The symptoms of Parkinson’s disease (PD) have been described in various forms since the ancient Greeks. Nevertheless, it was James Parkinson who in 1819 wrote the essay on “The Shaking Palsy,” in which he described the four cardinal symptoms as tremor, rigidity, slowness of gait, and postural instability. This description was dependent upon his observations over the years of a total of 6 people he had seen outside his office in London. Fifty years later, the great Charcot named the disease in honor of Parkinson.
There is some debate as to where the disease begins in the brain. Recently, Braak has hypothesized that the disease begins in the olfactory neurons and in the base of the brain stem. What is not in question is that in almost all cases of symptomatic PD, there is involvement of a nucleus at the top of the brain stem, the substantia nigra. This nucleus is so-called because of its dark color under the microscope. It consists of pigmented neurons that generate a neurotransmitter known as dopamine. In PD, therefore, there is a loss of dopamine, and this accounts for most of the four cardinal symptoms. Levodopa enables the remaining neurons to generate more dopamine and thus reverse the symptoms. Since the introduction of levodopa into clinical practice in 1965, it has remained the master drug for treating Parkinson’s disease.
Yet there are several other drugs that can be used - on their own, or in conjunction with levodopa and these include the classes of dopamine agonists, MAO inhibitors, anti-cholinergic drugs, as well as long-acting versions of levodopa and COMT inhibitors (which reduced the metabolism of levodopa by the liver). The art of clinical management of Parkinson’s disease depends upon using judicious combinations of these medications for optimum control of symptoms. Our approach is minimalist, to use the smallest number and smallest doses of medications to control the symptoms. For example, some patients with prominent tremor-dominant Parkinson’s disease need a combination of levodopa and dopamine agonists, and nothing else. Patients with early disease may do just fine with a dopamine agonist, without using levodopa.
By the time someone has had Parkinson’s disease for 10 years, it is very likely that he will need to be on levodopa, and can be managed for many years thereafter using this as the mainstay.
Lewy Body Dementia
Up to 30-40% of people with advanced PD will develop a fluctuating confusional state with visual hallucinations. This is known as Lewy body dementia (LBD). Such a condition is not a certainty, indeed we have seen people go out 20 to 25 years without loss of cognitive function. Nevertheless, LBD is a common condition and is highly treatable. We pioneered the use of cholinesterase inhibitors in this condition, at a time (1994) when such treatment was considered contraindicated. We showed that patients could do very well indeed on these drugs, some even showing improvements in physical symptoms as well. This treatment is now standard-of-care.
The first drug used, tacrine, is extremely potent but is no longer available. However, there are 3 other drugs including galantamine, Exelon, and Aricept that are available. All 3 of these drugs have been FDA-approved for Alzheimer’s disease. Unfortunately, their effect on Alzheimer’s disease is limited. In LBD, on the other hand, they can have a much bigger effect. In our experience, galantamine and Exelon are both far more potent than Aricept, and we sometimes use combinations of galantamine and Exelon for optimal control.
If a patient develops LBD, then he should be managed with levodopa and a cholinesterase inhibitor alone. The dose of levodopa should be as low as possible, in order to prevent exacerbations of hallucinations and confusion.
Surgical Treatments for Parkinson's Disease
Almost 60 years ago, while working at NYU, Irving Cooper used to perform surgeries on Parkinson patients to cut the corticospinal tracts contralateral to the more affected side, in patients with severe tremors. This paralyzed the more affected side, but it also eliminated the tremor. Presumably, patients undergoing this surgery thought that it would be preferable to be paralyzed on one side than to have a tremor on that side. Nevertheless, in retrospect, it seems quite extreme.
After one of these surgeries, Cooper noted that the patient had markedly reduced tremor, but was not paralyzed. Since we didn’t have MRI scanners in those days, Cooper had to wait several years until the patient died of natural causes, and then he could examine the brain. He discovered that he had missed the corticospinal tract, but had made a lesion in the ventrolateral thalamus. From then onwards, his surgeries were performed on the ventrolateral thalamus of the contralateral side, and he had good success. 10 years later, one of his patients had markedly reduced rigidity as well as loss of tremor and was later found to have a lesion in a nearby structure known as the globus pallidus. From then on with all his surgeries were on this structure and were known as “pallidotomies.” Shortly thereafter, levodopa was introduced and the surgical approach was abandoned. It made a comeback in the 1990s, however, for those with advanced symptoms of Parkinson’s disease who were having side effects of dyskinesia on the levodopa.
Subsequently, bilateral stimulation of a structure known as the subthalamic nucleus (STN) was achieved by implantation of 2 pacemakers, one on each side. This surgery is known as deep brain stimulation (DBS) – although it is of a less stimulator and more of a jamming device as it blocks signals from the STN. Over 100,000 of these surgeries have now been performed worldwide.
A useful pharmacological alternative to DBS is in the reintroduction of Tasmar (tolcapone) in patients with advanced Parkinson’s Disease. We have approximately 40 people on this drug with generally excellent results. Just like the DBS it reduces off time, increases on time, can eliminate tremor and decrease dyskinesias.
GDNF (Glial-Derived Neurotrophic Factor) is a very promising growth factor that has been shown to have potent effects on neuronal regeneration. Intraputamenal GDNF is a surgery that is much simpler than DBS, wherein a tiny plastic catheter (with a width less than 1 millimeter) is surgically implanted in the putamen and connected to a small subcutaneous plastic reservoir behind the ear. The surgery can be performed in an hour, without general anesthetic. The patient receives a tiny infusion of GDNF through this catheter, and can then return as an outpatient monthly for further infusions through the plastic reservoir, without the need for further surgery. This technique is being pioneered by Professor Stephen Gill at the University of Bristol in England. If successful, we may soon be talking for the first time about actual reversal of Parkinson’s Disease.
