Thalamic Deep Brain Stimulation for Secondary Dystonia in Children and Young Adults
| Status: | Recruiting |
|---|---|
| Conditions: | Neurology, Orthopedic |
| Therapuetic Areas: | Neurology, Orthopedics / Podiatry |
| Healthy: | No |
| Age Range: | 7 - 25 |
| Updated: | 5/3/2017 |
| Start Date: | March 3, 2017 |
| End Date: | May 2019 |
| Contact: | Amy R Viehoever, MD, PhD |
| Email: | amy.viehoever@ucsf.edu |
| Phone: | 415-353-2311 |
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.
"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.
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.
"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.
Inclusion Criteria:
1. Ability to give informed consent or assent for the study
2. 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
3. Age 7-25
4. Stable doses of anti-dystonia medications (such as levodopa, baclofen, or diazepam)
for at least 30 days prior to baseline assessment
5. If patient receives botulinum toxin injections, patient should be on a stable
injection regimen
6. Intact thalamic anatomy as determined by standard clinical MRI
Exclusion Criteria:
1. Pregnancy or breast feeding
2. Major comorbidity increasing the risk of surgery (severe hypertension, severe
diabetes, or need for chronic anticoagulation other than aspirin)
3. Inability to comply with study follow-up visits
4. Any prior intracranial surgery
5. Uncontrolled epilepsy
6. Immunocompromised
7. Has an active infection
8. Requires diathermy, electroconvulsive therapy (ECT) or transcranial magnetic
stimulation (TMS) to treat a chronic condition
9. Has an existing implanted neurostimulator or cardiac pacemaker.
10. Dystonia caused by known genetic mutation in any DYT genes
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