Surgery for PD - a Layman's Explanation Last month, The Parkinson's Institute Auxiliary Bulletin had quite a bit of data of general interest, so I posted a copy here. This month, the Bulletin has mostly items of interest to members. It seemed, therefore, to be a good time to bring you a series of three articles written by our contributing editor, David Rosner. David is the Institute's Administrative Manager and Medical Librarian. Most issues of the Auxiliary Bulletin carry an a rticle of general interest by David. PALLIDOTOMY - A LAYMAN'S EXPLANATION by David Rosner, The Parkinson's Institute INTRODUCTION The pallidotomy is a neurosurgical procedure that involves insertion of a probe (a long needle) into a specific region of the brain known as the globus pallidus. The neurosurgeon then activates the tip of the probe, purp osfully damaging certain neurons that, in patients with Parkinson's disease, have become overactive. The initial rationale for using this technique to treat Parkinson's disease derived from the observation in the 1930s that minor strokes in the globus pallidus in Parkinson's patients resulted in alleviation of tremor. T hus, it was theorized that using a probe to lesion (damage) this same area of the brain could reproduce the effects of the stroke. However, the early results of this technique were variable and often fraught with surgica l complications. One of the reasons for the rather poor results was the inability to accurately locate this rather small group of neurons. With the introduction of stereotaxic surgery in the 1940s, the results improved. Stereotaxic surgery involves bolting a "frame" on the skull which provides fixed reference points for localizing a target in the brain. This frame guides the surgeon, through the use of previously determined anatomic co ordinates, in placing a probe to reach the desired neuronal cells. Stereotaxic techniques made the process less "hit-and-miss" but still somewhat "blinded"; it was still very difficult to specify the area that should be lesioned for best results. In addition, clinical trials for the procedure were rather poorly designed and documented. Thus, by the 1960s, use of the pallidotomy was beginning to diminish and was all but abandoned with th e advent of levodopa therapy in the late 1960s. THE MODERN AGE OF PALLIDOTOMIES In 1985, Dr. Lauri Laitinen, a Swedish neurosurgeon, began lesioning the posteroventral part of the inner globus pallidus, building upon studies by another neurosurgeon (Dr. Leksell) and his colleagues. Dr. Laitinen foun d that lesioning this area relieved most of the symptoms of parkinsonism, including tremor, rigidity, and bradykinesia (slowness). He reported that the improvement was sustained over time. He also reported that on-off f luctuations and levodopa-induced dyskinesias could be reduced in some patients. In the early 1990s, Dr. Mahlon DeLong, a neurologist at Emory University in Atlanta, discovered that lesions of a small cluster of neurons called the subthalamic nucleus abolished tremor, bradykinesia and rigidity in the MPTP monkey model of Parkinson's disease. This discovery suggested that dopamine deficiency, which occurs in Parkinson's disease, causes neurons of the subthalamic nucleus to be overactive. Since these neurons activate the inner globus pallidus, these neurons are, in turn, overactive. Further refinement of this work by DeLong and his colleagues led to the identification of specific neurons whose overactivity seem to cause many of the f eatures of Parkinson's disease. It turns out that the discharges from these neurons are unique and can be identified by a method called "single cell recording". Researchers are now utilizing this neurophysiological meth od to identify the exact area that will be lesioned. Using a microelectrode probe that measures cellular activity, and by "listening" to the cells' pattern of discharge, the surgeon and surgical team are better able to p lace the lesion in the desired area of brain for optimum results. How can we listen to the cells discharge? The inserted probe is specially designed to record and amplify the sounds made by the cells as the probe passes through the brain. These neurophysiological techniques are augmented by improved imaging systems (computerized axial tomography [CAT] and magnetic resonance imaging [MRI]). All of this information, when added to the im proved anatomical coordinates provided by the stereotaxic frame, allows the neurosurgeon to pinpoint the precise cells to be lesioned. The neurophysiological techniques mentioned above are still in the experimental stage. Dr. Laszlo Tamas, who has been appointed Director of Functional Neurosurgery programs at the Parkinson's Institute, has extensive exp erience with this technique. He has used neurophysiological methods in treating patients with disabling tremor by placing precise lesions in the thalamus