically refractory unilateral or bilateral upper extremity tremor. Patients with associated ipsilateral lower extremity tremor are not excluded. * The tremor must meet the following specific diagnostic criteria: * The tremor must be predominantly postural or action (versus resting) and have a rhythmic and/or ballistic characteristic. * The tremor may not have features that indicate a significant cerebellar etiology (i.e., non-prominent ataxia, dysdiadokokinesia, dysmetria). * The tremor must have been present and either stable or progressing for greater than one year. * The tremor must be disabling. Disabling is defined as significant impairment of the normal functions of daily life as indicated by a score of at least 5 on the Clinical Global Impression (CGI)-Severity scale.
Exclusion criteria
* Significant medical disease that would excessively increase risk of peri-operative complications (significant cardiac or pulmonary disease, uncontrolled hypertension, inadequately treated major depression). * More than mild non-tremor cerebellar dysfunction (ataxia, dysmetria, dysdiadokokinesia). * Evidence of secondary/atypical movement disorder as suggested by presence of the following: * history of stroke(s) * exposure to toxins or neuroleptics * history of encephalitis * neurological signs of upper motor neuron disease, supranuclear gaze palsy, or significant orthostatic hypotension * MRI with significant evidence of severe brain atrophy or other prohibitive abnormalities (absence of thalamic target for Deep Brain Stimulation (DBS), lacunar infarcts, or iron deposits in the putamen). * Cognitive dysfunction as evidenced by a score of less than 120 on the Mattis Dementia Rating Scale (MDRS) Such patients will be excluded because significant dementia places the patient at high risk for surgery-induced deterioration of cognitive function, and such patients might have limited ability to accurately assess the impact of DBS. * Major psychiatric disorder on the Structured Clinical Interview (SCID-IV) for the Diagnostic and Statistical Manual Version 4 (DSM-IV). 45 Patients with Major Depression within 3 months of entry into the study will be excluded. High rates of psychiatric co-morbidity can complicate any neurosurgical study. While the cleanest study would exclude patients with psycho-pathology, we do not believe this is realistic or practical, given the majority of patients with advanced movement disorders will suffer from some degree of anxiety or depression. We will screen patients for psychiatric disorders, treat disorders prior to DBS and admit patients who are psychiatrically stable for at least 3 months prior to entry (without active psychiatric diagnosis by SCID criteria). * Patients with any implanted device that precludes magnetic resonance imaging (MRI) will be excluded from this study. Examples of such devices include cochlear implants, spinal cord stimulators, many cardiac pacemakers, and some older aneurysm clips * Patients who have a known need for future MRIs or diathermy treatments will be excluded from this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fain-Tolosa-Marin Tremor Rating Scale (TRS) Change Score for Both VIM and VO ON (Baseline Minus 6 Months Post-implant) | Change from Baseline to Six Months | Tremor was evaluated using the Fain-Tolosa-Marin Tremor Rating Scale (TRS). Score was obtained by summing all 21 items, each of which assessed tremor on a scale of 0-4. Because some of the 21 items contained more than one subsection, total maximum score was 144, and minimum score was 0. Higher scores represent worse tremor. Both VIM and VO stimulators will be turned ON and TRS score at 6 months will be compared to pre-implant (baseline). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fain-Tolosa-Marin Tremor Rating Scale (TRS) Change Score for Either VIM or VO On, and for Both VIM and VO Off (Baseline Minus 6 Months Post-implant) | Baseline to Six Months | Tremor was evaluated using the Fain-Tolosa-Marin Tremor Rating Scale (TRS). Score was obtained by summing all 21 items, each of which assessed tremor on a scale of 0-4. Because some of the 21 items contained more than one subsection, total maximum score was 144, and minimum score was 0. Higher scores represent worse tremor. Both VIM and VO stimulators will be turned ON and TRS score at 6 months will be compared to pre-implant (baseline). Either VO or VIM stimulator will be turned on (as opposed to both stimulators, as in outcome measure 1), and change in Tremor Rating Scale scores will be compared. The effects of each individual stimulator will also be compared to both being turned on. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Subjects All eligible subjects were enrolled and the intent was to treat for six months on dual lead deep brain stimulation in the VIM and VO regions. | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 6 Months of DBS | Withdrawal by Subject | 1 |
| Screening | screen failures | 3 |
| VIM=ON VO=OFF at 6 Months | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | All Subjects |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age, Continuous | 41.54 years STANDARD_DEVIATION 15.03 |
| Baseline Total Fain-Tolosa-Marin Tremor Rating Scale (TRS) | 56.2 units on a scale STANDARD_DEVIATION 9.4 |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 6 / 13 |
Outcome results
Primary
Fain-Tolosa-Marin Tremor Rating Scale (TRS) Change Score for Both VIM and VO ON (Baseline Minus 6 Months Post-implant)
Tremor was evaluated using the Fain-Tolosa-Marin Tremor Rating Scale (TRS). Score was obtained by summing all 21 items, each of which assessed tremor on a scale of 0-4. Because some of the 21 items contained more than one subsection, total maximum score was 144, and minimum score was 0. Higher scores represent worse tremor. Both VIM and VO stimulators will be turned ON and TRS score at 6 months will be compared to pre-implant (baseline).
