Parkinson’s Disease

Clinical KeyParkinson's disease, which results from the death of nerve cells in the brain, is a chronic, degenerative neurological disorder. Since the risk of developing the disease increases with age, research indicates that one in 100 people over the age of 60 suffer from this debilitating disease. It affects more than 5 million people worldwide.

Motor impairments—the disease's cardinal symptoms—include resting tremor, uncontrolled movement (dyskinesia), slowness of movement (bradykinesia), rigidity (muscle stiffness), and postural instability. Non-motor symptoms include sleep difficulties, loss of sense of smell, constipation, speech and swallowing problems, and low blood pressure when standing. There may also be mood disorders and cognitive impairment ranging from mild memory difficulties to dementia.

The area of the brain that is most affected by Parkinson’s disease is the substantia nigra in the brainstem. Nerve cells lost there are the ones that produce dopamine, a chemical involved in communication to the part of the brain that controls movement and coordination. As the disease progresses, the amount of dopamine produced in the brain decreases, leaving the patient unable to control movement normally, resulting in tremor, stiffness of the limbs, slowed movements and imbalance.

Current Treatment

Currently there is no cure for Parkinson’s disease—the therapies listed here provide only symptomatic improvement.

Drug Therapy
Drug therapy involves stimulating communication to the motor part of the brain. Different classes of drugs can provide more dopamine to the brain (levodopa therapy), reduce dopamine breakdown (MAO-inhibitors or COMT-inhibitors), or mimic the effects of dopamine (dopamine agonists). As the disease progresses, there is a need to use the most potent medication, levodopa therapy. However, within a few years of initiating levodopa therapy, most patients develop motor fluctuations (on-off periods) and dyskinesias in addition to treatment refractory Parkinson's disease symptoms, like freezing and dementia. Dyskinesias are involuntary movements that represent the most challenging of the drug therapy complications faced by Parkinson’s disease patients. 

Deep Brain Stimulation
Implantation of a DBS device involves creating an opening in the patient’s skull and inserting electrodes into a specific area in the brain. The surgeon implants the stimulator under the skin and connects it to the electrodes in the brain. Small electrical pulses emitted from the DBS device block some of the Parkinson's symptoms and reduce the adverse effects associated with prolonged use of drugs. DBS is the most common surgical intervention used to treat Parkinson’s disease.

Lesioning
Lesioning is a procedure whereby a small volume of tissue is destroyed. In a lesioning procedure done for treatment of Parkinson’s disease, the targeted cells are interfering with motor function, and destroying these cells can improve the patient’s residual motor capacity. The following procedures can be done by radiosurgery or radiofrequency ablation:

Radiosurgery

  • Using stereotactic radiosurgery, a very high dose of ionizing radiation is delivered to a predefined small volume in the brain thereby destroying the vast majority of living cells in this location.

Radiofrequency ablation 

  • In a radiofrequency ablation procedure, a small volume in the brain is heated via a needle inserted through a small opening in the skull. This temperature rise cooks and kills the living cells by heat denaturation of the cell proteins.

 

Focused Ultrasound Treatment

Focused ultrasound is a completely non-invasive way to perform the lesioning procedure described above without exposing the patient to potentially harmful ionizing radiation. Using this treatment modality in conjunction with image guidance, the physician directs a focused beam of acoustic energy through the patient’s scalp, skull, and brain to thermally coagulate a small area of the brain, thereby destroying targeted tissue without damaging nearby tissue or the tissues through which the beam passes on its way to the target.

Using magnetic resonance imaging (MRI) thermometry during the focused ultrasound procedure, the physician is able to control the location and extent of the thermal tissue destruction in real time.

Focused ultrasound is being studied to treat symptoms of Parkinson’s through lesioning of one of the target areas of the brain:

  • Parkinsonian tremor – lesioning target in the thalamus (thalamotomy)
  • Parkinsonian dyskinesia – lesioning target in the globus pallidus (pallidotomy) or subthalamic nucleus
  • Parkinsonian tremor or akinesia – lesioning target in the pallidothalamic tract 

fishman webinar graphicAt this time, focused ultrasound is only being assessed to treat one side of the brain, so it will affect tremor or dyskinesia unilaterally. Using the target in the pallidothalamic tract may offer the possibility of treating patients bilaterally. 

Focused ultrasound offers several potential benefits:

  • Focused ultrasound treatment is non-invasive just like radiosurgery; however, its therapeutic effects are immediate and it does not have the risks or limitations of ionizing radiation.
  • Compared to radiofrequency ablation, focused ultrasound is non-invasive and therefore has significant reduced risk for infection. Also as focused ultrasound is done under closed loop thermal feedback, it is more likely to damage only targeted tissue and spare non-targeted healthy brain.
  • Compared to implantation of a deep brain stimulation device, focused ultrasound is a single procedure, and does not require subsequent procedures to replace batteries. It also does not involve the collateral damage to healthy tissue or the risk of blood clots and infections associated with implanting a foreign body.

Pre-clinical Research

The Foundation supports pre-clinical research which may yield better understanding and treatment options for Parkinson’s disease.

In addition to lesioning, pre-clinical studies suggest focused ultrasound may be able to reversibly open the blood-brain barrier (BBB) to improve the delivery of drugs, gene therapy or even stem cells to targeted areas of the brain.

A study with combined efforts from Johns Hopkins and the University of Virginia is looking at gene-bearing nanoparticle delivery across the BBB that may cause reversal of the neurodegeneration.

Work with Columbia University is looking at the abnormal accumulation of alpha synuclein in the brain, which occurs in Parkinson's patients, and using focused ultrasound to deliver material across the BBB that may reduce the accumulation of alpha synuclein.

