Convection-Enhanced Delivery to Study the Pathophysiology Underlying the Clinical Features of Parkinson s Disease
| Status: | Not yet recruiting |
|---|---|
| Conditions: | Parkinsons Disease |
| Therapuetic Areas: | Neurology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/21/2016 |
| Start Date: | June 2009 |
| Contact: | Gretchen C Scott, R.N. |
| Email: | SNBrecruiting@nih.gov |
| Phone: | Not Listed |
Convection Enhanced Delivery of Muscimol to Study the Pathophysiology Underlying the Clinical Features of Parkinson's Disease
Background:
- Parkinson s disease (PD) is a progressive neurodegenerative disorder that affects the
brain cells that make the chemical dopamine. The primary medical treatment for PD has
been to use medications to replace the dopamine that is missing from the brain. These
medications can be effective at first, but after many years side effects and tolerance
develop.
- Surgery can treat basic PD symptoms and complications. Deep brain stimulation (DBS)
offers a safer alternative as the therapy can be adjusted and reversed to minimize side
effects and optimize beneficial effects. DBS treats the symptoms of PD but does not
alter its course.
- Infusions of neurochemicals or medications are another PD treatment method. NIH
researchers have developed the technique of convection-enhanced delivery, which very
precisely and consistently delivers infusions of many types into the brain. This
project will allow researchers to infuse a medication, Muscimol, into the subthalamic
region of the brain to see if it is as safe and effective as DBS.
Objectives:
- To determine whether an infusion of Muscimol into the brain is safe and relieves the
symptoms of Parkinson s disease.
- To demonstrate that the infusion can be monitored with magnetic resonance imaging (MRI)
using gadolinium.
Eligibility:
- Patients 18 years of age and older who have Parkinson s disease and are preparing for
bilateral subthalamic nucleus (STN) DBS surgery.
- Patients will be divided into two groups. One group of patients will have a partial
infusion of Muscimol into the STN, and the second group of patients will have complete
infusion of Muscimol into the STN.
Design:
- This study will begin 5 days before the patient undergoes bilateral subthalamic DBS
surgery.
- On Day 1 of the study, small thin tubes (microcatheters) will be inserted into the STN
through the same incision and burr holes that are used for DBS. Two infusion studies of
Muscimol will be performed on successive days: the first without PD medication (Day 3
of study) and the second with PD medication (Day 4 of study).
- Each infusion will be monitored in the MRI suite, and researchers will perform clinical
examinations of patients PD symptoms.
- Following the study experiments, a second surgery will be performed to remove the
microcatheters and to place DBS electrodes in the standard fashion.
- Parkinson s disease (PD) is a progressive neurodegenerative disorder that affects the
brain cells that make the chemical dopamine. The primary medical treatment for PD has
been to use medications to replace the dopamine that is missing from the brain. These
medications can be effective at first, but after many years side effects and tolerance
develop.
- Surgery can treat basic PD symptoms and complications. Deep brain stimulation (DBS)
offers a safer alternative as the therapy can be adjusted and reversed to minimize side
effects and optimize beneficial effects. DBS treats the symptoms of PD but does not
alter its course.
- Infusions of neurochemicals or medications are another PD treatment method. NIH
researchers have developed the technique of convection-enhanced delivery, which very
precisely and consistently delivers infusions of many types into the brain. This
project will allow researchers to infuse a medication, Muscimol, into the subthalamic
region of the brain to see if it is as safe and effective as DBS.
Objectives:
- To determine whether an infusion of Muscimol into the brain is safe and relieves the
symptoms of Parkinson s disease.
- To demonstrate that the infusion can be monitored with magnetic resonance imaging (MRI)
using gadolinium.
Eligibility:
- Patients 18 years of age and older who have Parkinson s disease and are preparing for
bilateral subthalamic nucleus (STN) DBS surgery.
- Patients will be divided into two groups. One group of patients will have a partial
infusion of Muscimol into the STN, and the second group of patients will have complete
infusion of Muscimol into the STN.
Design:
- This study will begin 5 days before the patient undergoes bilateral subthalamic DBS
surgery.
