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Reflections on Therapy for Parkinson's Disease: Medication and Neurosurgery by Bill Harshaw Parkinson's Disease is associated with free radicals which in turn are associated with the deposition of iron. The human brain is encased in fat. For a person with Parkinson's, the brain, which is the source of the highest creativity and reasoning, spoils and rusts The two procedures I had - the pallidotomy in 1993 and deep brain stimulation the following year - are much in the news as Parkinson's patients search out possible ways to mitigate their symptoms and improve the quality of their lives. Media accounts of these procedures focus on the successes, sometimes spectacular, and give less coverage to the patients whose lives have not increased in quality. Neurosurgery as a therapy for Parkinson's disease continues to be both experimental and controversial. Pallidotomy, thalamotomy, deep brain stimulation and foetal transplants haven't yet reached the status of bypass surgery for cardiac patients - the gold standard. But it is useful to remember that they are all based on what the noted American physician Lewis Thomas calls ‘halfway technologies'.He does not use this term derisively, but to point out that they do not represent a cure, only better symptom management. Foetal transplant surgery is to the doctors an extension of the current ‘gold standard' of treatment, ‘dopamine replacement therapy', as represented by the L-dopa based medications. However, it has a number of ethical and moral hurdles to clear before becoming acceptable to society generally. The other procedures fall into the general category of what surgeons do best: "if its broke, fix it" (with apologies to Bert Lance). To put neurosurgery in the context of the universe of treatment for Parkinson's it is important to remember that pallidotomy and thalamotomy have been around for fifty years. They were the therapy of choice for advanced PWPs.untl the mid 1960s when L-dopa was discovered to be efficacious. As L-dopa gained acceptance, its superiority to all other drug therapies became apparent. Neurosurgery went into eclipse, not to have a renaissance for a quarter century, a period which saw the development of two generations of a new type of drug - dopamine agonists - which increase and prolong the effectiveness of L-dopa. A quarter century's use of L-dopa as the medication of choice demonstrated its superiority in symptom management; it also revealed the drug's shortcomings - dyskinesia and psychiatric side-effects in advanced patients who were on high doses being among the more significant.. In the early 1990s, technological advances, the miniaturization of surgical instruments, a more nuanced and comprehensive understanding of neuroanatomy, a new era in neuroimaging and the need to provide some sort of relief to advanced patients led to a renewal of interest in neurosurgery - the old operations being done more successfully and with greater precision and the invention of DBS by Alim Benabid and his colleagues in Grenoble France. Almost paralleling the surgical innovation was the development of a third generation of agonists which, if they live up to their press releases, will provide a meaningful advance on current drug therapy. The procedures and the drugs are at the limit of human knowledge. Foetal transplantation is considered separately. As a class of surgery, it belongs with organ transplants - heart, lungs, kidney ... the list goes on. It first showed its face in the late 1970s and has been developing quickly since then. At times the pace of progress seems slow to patients, but the rate of change of progress has been nothing short of exponential. Results of a recent double blind study are every bit as good as were expected and parallel the results of other the types of surgery . Comparing the state of therapy for Parkinson's today to what it was a mere quarter-century ago, the progress is staggering. Before L-dopa, the medications available were a variety of drugs which were serendipitously found to be beneficial as therapy. They were really pretty primitive. Now, there is L-dopa, three generations of agonists, neurosurgery and a whole new array of research projects, any one of which has the potential to advance treatment markedly. It should be noted that every therapy has its drawbacks, called side effects, which range from the trivial to the serious. Some of these side effects are major enough to prevent certain patients from using some therapies. Indeed, there is a website on the internet devoted to patient accounts. The implications of these advances on a broad field of new and newly adapted drug and surgical therapies is that physicians will have several arrows in their quiver when presented with a patient with symptoms that previously would have been intractable. The other aspect is the hope that these developments engender. The American philosopher John Searle noted in a 1995 article: As far as we know the relevant processes take place at the micro levels of synapses, neurons and cell assemblies. All our conscious life is caused by these lower level processes, but we have only the foggiest idea of how it all works. The doctors know that lesioning works and that chronic stimulation works, yet they do not know how or