Time frame: Change from Baseline to Six Months
Population: All Subjects completing Period 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Multiple Sclerosis Tremor On VIM and VO | Fain-Tolosa-Marin Tremor Rating Scale (TRS) Change Score for Both VIM and VO ON (Baseline Minus 6 Months Post-implant) | -17.6 units on a scale | Standard Deviation 19.4 |
Comparison: The null hypothesis is that the mean change in Tremor Rating Scale score from baseline to six months post-implant (with VIM and VO stimulators turned ON) will be zerop-value: 0.02695% CI: [-30.61, -4.65]two-sided sign-rank test
Secondary
Fain-Tolosa-Marin Tremor Rating Scale (TRS) Change Score for Either VIM or VO On, and for Both VIM and VO Off (Baseline Minus 6 Months Post-implant)
Tremor was evaluated using the Fain-Tolosa-Marin Tremor Rating Scale (TRS). Score was obtained by summing all 21 items, each of which assessed tremor on a scale of 0-4. Because some of the 21 items contained more than one subsection, total maximum score was 144, and minimum score was 0. Higher scores represent worse tremor. Both VIM and VO stimulators will be turned ON and TRS score at 6 months will be compared to pre-implant (baseline). Either VO or VIM stimulator will be turned on (as opposed to both stimulators, as in outcome measure 1), and change in Tremor Rating Scale scores will be compared. The effects of each individual stimulator will also be compared to both being turned on.
Time frame: Baseline to Six Months
Population: Patients completing 6 months were tested for VIM and VO both on vs. both off. Score is TRS scale with both off minus both on. Positive value favors DBS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Multiple Sclerosis Tremor On VIM and VO | Fain-Tolosa-Marin Tremor Rating Scale (TRS) Change Score for Either VIM or VO On, and for Both VIM and VO Off (Baseline Minus 6 Months Post-implant) | 8.4 units on a scale | Standard Deviation 9.1 |
| TRS Scale Vo Only on vs. Vim Only on at 6 Months | Fain-Tolosa-Marin Tremor Rating Scale (TRS) Change Score for Either VIM or VO On, and for Both VIM and VO Off (Baseline Minus 6 Months Post-implant) | 0.73 units on a scale | Standard Deviation 8.49 |
Comparison: The null hypothesis is that difference in change in Tremor Rating Scale (TRS) score from baseline to 6 months when both stimulators are on (VIM and VO), versus when both stimulators are off, will be zero (i.e., that there will be no difference in effect between having both stimulators on versus both stimulators off)p-value: 0.01195% CI: [2.2, 14.5]Sign-Rank test
Comparison: The null hypothesis is that difference in change in Tremor Rating Scale (TRS) score from baseline to 6 months when VO is on and VIM is off, versus when VIM is on and VO is off, will be zero (i.e., that there will be no difference in effect between having exclusively VIM versus VO on)p-value: 0.6895% CI: [-4.96, 6.42]two-sided sign rank test