News from the 18th Congress of Parkinson’s Disease and Movement Disorders
Thomas L. Davis, M.D. July 16, 2014.
This summer thousands of international researchers met in Stockholm Sweden to present the latest research in Parkinson’s disease (PD). It would be impossible to review all of the topics presented and at this time I will limit my discussion to recent advances in surgical treatments for PD. Although deep brain stimulation (DBS) is the most popular surgical procedure performed for PD, many other strategies are being investigated. These are summarized below.
Selective lesions were the first surgeries to be developed for PD. Initially these surgeries were performed by placing a rigid electrode deep in the brain and progressively stimulating to find the precise area of the brain providing symptomatic benefit without adverse effects. Once this site was found the voltage (current) through the electrode was increased until enough heat was generated to produce a lesion. Prior to the advent of levodopa it was recognized that lesioning of a small area of the thalamus dampened Parkinson’s tremor in the contralateral side. This provided a dramatic reduction in tremor but much less benefit for rigidity and bradykinesia. These surgeries were also limited in that they could only be performed on one side of the brain due to the high incidence of difficulty speaking and or swallowing following bilateral lesions. Because of these limitations lesioning surgery became much less popular following the advent of levodopa. Recently, with improvements in targeting technology, researchers have regarding to do noninvasive lesioning of the thalamus using either focused radiation or ultrasound. Like the traditional thermal lesions these can generally only be performed unilaterally but lack the risk of invasive surgery or anesthesia. For select patient, primarily those with medical contraindications to deep brain stimulation, noninvasive lesioning may offer dramatic improvement in medication resistant tremor.
Advances in DBS
As noted above, DBS has generally replaced lesioning surgery for PD as it offers the additional benefit of being able to adjust the stimulation to better suit the patient’s needs post operatively. Although DBS provides dramatic benefit to many patients, its effects are often limited by either voltage dependent adverse effects or the presence of stimulation resistant symptoms. The effects of DBS (both good and bad) are dependent of the total area of the brain influenced by the stimulation. This is frequently referred to as the volume of tissue activation (VTA). In the simplest of situations with one active contact the VTA can be modeled as a sphere that increases in size as the voltage is increased. This is not always optimal as the target within the brain may not be spherical in relation to electrode placement. To lessen this problem new DBS systems are experimenting with new ways to shape the VTA to better match the target providing improved efficacy with fewer adverse effects. These strategies involve the activation of multiple contacts at different voltages to steer current towards the target. The ability to steer current and better shape the VTA offers a number of potential benefits but dramatically increases the complexity of programming due to the millions of different possible configurations. Because of this researchers are developing computer modeling programs to aid the optimal programming of these new devices.
At the Congress in Sweden Vanderbilt researchers presented data, supported by the NIH and the Peterson Foundation, demonstrating the potential of a computerized brain atlas to assist in post-operative programing. The atlas allows for a patient’s post-operative CT scan to be morphed into an atlas and then be available for computer simulated programming. This simulation gives the physician programmer a 3-D picture of the patient’s anatomy and has the potential to dramatically shorten the time from implantation to optimal response.
Another new strategy for DBS is interactive stimulation. Currently available DBS pulse generators provide constant stimulation at a prescribed frequency, pulse width, and voltage / current when the device is functioning. Experimental internal pulse generators now have the ability to simultaneously record signals from the brain and stimulate. This allows for the possibility of a device that can read and react to an individual patient’s motor fluctuations. It is hoped that this would provide a broader range of symptomatic control to patients undergoing deep brain stimulation.
Gene therapy is the use of DNA as a drug to treat disease by delivering therapeutic DNA into a patient's cells. Recent trials of gene therapy in PD have been aimed at increasing production of dopamine or decreasing production of a neurotransmitter glutamate. Both of these strategies were aimed at providing immediately symptomatic benefit immitiaing the effects of levodopa or DBS. Although these looked promising in early trials, larger controlled studies have been unable to show a benefit. Despite this lack of early success promising advances have been made using animal models of PD. Some of these trials involved the use of genes for growth factors (brain derived neurotrophic factor) rather than neurotransmitter replacement. This represents a shift in using gene therapy to fundamentally change the natural history of the disease rather than provide symptomatic benefit. The lessons learned in these negative trials will be important in future trials of gene therapy.
Cellular transplant can be defined as the use of cells (usually progenitor or stem cells) to replace loss of function from disease. Cellular transplant has a long history in PD. Many of the pioneers of these techniques were Swedish and therefore cellular transplant was a major topic at the Stockholm meeting. Trials grafting cells from a patient’s adrenal gland to the caudate in the brain were performed in approximately 200 patient’s with Parkinson’s disease in the late 80s. Initially these trials were thought to be very effective but I’m more systematic look at the pool data showed no significant lasting benefit for most patients. The first controlled trials of cellular transplant (utilizing human fetal tissue) were performed almost 20 years ago. These showed very mixed results with some patients having evidence of cellular growth and excessive dopamine production leading to uncontrolled dyskinesias. Sham surgeries were also effective and made interpretation of these trials very difficult. Additional trials of cell transplantation have been done with porcine (pig) fetal cells have also been negative. Challenges to cellular transplant include: Developing a safe and reliable source of cellular material, determining the amount and location for each individuals transplant depending on their type of PD. With these limitations, enthusiasm for cellular transplant waned with the success of DBS. Although DBS, as noted above, is making rapid advances is clear that it is not effective for all the symptoms associated with PD. For these reasons advances in cellular technology such as the ability to produce induced pluripotent stem cells have led to a great resurgence of interest in cellular transplant for PD.
As you can see, in addition to new medications in development for the treatment of PD (a topic for later discussion), surgical research is also advancing. It is becoming increasingly clear that optimal therapy for individual patient’s will need to be personalized and that no one procedure will be best for everyone. As research accelerates it is likely that some of the strategies noted above will be translated into improved care for patients with PD.