Thalamic Deep Brain Stimulation for Secondary Dystonia in Children and Young Adults

Study Overview
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Brief Summary
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Dystonia is a movement disorder seen in both children and adults that is characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Secondary dystonia is far more common in pediatric populations than primary dystonia, and far more recalcitrant to standard pharmacologic and surgical treatments including Deep Brain Stimulation (DBS). There exists a large unmet need to develop new therapeutics, treatment strategies, and outcome measures for pediatric secondary dystonia. The investigators are proposing to investigate the ventralis oralis posterior nucleus (Vop) of the thalamus as a new target for DBS in secondary dystonia. Prior to the development of DBS, the main surgical treatment of dystonia was thalamotomy. Although there were many different targets in the thalamus, often done in staged procedures, the most common and successful targeted nuclei was the Vop, which is traditionally thought to be the pallidal receiving area. Previous lesioning of Vop produced improvements in dystonia but intolerable side effects, especially when implanted bilaterally. However, given that secondary dystonia patients were often reported to have superior results to primary dystonia it is reasonable to believe that if the side effects can be modulated, that targeting of the Vop nucleus with DBS could be a viable alternative to Globus Pallidus interna (GPi). Given that Deep Brain Stimulation is a treatment that is inherently adjustable, it is conceivable that settings on the Deep Brain Stimulation could be adjusted to allow for clinical benefit with minimal side effects. Indeed, there have been several scattered successful case reports attesting to this possibility.

Detailed Description
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Dystonia is a movement disorder seen in both children and adults that is characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Secondary dystonia has evolved to refer to dystonia resulting from damage to the nervous system or degenerative disease processes. While primary dystonia is generally thought to arise from genetic causes, secondary dystonias have a variety of causes including perinatal injuries (cerebral palsy), central nervous system infections, traumatic brain injuries, and many different metabolic, neurodegenerative, and mitochondrial conditions. Secondary dystonia is far more common in pediatric populations than primary dystonia, and far more recalcitrant to standard pharmacologic and surgical treatments including Deep Brain Stimulation. Given that most treatments for dystonia are developed for primary dystonia and then applied to secondary dystonia, it is not surprising that this effectiveness gap exists. Thus, there exists a large unmet need to develop new therapeutics, treatment strategies, and outcome measures for pediatric secondary dystonia. Deep Brain Stimulation (DBS) is one such therapeutic intervention that has potential to improve secondary dystonia. DBS is a surgical treatment for several different movement disorders that evolved from functional stereotactic neurosurgery techniques initially used to lesion specific deep brain structures. While Essential Tremor and Idiopathic Parkinson's Disease have predictable and consistent response rates to DBS in carefully selected patients, response rates of dystonia have been much more inconsistent. One predictor of success has been the presence of DYT-1 mutation, the most common known genetic cause of primary dystonia. Success rates in DYT-1 dystonia are consistently high with reductions in dystonia typically greater than 80%. However, the results in secondary dystonia have been much more modest and inconsistent. A recent meta-analysis found that on average, dystonia symptoms as measured by common rating scales improve 23% following DBS for dystonic cerebral palsy (the most common cause of secondary dystonia), however there are frequent cases of non-responders. Additionally, there have been very few examination, radiological or laboratory predictors of good response to DBS, except for genetic confirmation of DYT-119. However, across both primary and secondary dystonia, younger age at the time of surgery (less than 21 years old) and shorter duration of symptoms (less than 15 years) have been shown to be the most likely predictive factors for a good postoperative outcome. This has led many to suggest that DBS should be offered earlier in the course of intractable dystonia, prior to the development of permanent complications such as orthopedic contractures. Thus, we are setting an upper age limit of 25 to account for the concern that earlier implantation leads to improved outcomes. The lower age limit of 7 reflects the fact that the current humanitarian exemption for DBS for dystonia currently goes down to age 7. Thus, there exists a need to both improve patient selection as well as application of DBS for secondary dystonia in children.

Official Title
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Thalamic Deep Brain Stimulation for Secondary Dystonia in Children and Young Adults

Conditions
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Dystonia

Intervention / Treatment
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* Device: Activa PC Primary Cell Neurostimulator - (Model 37601)
* Device: Activa RC Rechargeable Neurostimulator - (Model 37612)
* Device: Activa SC Single Cell Neurostimulator (Models 37602/37603)
* Device: DBS Lead - (Model 3387
* Device: DBS Extension - (Models 37085/6)
* Device: Patient Programmer - (Model 37642)
* Device: Test Stimulator - (Model 3625)
* Device: N'Vision Clinician Programmer - (Model 8840)
* Device: N'Vision Software Application Card - (Model 8870)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to give informed consent or assent for the study Dystonia symptoms that are sufficiently severe, in spite of best medical therapy, to warrant surgical implantation of deep brain stimulators according to standard clinical criteria Age 7-25 Stable doses of anti-dystonia medications (such as levodopa, baclofen, or diazepam) for at least 30 days prior to baseline assessment If patient receives botulinum toxin injections, patient should be on a stable injection regimen Intact thalamic anatomy as determined by standard clinical MRI Exclusion Criteria: Pregnancy or breast feeding Major comorbidity increasing the risk of surgery (severe hypertension, severe diabetes, or need for chronic anticoagulation other than aspirin) Inability to comply with study follow-up visits Any prior intracranial surgery Uncontrolled epilepsy Immunocompromised Has an active infection Requires diathermy, electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS) to treat a chronic condition Has an existing implanted neurostimulator or cardiac pacemaker. Dystonia caused by known genetic mutation in any DYT genes

