SURGERY FOR PARKINSON'S DISEASE

In 1961, neurosurgeon Irving Cooper published an authoritative monograph titled "Parkinsonism: Its Medical and Surgical Therapy." It devoted 2 of its 237 pages to medical therapy. The rest of the book was described neurosurgical procedures designed to alleviate intractable symptoms of advanced Parkinson’s disease (PD). The dramatic effects of the drug levodopa, first successfully used by Dr. George Cotzias in 1967, pushed surgery into the background.

In recent years, however, neurosurgery has re-emerged as an important strategy in treating certain symptoms of PD. Advances in basic science have also provided researchers with fundamental rationale for surgical approaches as well. Surgery does not cure the disease, however, it is a way of setting the clock back on the disease.

Deep Brain Stimulation (DBS) involves placing an electrode in various parts of the brain to deliver continuous high-frequency electrical stimulation to control movements. This stimulation is thought to suppress abnormal pattern of excessive activity in these brain areas and returns them closer to normal, although the exact mechanism of the DBS effect is still not fully understood. DBS can be performed on both sides of the brain or in a combination of different targets. The selection of different DBS targets depends on the symptoms or the disease to treat and may include thalamus, globus pallidus, or the subthalamic nucleus.
FDA approved DBS of ventral intermediate nucleus (VIM) of thalamus for essential tremor and medically refractory parkinsonian tremor in 1997; Globus pallidus interna (GPi) or subthalamic nucleus (STN) DBS for PD in 2002; and GPi or STN DBS for primary dystonia under humanitarian device exemption program in 2003. Below is the general criteria and effectiveness of DBS for PD, tremor and dystonia based on the knowledge and evidence we have so far.

Who is a good candidate of PD for DBS? Those who have:

• Severe motor fluctuation with severe “off” period symptoms but good response to levodopa (in combination with carbidopa such as in Sinemet) with disabling dyskinesia or medication-induced side effects, or medication-refractory parkisonian tremor.
• PD > 5 years.
• No significant cognitive dysfunction/dementia or psychiatric issue (suicide, depression, psychosis).
• General condition tolerable to surgery.
• No severe lesion or atrophy in brain MRI.
• Realistic expectation for DBS.
• Good social support.

What’s the effectiveness of DBS on carefully selected patient with PD?

• VIM DBS is effective for tremor in PD, but not on other symptoms of PD, such as rigidity, bradykinesia, and dyskinesia.
• STN or GPi DBS is effective for tremor, rigidity, bradykinesia and dyskinesia.
• Bilateral DBS (STN or GPi) is more effective than best medical treatment for the treatment of PD in carefully selected patients, with the reduction in levodopa equivalent dose (LED) as well (Deuschl et al., NEJM 2006; Weaver et al., JAMA 2009; Williams et al., Lancet 2010).
• Patient with PD has a similar improvement in motor function and quality of life with bilateral STN or GPi stimulation.
• A meta-analysis of GPi and STN stimulation also shows that motor function improves in a similar manner for the two targets at 6 months (Weaver et al 2005).
• Non-motor profile seemingly favors GPi DBS especially for cognition and mood.
• STN DBS results in more reduction in LED than GPi (Follett et al, NEJM 2010).
• A study comparing unilateral GPi with unilateral STN also shows equivalent motor outcomes (Okun et al., 2009; Zahodne et al., 2009), but greater improvement in quality of life with the GPi stimulation (Zahodne et al., 2009).
• STN has no long-term benefit on postural instability and gait disturbance (PIGD) (George et al., 2010), and GPi may produce some benefit in PIGD based on small number of cases.
• Pedunculopontine nucleus (PPN) DBS is effective for PIGD or primary progressive freezing of gait in some studies.

Who is a good candidate of ET for DBS? Those who have:

• Refractory response to medications, including propranolol and primidone.
• Significant disability by the tremor.
• No significant cognitive dysfunction/dementia or psychiatric issue (suicide, depression, psychosis).
• General condition tolerable to surgery
• No severe lesion or atrophy in brain MRI
• Realistic expectation for DBS
• Good social support

What’s the effectiveness of DBS on ET?

• Unilateral VIM DBS effectively improves contralateral extremity rest tremor and postural tremor, ranging from 50% to 100%, though its effect may slightly decrease over time.
• Axial tremor (trunk, head, vocal tremor) tends to be relieved better by bilateral than unilateral DBS, though results vary and are less effective than arm tremor.
• Poor efficacy to alleviate intention tremor.
• 30-50% risk of developing dysarthria and disequilibrium, particularly after bilateral VIM.
• In general, VIM is more effective for limb tremor than axial tremor, and more effective for rest tremor and postural tremor than intention tremor.
• DBS at the posterior subthalamic area (cZI, PLR, upper STN) could possibly be more effective than VIM, particularly for those tremors refractory to VIM DBS, based on limited studies so far.