and has been active in the Institute's experimental studies on pal lidotomies. As the number of centers providing pallidotomies as a treatment for Parkinson's disease has grown, anecdotal reports of dramatic improvement have been reported in the media and elswhere. However, as of March, 1995, not one report of a well-designed study of this procedure has been published. What do we mean by a "well-designed study"? It is commonly recognized that before a drug is placed on the market, a pharmaceutical firm is required by the Food and Drug Administration (FDA) to undertake a series of clini cal drug studies starting with tolerability in animals and ending with a double-blind study in a large number of patients (usually a multi-centered study). These double-blind studies are important to ensure that the effe cts of the drug on a group of subjects are measured against a matched control group not receiving the drug. This type of study eliminates three factors that can obscure interpretation of the study: 1) the placebo effect, 2) subject bias, and 3) examiner bias. With surgical therapies, there is no FDA equivalent that oversees the safety (i.e., efficacy and tolerability) of a given procedure. Usually, the only regulatory body governing wh ether or not a surgical procedure can be performed is the institution's own investigational review board (IRB). Thus, carefully designed studies are essential for judging the surgical outcome and complications of any given surgical procedure. It is disturbing that in some centers literally hundreds of individuals have undergone a p allidotomy and yet there has been no reliable assessment whereby other physicians can judge the value of the procedure. For this reason, we are advising our patients to use caution in deciding on this procedure as a trea tment. In the near future, Dr. Tamas will be perfoming this procedure. We are now completing a comprehensive protocol that ensures appropriate selection of patient for this procedure as well as pre-operative and post-op erative assessment. In this way, we hope to optimize the outcome of this treatment for our patients. In addition, by carefully evaluating our patients post-operatively, we will hope to learn what features of Parkinson's improve, the length of improvement and the risks of surgery. Our goal is to be performing pallidotomies on Parkinson patients before the end of 1995. Much work needs to be done before we can get started - a hospital needs to be selected and an operating room must be outfitted with electrophysiological shielding and other specialized surgical equipment. Preliminary financial agreements and arrangements between the Parkinson's Institute and the hospital must be put in place, and the relationship be tween the patient's insurance company must be defined, especially since we now have various "managed-care" and health maintenance organizations (HMO's) to deal with. Most importantly, a protocol needs to be set up to ade quately assess the results of a clinical trial of pallidotomies. This will help to ensure that patients are benefitted by this surgical procedure and will allow us to determine the duration of that benefit. These steps a re in progress and further updates will be given to you as soon as they are available. ONE LAST NOTE You are probably be aware that several private neurosurgeons and neurosurgeons at large medical institutions throughout California are already performing pallidotomies. We will not critique other surgical programs, and w ould not recommend one over another. Neither will we tell someone not to go somewhere for this procedure. It is certainly tempting for a patient to go ahead and have someone else perform the procedure now, rather than wa iting for the Parkinson's Institute and for research advances that will likely make the technique safer and possibly more beneficial. However, it certainly seems worthwhile to wait, for at least just a few more months, so that more information about the results of pallidotomies that have already been performed can be reported. Please consider having the person who will undergo this operation talk with his/her neurologist and get an inform ed opinion - is the patient a good candidate for the pallidotomy? Does the doctor feel this procedure will be beneficial for that patient? What benefit would the doctor expect for the patient? Getting an opinion from t he patient's own doctor is better than relying on anecdotal information, newspaper reports or telephone surveys to determine whether an experimental surgical procedure is something you want to do. ********************************************* Next - Thalamotomy ********************************************* THALAMOTOMY - A LAYMAN'S EXPLANATION by David Rosner, The Parkinson's Institute Last month, we started to explain various surgical approaches to Parkinson's disease. As noted in that article, there are four