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DBS active<br>All participants will be enrolled in DBS placement and active stimulation. The following components will be used: Activa PC Primary Cell Neurostimulator - (Model 37601) Activa RC Rechargeable Neurostimulator - (Model 37612) Activa SC Single Cell Neurostimulator (Models 37602 and 37603) DBS Lead - (Model 3387) DBS Extension - (Models 37085/6) Patient Programmer - (Model 37642) Test Stimulator - (Model 3625) N'Vision Clinician Programmer - (Model 8840) N'Vision Software Application Card - (Model 8870) | Device: Activa PC Primary Cell Neurostimulator - (Model 37601)<br>* Deep Brain Stimulator system will be implanted using standard neurosurgical techniques. The device will deliver constant stimulation to the thalamus using settings programmed by study team.<br>Device: Activa RC Rechargeable Neurostimulator - (Model 37612)<br>* Deep Brain Stimulator system will be implanted using standard neurosurgical techniques. The device will deliver constant stimulation to the thalamus using settings programmed by study team.<br>Device: Activa SC Single Cell Neurostimulator (Models 37602/37603)<br>* Deep Brain Stimulator system will be implanted using standard neurosurgical techniques. The device will deliver constant stimulation to the thalamus using settings programmed by study team.<br>Device: DBS Lead - (Model 3387<br>* Deep Brain Stimulator system will be implanted using standard neurosurgical techniques. The device will deliver constant stimulation to the thalamus using settings programmed by study team.<br>Device: DBS Extension - (Models 37085/6)<br>* Deep Brain Stimulator system will be implanted using standard neurosurgical techniques. The device will deliver constant stimulation to the thalamus using settings programmed by study team.<br>Device: Patient Programmer - (Model 37642)<br>* Deep Brain Stimulator system will be implanted using standard neurosurgical techniques. The device will deliver constant stimulation to the thalamus using settings programmed by study team.<br>Device: Test Stimulator - (Model 3625)<br>* Deep Brain Stimulator system will be implanted using standard neurosurgical techniques. The device will deliver constant stimulation to the thalamus using settings programmed by study team.<br>Device: N'Vision Clinician Programmer - (Model 8840)<br>* Deep Brain Stimulator system will be implanted using standard neurosurgical techniques. The device will deliver constant stimulation to the thalamus using settings programmed by study team.<br>Device: N'Vision Software Application Card - (Model 8870)<br>* Deep Brain Stimulator system will be implanted using standard neurosurgical techniques. The device will deliver constant stimulation to the thalamus using settings programmed by study team.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Burke-Fahn-Marsden Dystonia Rating Scale | Rating scale that measures movement and disability related to dystonia, range 0-120 motor, 0-30 disability , higher number indicates more severe dystonia Change from Baseline in Burke-Fahn-Marsden Dystonia Rating Scale | Change from baseline to 12 months postoperatively | 
| Percent Change in Pediatric Quality of Life Inventory (PedsQL) | Quality of life measure, scored 0-100, larger scores indicate greater hinderance (ie. lower quality of life) | baseline to 12 months postoperatively | 
| Change in Barry Albright Dystonia Rating Scale | Severity scale for secondary dystonia, range 0-32, higher scores indicates more severe dystonia | Change from baseline to 12 months postoperatively | 
| Change in Blinded Burke-Fahn-Marsden Dystonia Rating Scale | Rating scale that measures movement and disability related to dystonia, range 0-120 motor, 0-30 disability , higher number indicates more severe dystonia. These ratings were carried out retroactively by a neurologist who was unfamiliar with the four study participants and who had no knowledge of their unblinded scores. | change from baseline to 12 months postoperatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Modified Ashworth Scale - Upper Limbs | Measure of spasticity, range 0-32, higher values indicate more spasticity | Change from baseline to 12 months postoperatively | 
| Change in Diadochokinetic Syllable Rates | Articulation, range (min 6- no upper limit), longer times indicate less articulation/more difficulty with speech | Change from baseline to 12 months postoperatively | 
| Children's Memory Scale | Will include the following subtests: Memory for Faces, Dot Locations, and Digit Span | Change from baseline to 12 months postoperatively | 
| Change in Behavioral Assessment System, 3rd Edition: Self Report of Personality | Mood and behavior assessment, main use as a screening tool for depression. | Change from baseline to 12 months postoperatively | 
| Change in Modified Ashworth Scale Spasticity Ratings - Lower Limbs | This scale is used to measure spasticity, which is a velocity-dependent increase in muscle stretch reflexes associated with increased muscle tone as a component of upper motor neuron syndrome. It is scored 0-4 with higher scores indicating greater severity. | Change from baseline to 12 months postoperatively | 
| Change in Kaufman Brief Intelligence Test - Second Addition | Kaufman Brief Intelligence Test Second Edition (KBIT-2) is a brief measure of verbal and nonverbal intelligence used with individuals ages 4 through 90 years, raw scores 0 - unlimited, with higher scores indicating higher ability. | baseline to 12 months postoperatively | 
| Change in Burke-Fahn-Marsden Dystonia Disability Subscale | This scale is a measurement of quality of life related to dystonia, with lower scores indicating greater quality of life and high scores indicating more hinderance. It is scored 0-100. | baseline to 12 months postoperatively | 
| Change in Modified Unified Parkinson's Disease Rating Scale - Second Edition | This scale is a measurement of quality of life related to dystonia, with lower scores indicating greater quality of life and high scores indicating more hinderance. It is scored 0-199 | baseline to 12 months posoperatively |