Who is a good candidate of dystonia for DBS? Those who have:

• Significant disability
• Poor controlled by medications.
• Failed botulinum toxin injection for focal or segmental dystonia.
• No fixed contractures (under anesthesia evaluation)
• No dementia, major psychiatric disorders, structural brain lesions, or serious general medical conditions.
• Age of 7 or above, with primary dystonia, including generalized dystonia, hemidystonia, segmental dystonia, and cervical dystonia.
• Meige syndrome, tardive dystonia, traumatic dystonia may benefit from DBS (Capelle et al., 2003; Kupsch et al., 2006).

What’s the effectiveness of DBS on dystonia?

• GPi DBS induces slow improvement of dystonia over days to months.
• Some therapeutic effects of the stimulation last for up to 10 h after its discontinuation.
• Equally effective for DYT1-positive and DYT1-negative dystonia.
• Not effective for dystonia due to birth injury and encephalitis (Holloway et al., 2006).
• DBS for primary generalized dystonia have shown a 30% to 50% improvement in symptoms (Eltahawy et al., 2004; Vidailhet et al., 2005), and even 60% improvement on bilateral GPi DBS at 20-month follow-up.
• Could have rebound dystonia after discontinuation of chronic GPi stimulation.
• GPi DBS patients with dystonia receive higher voltage and pulse width than PD or tremor and as a result require more frequent battery change.
• DBS for dystonia has not been associated with deterioration on cognition, and in fact can lead to some improvement in executive function (Halbig, 2005; Pillon et al., 2006).

The criteria and effectiveness may vary among different centers and patients. A detailed evaluation is made for every case by our DBS team consisting of movement disorder specialists, functional neurosurgeons, and a neuropsychologist, etc. As seen in any other surgical procedures, the DBS surgery also has some complications.

Lesioning involves destruction of a part of the brain that has become overactive or has abnormal function. Ablation of the thalamus is called thalamotomy, which is usually performed on one side due to the severe complication of bilateral thalamotomy. Ablation of the globus pallidus is called pallidotomy. In general, these procedures have been replaced by aforementioned DBS.

NEW EXPERIMENTAL APPROACHES

Cell Transplantation The major motor symptoms of PD are due to the lack of dopamine and medications that replace dopamine successfully treat these symptoms. The major limitations of these medications fall into three broad categories: 1) fluctuating responses to these medications, 2) side effects that limits medication use, and 3) progression of symptoms that do not respond to dopaminergic medications at any point. As discussed in the medication section, various pharmacological approaches can be taken to lessen the fluctuating response. One basic principle underlying the approach is to deliver dopaminergic stimulation in a sustained fashion instead of fluctuations levels achieved by oral medications. The second principle is to deliver only to the brain areas where the dopamine supply is missing, to avoid side effects that result from delivering dopamine where it is not missing. Therefore, the idea of cell transplantion to the brain area, putamen is very attractive. Placement of embryonic dopamine tissue in the putamen have been most successfully in animal models of PD. Although benefits have been noted in open label studies in small number of patients, NIH-funded double-blind placebo-controlled trials of fetal graft transplantation surgery reported in 2001 and 2003 failed to support these anecdotal observations. These two studies have shown only modest improvement only for younger (not older than 60) or milder patients in motor symptoms. However, there was a risk of unpredictable and disabling dyskinesias in up 50% of the patients. Further caution about this approaches is raised by recent follow up studies that showed development of PD pathology in transplanted cells after 11 to 16 years.

Stem cells from various sources could provide dopamine-producing cells that 1) have optimal dopamine production and other desirable properties, 2) have less undesirable components, 3) are available more readily, 2) have more consistent quality control than fetal dopamine cells that had been used. However, much further research is need to produce such cells and test them in animal models to achieve these goals. In addition, these new cell types will have to address how they can do better than fetal dopamine cells since we do not understand why these fetal cells failed to improve patients in a significant way and produced side effects. As of early 2011, there are no cell types that could be used for human trials.

For other opinions (similar conclusion as ours) on this issue, 2007 research area position paper by Michael J. Fox Foundation for Parkinson's Research.

Gene Therapy is an exciting and potentially very versatile therapeutic approach since various different types of genes can be delivered into specific areas of the brain. Depending on genes introduced into the brain, one could envision delivery of genes that can optimize dopamine supply, suppression of neuronal activity that can mimic the effect of DBS, or delivery of molecules that can make the dopamine cells function better or protect it from further degeneration. The University of Chicago has been an early pioneer of this approach in studies involving animal models, but in our view, this approach is at a very early explorative stage with many questions and hurdles to overcome.