- On Day 1 of the study, small thin tubes (microcatheters) will be inserted into the STN
through the same incision and burr holes that are used for DBS. Two infusion studies of
Muscimol will be performed on successive days: the first without PD medication (Day 3
of study) and the second with PD medication (Day 4 of study).
- Each infusion will be monitored in the MRI suite, and researchers will perform clinical
examinations of patients PD symptoms.
- Following the study experiments, a second surgery will be performed to remove the
microcatheters and to place DBS electrodes in the standard fashion.
Objective: The objectives of this pilot study are to gain insight into the safety,
feasibility and clinical effects of infusion of a temporary acting GABAA agonist (muscimol)
by convection-enhanced delivery into the subthalamic nuclei (STN) of Parkinson s disease
(PD) patients undergoing deep brain stimulation (DBS) surgery.
Study population: Eight adult male and female patients with medically-intractable PD who are
preparing to undergo DBS surgery and who meet all Inclusion and Exclusion Criteria will be
enrolled. Six subjects will be treated (2 may be screening failures).
Design: We propose a single center pilot study of infusion of muscimol into the bilateral
STN of PD patients that will undergo DBS. Subjects will be enrolled into 1 of 2 cohorts.
Both cohorts will contain 3 patients each (total of 6 patients). Patients in both cohorts
will undergo pre-, intra- and post-operative PD assessments. The first cohort will undergo
bilateral perfusion of half of the volume (infusion of 8 microliters)of the STN with
muscimol (8.8 mM) and gadolinium-DTPA ([1 mM] in off and on medication states on sequential
days). The second cohort will undergo bilateral perfusion of the entire of the volume
(infusion of 16 microliters) of the STN with muscimol (8.8 mM) and gadolinium-DTPA ([1 mM]
in off and on medication states on sequential days). Distribution of muscimol using a
surrogate imaging tracer (gadolinium-DPTA) will be tracked using real-time MR-imaging and
correlated to clinical effect. After the infusions are completed, the catheters will be
removed and patients will undergo placement of bilateral STN DBS. Patients will be evaluated
using standard PD rating scales to determine the effects to STN neuronal suppression and to
compare the effects of muscimol pharmacologic neuronal suppression to DBS effects.
Outcome measures: To determine the distribution of muscimol in the STN and to provide an
anatomic correlate for clinical effects of neuronal suppression, real-time 3D-volumetric
MR-imaging will be used during infusions. To assess safety, tolerability and clinical
effects of muscimol infusion, standard PD rating scales (motor subsection of the Unified PD
Rating Scale, timed-up-and-go gait assessment and peg board bradykinesia testing) will be
performed following infusion and correlated to real-time infusion MR-imaging studies. To
compare the effects of muscimol infusion to STN DBS, the assessments obtained during
infusion will be compared to the similar assessment 6 months after DBS placement.
feasibility and clinical effects of infusion of a temporary acting GABAA agonist (muscimol)
by convection-enhanced delivery into the subthalamic nuclei (STN) of Parkinson s disease
(PD) patients undergoing deep brain stimulation (DBS) surgery.
Study population: Eight adult male and female patients with medically-intractable PD who are
preparing to undergo DBS surgery and who meet all Inclusion and Exclusion Criteria will be
enrolled. Six subjects will be treated (2 may be screening failures).
Design: We propose a single center pilot study of infusion of muscimol into the bilateral
STN of PD patients that will undergo DBS. Subjects will be enrolled into 1 of 2 cohorts.
Both cohorts will contain 3 patients each (total of 6 patients). Patients in both cohorts
will undergo pre-, intra- and post-operative PD assessments. The first cohort will undergo
bilateral perfusion of half of the volume (infusion of 8 microliters)of the STN with
muscimol (8.8 mM) and gadolinium-DTPA ([1 mM] in off and on medication states on sequential
days). The second cohort will undergo bilateral perfusion of the entire of the volume
(infusion of 16 microliters) of the STN with muscimol (8.8 mM) and gadolinium-DTPA ([1 mM]
in off and on medication states on sequential days). Distribution of muscimol using a
surrogate imaging tracer (gadolinium-DPTA) will be tracked using real-time MR-imaging and
correlated to clinical effect. After the infusions are completed, the catheters will be
removed and patients will undergo placement of bilateral STN DBS. Patients will be evaluated
using standard PD rating scales to determine the effects to STN neuronal suppression and to
compare the effects of muscimol pharmacologic neuronal suppression to DBS effects.