Another proposal involves use of stem cells which can be delivered into the brain. The goal would be that they would attach and release products that would restore normal brain function to patients with Parkinson’s disease.

Clinical Trials

Tremor-dominant Parkinson's
This trial has completed enrollment for patients with tremor-dominant Parkinson’s (thalamotomy) disease.   

Parkinson's dyskinesia (pallidotomy)
A study evaluating the safety and initial efficacy of focused ultrasound for the treatment of Parkinsonian dyskinesia (pallidotomy) is approaching completion. This study is being conducted through the collaboration and funding from the Michael J. Fox Foundation for Parkinson's Research. After the patients complete the follow-up period for the study, we anticipate moving toward regulatory certification. 

To inquire about this trial at the University of Maryland, contact Charlene Aldrich at (410) 328-5332 or email at  

See here for a list of all Parkinson's clinical trials

The Foundation is also supporting a dystonia study in Tokyo, which is targeting writer’s cramp or musicians' dysfunctions of the hand. While dystonia is sometimes associated with Parkinson’s Disease, its cause is unknown. 

To inquire about this trial at Tokyo Women’s Medical University, contact Shiro Horisawa at or 03-3353-8111.

Regulatory Approval and Reimbursement

The ExAblate system manufactured by InSightec is approved in Europe for treating tremor-dominant Parkinson's Disease. The treatment is not reimbursed by medical payers at this time in Europe.

Treatment Sites

See here for a list of treatment sites

Equipment Manufacturers

ExAblate Neuro by InSightec LTD
http://www.insightec.com/ExAblate-Neuro.html

Notable Papers

Zaaroor M, Sinai A, Goldsher D, Eran A, Nassar M, Schlesinger I. Magnetic resonance-guided focused ultrasound thalamotomy for tremor: a report of 30 Parkinson's disease and essential tremor cases. J Neurosurg. 2017 Feb 24:1-9. doi: 10.3171/2016.10.JNS16758.

Krack P, Martinez-Fernandez R, Del Alamo M, Obeso JA. Current applications and limitations of surgical treatments for movement disorders. Mov Disord. 2017 Jan;32(1):36-52. doi: 10.1002/mds.26890.

Giugno A, Maugeri R, Graziano F, Gagliardo C, Franzini A, Catalano C, Midiri M, Iacopino DG. Restoring Neurological Physiology: The Innovative Role of High-Energy MR-Guided Focused Ultrasound (HIMRgFUS). Preliminary Data from a New Method of Lesioning Surgery. Acta Neurochir Suppl. 2017;124:55-59. doi: 10.1007/978-3-319-39546-3_9.

Dunn LK, Durieux ME, Elias WJ, Nemergut EC, Naik BI. Innovations in Functional Neurosurgery and Anesthetic Implications. J Neurosurg Anesthesiol. 2016 Dec 23. doi: 10.1097/ANA.0000000000000398.

Guridi J, Marigil M, Becerra V, Parras O. [Neuroprotective subthalamotomy in Parkinson's disease. The role of magnetic resonance-guided focused ultrasound in early surgery]. Neurocirugia (Astur). 2016 May 5. pii: S1130-1473(16)00035-X. doi: 10.1016/j.neucir.2016.02.006. Spanish. 

Fan CH, Ting CY, Lin CY, Chan HL, Chang YC, Chen YY, Liu HL, Yeh CK. Noninvasive, Targeted, and Non-Viral Ultrasound-Mediated GDNF-Plasmid Delivery for Treatment of Parkinson's Disease. Sci Rep. 2016 Jan 20;6:19579. doi: 10.1038/srep19579.

Hinow P, Radunskaya A, Mackay SM, Reynolds JN, Schroeder M, Tan EW, Tucker IG. Signaled drug delivery and transport across the blood-brain barrier. J Liposome Res. 2015 Nov 16:1-13.

Schlesinger I, Eran A, Sinai A, Erikh I, Nassar M, Goldsher D, Zaaroor M. MRI Guided Focused Ultrasound Thalamotomy for Moderate-to-Severe Tremor in Parkinson's Disease. Parkinsons Dis. 2015;2015:219149. doi: 10.1155/2015/219149. Epub 2015 Sep 2.

Metman LV, Slavin KV. Advances in functional neurosurgery for Parkinson's disease. Mov Disord. 2015 Sep 15;30(11):1461-70. doi: 10.1002/mds.26338. Epub 2015 Aug 14.

Samiotaki G, Acosta C, Wang S, Konofagou EE. Enhanced delivery and bioactivity of the neurturin neurotrophic factor through focused ultrasound-mediated blood--brain barrier opening in vivo. J Cereb Blood Flow Metab. 2015 Mar 31;35(4):611-22. doi: 10.1038/jcbfm.2014.236.

Magara A, Bühler R, Moser D, Kowalski M, Pourtehrani P, Jeanmonod D; First experience with MR-guided focused ultrasound in the treatment of Parkinson's disease. Journal of Therapeutic Ultrasound 2014, 2:11

Monteith S, Sheehan J, Medel R, Wintermark M, Eames M, Snell J, Kassell NF, Elias WJ. Potential intracranial applications of magnetic resonance-guided focused ultrasound surgery. J Neurosurg. 2013 Feb;118(2):215-21. doi: 10.3171/2012.10.JNS12449. Epub 2012 Nov 23.

Hynynen K, Clement G: Clinical applications of focused ultrasound-the brain. Int J Hyperthermia 23:193-202, 2007.

Click here for additional references from PubMed.

Animated treatment video courtesy of Insightec

     

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