main surgical approaches being investigated by Parkinson's researchers today: 1) Pallidotomy, 2) Thalamotomy, 3) Stimulation of the ventral intermedius nucleus (VIM) of the thalamus, and 4) Transplantation of fetal tissue. In this article, I'd like to try and give a layman's explanation of the thalamotomy, which is used mostly to relieve tremor in patients with Parkinson's disease and essential tremor. THALAMOTOMY - RATIONALE AND THE PROCESS The earliest mention of thalamotomy as a surgical procedure to alleviate tremors dates back to 1906 when Dr. R.H. Clarke described a stereotaxic instrument and procedure for lesioning the brain. Dr. Clarke, working with Dr. Victor Horsley, did not specify the lesioning of the thalamus. Thalamotomies were actually first performed in the late 1940s by Drs. Spiegel and Wycis and their colleagues, utilizing a stereotaxic frame to identify the thalamus. Why the thalamus? The thalamus is an area deep within the brain that coordinates the activity of motor and sensory commands throughout the brain. It is part of a major neuronal "highway" which runs throughout the brain (i.e., cortex to striatum to pallidum to thalamus and back to cortex). Normally, this "highway" runs smoothly as the neurons interact. When this system is working properly, signals are sent between these neurons, allowing the brain to communicate with various parts of the body. In patients with Parkinson's disease, because of the loss of dopamine, an imbalance occurs in this system resulting in tremor, slowing of movement and rigidity. It has been known for decades that lesions placed in a specific region of the thalamus can abolish tremor on the contralateral (opposite) side of the body. The target is located by recording cell discharges from a microelectrode placed in the thalamus. The neurosurgeon and "neurophysiologist" who assists him then listen for the tale-tell sound of the neurons that, when lesioned, will abolish the tremor. Once the target area is identified, the probe is heated and the lesioning is accomplished. The patient is usually awake and communicating with the surgeon during this process. It should be noted that this procedure only benefits tremor and no other symptom of Parkinson's disease. WHO IS A CANDIDATE? Since this procedure really only affects only tremor, those patients with "tremor-predominant" Parkinson's disease whose tremor is not adequately treated by antiparkinsonian medications would be candidates. This procedure also can benefit individuals with essential tremor who lack sufficient response to medications. The thalamotomy is best limited to patients with young-onset Parkinson's disease whose symptoms are confined to one side of the body (i.e., unilateral tremor). This does not automatically exclude older subjects or those with bilateral tremor; however, these patients may have more risk of complications from the surgery, such as mental changes (i.e., confusion), impairment of speech and/or balance, swallowing problems, etc. Recent advances in the technology for locating the area to be lesioned has tended to reduce these complications. RESULTS, AND A FEW FINAL NOTES It is estimated that thalamotomy is effective in relieving 80-90% of tremor in patients with Parkinson's disease and essential tremor. It may also help ease dyskinesias in patients experiencing these movements due to antiparkinson medications. Thalamotomy does not relieve symptoms such as bradykinesia (slowness of movement), postural instability or gait problems. It will also not stop or slow the progression of Parkinson's disease. Bilateral thalamotomies can cause a profound impairment in speech and, unless this complication can be avoided with novel surgical techniques, only unilateral thalamotomies are recommended. How do you decide whether you are a candidate? Talk to the doctor who treats your Parkinson's disease or essential tremor. Make sure your doctor (i.e., internist, neurologist, etc.) is familiar with thalamotomies, and can recommend a qualified surgeon. It may be advisable to get a second opinion from a neurologist specializing in the diagnosis and treatment of movement disorders to determine whether you are a good candidate for surgery (and to help post-operatively in evaluating your response to the procedure). The thalamotomy is generally regarded as a safe procedure, has been performed for a good many years with success, and can result in significant long-term benefit for a number of candidates. However, it involves damaging neurons in order to cause a positive effect. This process cannot be reversed; patience and caution should be exercised as you carefully research the operation and the person who will be performing the actual surgery. *************************************************** Note: I wish to thank Dr. James Tetrud for his comments and advice on this article. I'd also like to thank (belatedly, I'm