Outcome measures: To determine the distribution of muscimol in the STN and to provide an
anatomic correlate for clinical effects of neuronal suppression, real-time 3D-volumetric
MR-imaging will be used during infusions. To assess safety, tolerability and clinical
effects of muscimol infusion, standard PD rating scales (motor subsection of the Unified PD
Rating Scale, timed-up-and-go gait assessment and peg board bradykinesia testing) will be
performed following infusion and correlated to real-time infusion MR-imaging studies. To
compare the effects of muscimol infusion to STN DBS, the assessments obtained during
infusion will be compared to the similar assessment 6 months after DBS placement.
- INCLUSION CRITERIA:
Diagnosed with idiopathic PD by UK criteria:
Bradykinesia: At least one of the following:
1. Muscular rigidity
2. 4-6 Hz resting tremor
3. Postural instability not caused by primary visual, vestibular, cerebellar or
proprioceptive dysfunction
Three or more required in addition to above for the diagnosis of idiopathic PD:
1. Unilateral onset
2. Rest tremor present
3. Progressive disorder
4. Persistent asymmetry affecting side of onset most
5. Excellent response (70-100%) to levodopa
6. Severe levodopa-induced chorea
7. Levodopa response for 5 years or more
8. Clinical course of ten years or more
The above clinical features must not be due to trauma, brain tumor, infection,
cerebrovascular disease, other known neurological disease (e.g., multiple system
atrophy, progressive supranuclear palsy, striatonigral degeneration, Huntington s
disease, Wilson s disease, hydrocephalus) or due to known drugs, chemicals or
toxicants.
Disability present despite optimal antiparkinsonian medication therapy.
Unequivocal responsiveness to levodopa, based on the single-dose levodopa test (as
described in the CAPIT and CAPSIT guidelines). In addition to a 33% or greater
improvement in one of the timed tasks, a 30% or greater improvement in the UPDRS
total motor score will be required to establish unequivocal responsiveness to
levodopa.
Patients must demonstrate at least 6 hours of non-on time and medication side-effects
such as levodopa-induced dyskinesias or motor fluctuations.
Neuropsychological evaluation does not indicate substantial depression or cognitive
dysfunction.
Able to provide proper Informed Consent.
EXCLUSION CRITERIA:
Presence of prominent oculomotor palsy, cerebellar signs, vocal cord paresis,
orthostatic hypotension (> 20 mm Hg drop on standing), pyramidal tract signs or
amyotrophy.
Presence of dementia (Clinical Dementia Rating Scale score > 1.0 or Mini Mental
Status Examination Score < 25).
Presence or history of psychosis, including if induced by anti-PD medications.
Presence of untreated or suboptimally treated depression (Hamilton Depression Scale
score > 10) or a history of a serious mood disorder (for example, requiring
psychiatric hospitalization or a prior suicide attempt).
Presence of substance (drug, alcohol) abuse.
Presence of hypointensity in the striatum on T2-weighted MR-imaging.
Contraindication to MR-imaging and/or gadolinium.
Coagulopathy, anticoagulant therapy, low platelet count, or inability to temporarily
stop any antithrombotic medication.
Prior brain surgery, including gene therapy, radiofrequency ablation or deep brain
stimulation.
Male or female with reproductive capacity who is unwilling to use contraception
throughout the study.
History of stroke or poorly controlled cardiovascular disease.
Uncontrolled hypertension or diabetes or any other acute or chronic medical condition
that would increase the risks of a neurosurgical procedure.
Clinically active infection, including acute or chronic scalp infection.
Received investigational agent within 12 weeks prior to screening.
Unable to comply with the procedures of the protocol, including frequent and
prolonged follow-up.
Baseline hematology, chemistry or coagulation values out of normal range unless not
clinically significant with respect to surgery.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: 800-411-1222
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