why. That should give some cause for pause. The same comment can be made, to a degree, with respect to drug therapy. We don't know why some drugs are more effective than others. Perhaps Parkinson's disease will, in the end, be found to be not one condition, but a cluster of conditions with several common characteristics and each one having unique properties which set it apart. The existence of progressive supra-nuclear palsy and multi-system atrophy are two cases in point. That is why it is a very good thing that there are half a dozen agonists on the market and three types of surgery - lesioning, stimulation and transplant. One agonist or type of surgery may be more effective than others in different varieties of the condition. Research is also yielding results on discovering the causes of Parkinson's. PD is caused by the death of the cells comprising the substantia nigra which produce dopamine. It is not known what causes the cells to die. The prevalent current hypothesis is the so-called ‘double hit' theory - which seems to be the case with other neurodegenerative conditions as well - an hereditary or genetic predisposition which can be hit by an environmental toxin, thus providing the double hit. The toxin could be anything from pesticide and fertilizer to industrial pollutants and smog - it is not known yet. This aspect has caused researchers to investigate the concept of neuroprotection, i.e. what could protect the brain from degeneration? Too, as we do not know what causes cell death in the substantia nigra, we do not now whether or not the disease mechanism mutates over time. For instance, were the men Christ cured of the ‘shaking palsy' in Matthew's Gospel PWPs? If they were, was their PD the same as mine? The answer may well be: "In the main, yes, but there are some important differences." The differences could arise from the nature of the environmental toxins (assuming the validity of the ‘double hit' theory) - PCBs weren't around in Biblical times, for example. Relatively few of these procedures have been performed - likely not more than 250 D.S., 2000 pallidotomies and under 100 transplants. In the context of five million PWPs worldwide, it amounts to a mere twentieth of one per cent. The time it takes to bring a new drug to market, from the animal trials through to it being readily available for physicians to prescribe is between five and ten years. Many observers think that too much time is taken up in report-writing and meetings - the bureaucracy that is the bane of humanity's existence on this planet. And they are likely both right and correct. But let one thing be perfectly clear: the design of a clinical trial, the analysis of the results of the trial and the conclusions drawn from the analysis and observation of the trial must never be compromised in the name of expediency. We need only look back forty years to a drug called Thalidomide and the deformed children its use produced to see the consequences of sloppy trials.. The spectacular results that neurosurgeons have achieved with, it must be added, the help of the patients, are a testament to innovation, imagination and modern technology. The problem is that there are not enough neurosurgeons to satisfy the demand for procedures. In a perfect market, more surgeons would elect functional neurosurgery as a subspecialty until demand and supply was in balance. Alternatively, the fee charged for the procedures could rise until it choked off demand. But, we do not live in a perfect world with only Adam Smith's "invisible hand" to guide us. The marketplace is littered with imperfections ranging from the government and physicians' regulatory bodies to competition amongst surgical specialties. I am exceedingly fortunate to have had such successful surgeries and had the leading neurosurgeons in this sub-specialty perform them. Others have not been so providential. There is an old aphorism attributed to Abraham Lincoln. The skills of an army general were being recounted to him. When the speaker had concluded, Lincoln responded: "Yes, but is he lucky?". It is not known what the reply was. I would say that luck goes to the well-prepared. There are numerous anecdotal accounts circulating about patients who have had unfortunate surgical results. To the extent that these histories are accurately reported, they would appear to be the result of one or more of the following factors: 1. The patients may not have been suitable for this type of surgery 2. The attending physicians and surgeons may not have been adequately qualified, and that standard is very high indeed 3. The patient and/or his caregiver may have had unrealistic expectations Considerations like age (the younger the better), absence of complicating conditions (blood clotting problems, cognitive problems, diabetes, history of stroke or other cerebro-vascular disease) and patient attitude are all important to the medical team in making their decision on whether or not to operate. Patient stamina also plays an important role because of the interactive nature of the procedures - the dialogue between patient and neurosurgeon that is so essential to success. Finally, the neurosurgeon must have an empathetic relationship with the patient because responses to stimuli vary from patient to patient; understanding those differences is crucial.