afraid) Dr. Heidi Shale for her helpful comments and advice on last month's article on pallidotomy. Copies of both articles will be available from the clinic staff for patients who would like general information on these procedures. David Rosner *************************************************** NEXT - STIMULATION OF THE VENTRAL INTERMEDIUS NUCLEUS (VIM) OF THE THALAMUS *************************************************** STIMULATION OF THE VENTRAL INTERMEDIUS NUCLEUS OF THE THALAMUS - A LAYMAN'S EXPLANATION by David Rosner, The Parkinson's Institute In past months, we have discussed two surgical approaches to Parkinson's disease (Thalamotomy, and Pallidotomy). As noted in those articles, there are two other surgical approaches being investigated by Parkinson's researchers today: 1) Stimulation of the ventral intermedius nucleus (VIM) of the thalamus, and 2) Transplantation of fetal tissue. In this article, I'd like to try and give a layman's explanation of Stimulation of the ventral intermedius nucleus (VIM) of the thalamus, which is used almost exclusively in patients whose tremor causes significant functional disability; generally, these patients have little or no response to standard anti-parkinson medication. Younger patients seem to have a better response to this treatment but older patients can also be candidates. THE PROCEDURE: Just like in a thalamotomy, the patient has a stereotactic frame bolted to his skull; this frame and a CT scan of the brain help to locate the general area to be addressed. The target (the VIM of the thalamus) is pinpointed by recording cell discharges from a microelectrode placed in the thalamus. The neurosurgeon and "neurophysiologist" who assists him then listen for the tell-tale sound of the neurons that must be dealt with to abolish the tremor. The patient is usually awake and communicating with the surgeon during this process. Once the target area is identified in this operation, however, the microelectrode probe is not heated so that lesioning is accomplished; instead, the electrode is sutured into place in the skull. Thin wires (which have to be implanted in the neck) connect the electrode to the "impulse generator", a very small stimulator unit which is placed under the skin of the chest region. As I've seen it described, the stimulator unit is sort of like a cardiac pacemaker, except it's hooked up directly to the brain. The device can last between three and five years. RESULTS: For reasons researchers have not been able to explain, this VIM stimulation has almost exactly the same effect as lesioning the thalamus - tremor is almost completely abolished, and other motor function seems to be restored. It would seem that this operation is much more positive, in that you don't have to permanently damage the area of the brain for the patient to be helped. Of course, a drawback is that you have to wear the "stimulator unit" in and on your body all the time - it's not detachable for social occasions, for example. However, approximately 88% of the Parkinson patients who have undergone this operation with Dr. Alim Benabid (the French Professor who pioneered this technique over the past twenty years) have reported major benefits. It is also helpful for almost 70% of the patients with essential tremor and for other types of tremor as well. HOW DO I SIGN UP? You're probably wondering why you haven't heard much about this procedure before. Well, it's still experimental and only being used in controlled clinical trials at this time. The Parkinson's Institute is very aware of the procedure and is looking to get involved in a clinical trial in the near future; this will probably happen once we have selected a site (i.e., a local hospital) for all of our surgical work on the various approaches we'd like to try. We'll keep you posted. OTHER NOTES: I'm not going to try and explain the fetal tissue implantation procedure for you - a better way to learn about it will be by watching ABC's "PrimeTime Live" segment highlighting Dr. Langston and Dr. Widner. Both Dr. Langston and Dr. Widner will be explaining the fetal tissue operation on Connie Sainz, one of the original MPTP-exposed subjects we've been following for years in the Institute's clinical facility, and discussing the effects we've seen so far. It should be a very informative program, and if you miss it, I'm sure the Institute will have a copy of the program available for you to borrow and watch. The Institute's latest newsletter just came out. We hope (and plan) to publish newsletters more often in the future and capture late-breaking research information for our patients and friends. Excerpted from *********************************************** * AUXILIARY BULLETIN * * Distributed monthly to selected TPI Staff * * and all Auxiliary Members * *********************************************** Editor: Arvid Rosenboom Contrib. Ed.: David Rosner