By Clarke Espy, MD

Parkinson's disease (PD) is a common, slowly progressive neurodegenerative disorder that increases in incidence with advancing age. It poses a challenge to the patient and ultimately the caregiver and the medical system itself. There are approximately 60,000 cases of Parkinson's diagnosed each year in the United States. Although PD patients survive on average 15 years, the impact of the disease on quality of life is ultimately what concerns most patients and family members. The cause of PD is still unknown. Its symptoms of tremor, stiffness, slowness and imbalance are the result of the dying off of neurons in the brain's dopamine system. A fragile mental status and even frank dementia will occur in approximately 30% of patients as the disease progresses.

The diagnosis of PD is presently based on clinical examination. A type of PET scan and perhaps a new SPECT scan can be helpful in confirming the diagnosis of PD in patients with atypical presentation.

There are diseases that can mimic PD, some of which are potentially reversible, such as drug-induced parkinsonism caused by certain medication like Haldol, Reglan and even some of the newer neuroleptics such as Zyprexa. Stopping these medications can result in resolution of the signs and symptoms over a period of one month or so. It should be recognized, however, that occasionally these medications will bring out a preclinical case of PD. Parkinsonism can also occur as a consequence of certain toxins such as manganese or as the result of certain viral infections in the brain, such as West Nile or Japanese B encephalitis. Other degenerative diseases (such as Alzheimer's disease) can, in the late stages, have parkinsonism signs and symptoms. There is an overlap syndrome, which has features of both Alzheimer's and Parkinson's disease called diffuse Lewy-body disease. Early falls and visual hallucinations are common in this latter illness.

Vascular disease, such as multiple small strokes, can also occasionally mimic PD in some respects, particularly the gait disorder. Vascular parkinsonism may respond somewhat to levodopa therapy along with gait training. Normal pressure hydrocephalus can also mimic PD in some ways, although urinary incontinence and early mental decline are usually part of the picture. Such patients often seem to be glued to the floor when they attempt to walk. A ventriculoperitoneal shunt can occasionally be dramatically effective in this condition. Predicting who will benefit from this shunt is difficult and there are no 100% accurate tests to predict response. In addition, there are occasional serious risks, such as bleeding, strokes and infections.

There are, in addition, several so-called Parkinson-plus syndromes that sometimes can be difficult to differentiate from idiopathic Parkinson's disease. These syndromes include progressive supranuclear palsy (PSP) and multi-systems atrophy (MSA) such as Shy-Drager syndrome. These illnesses are Parkinson-like, but have certain identifying features such as limitation in eye movement, particularly in downward gaze as we see in PSP, and dramatic blood pressure drops when standing, such as seen in Shy-Drager syndrome. The latter can make it virtually impossible for the patient to be upright.

The treatment of Parkinson-plus syndromes tends to be suboptimal and we often focus on the symptoms such as falling and blood pressure drops. Levodopa and some of the newer surgical procedures are not generally very effective in these Parkinson variances. In addition, dementia seems to be even more common than in typical PD. On a practical note, a trial of levodopa can sometimes be helpful in differentiating PD from Parkinson-plus syndromes. As a rule, a Parkinson's patient will respond nicely to levodopa whereas the Parkinson-plus syndromes respond little, if any.

Treatment of PD usually consists of replacing dopamine or directly stimulating dopamine receptors with various medications. In younger patients, we tend to favor drugs that directly stimulate dopamine receptors like Requip or Mirapex. The gold standard in therapy is still levodopa, usually administered in the form of Sinemet or most recently, in combination with Comtan in a drug known as Stalevo. Sinemet is available in both immediate release form and in slow release formulations called Sinemet CR. It has become increasingly common to use a combination of Sinemet along with the dopamine receptor stimulators. There is reason to believe that keeping Sinemet doses low and administering drugs that stimulate dopamine receptors in a more constant even fashion may be helpful in delaying the onset of erratic response to therapy.

Neuroprotective medications are desperately needed in treating PD. At the present time, there is some evidence to support the use of Selegiline (Eldepryl). This medicine can prolong the effect of Sinemet and may be somewhat neuroprotective. Coenzyme Q10 in high doses and perhaps high-dose vitamin E may also give some neuroprotective effect, thus slowing the pace of progression. A recent report on GDNF (glial-derived nerve growth factor) has been shown to be ineffective in spite of some early optimistic results in animal models. Rasagiline, a drug similar to Selegiline, is being developed in Europe and looks quite promising as both a symptomatic Parkinson medication, but also as a neuroprotective agent. It will be tested further in this country towards the end of this year. There is early evidence to suggest that it can be helpful in both early and advanced PD. It many respects, it is probably the most promising of the medications in the pipeline.

There have also been reports recently of using a dopamine stimulator via a transdermal patch. Early studies on Rotigotine showed that it was well tolerated and seemed effective. In addition, a new injection medication, Apokyn, has been released. This medication can be used to pull a patient out of an "off" period, characterized by immobility. The injection will usually work in a few minutes and last for several hours. Unfortunately, nausea is a common side effect so that concomitant usage of an anti-nausea medication is usually necessary. Currently Tigan or Domperidone can be used to block the nausea effect. The latter drug can be mail ordered from Canada and is also useful in patients who get persistent nausea from therapeutic doses of levodopa.

The general rule in the first five years of treating Parkinson's tends to be relatively easy for most people. As the disease progresses, however, changes occur that cause the levodopa to work for shorter periods and then eventually to work erratically with sudden swings from over-medication with dyskinesia to under-medication with freezing and immobility. In addition, problems such as fainting from low blood pressure and visual hallucinations eventually occur in many patients that require dosage adjustment and sometimes administration of medication to combat the side effects of levodopa.

The second five-year period of treatment tends to be more problematic as PD can come to affect virtually all body systems, necessitating more frequent visits to the doctor. In this period, small changes of medication and symptomatic treatment for such things as constipation, blood pressure drops, and other symptoms are the main therapeutic maneuvers. I call this "micromanagement."

In the third five-year segment in the life of a Parkinson's patient, there is often significant risk of falls with injuries. Injuries such as fractured hips can take the patient to a new low level of disability. Another common complication of this period is difficulty swallowing with aspiration and recurrent pneumonias. The insertion of a gastric feeding tube through the abdominal wall can decrease the risk of aspiration and ensure a way to give the PD patient medication, adequate hydration and nutrition. This procedure is no longer considered a "heroic measure" by most physicians treating PD.

This period is also a time when delusions, confusion and hallucinations are common. We have had considerable luck in using some of the newer neuroleptic medications such as Seroquel. These can often suppress the psychotic symptoms without aggravating the Parkinson's disease.

These mental changes, as well as incontinence and immobility often lead to placement in long-term care facilities. Home care is generally a better option than placement, but it is extremely taxing on the caregiver and is often more expensive.

At this time, we are entering a period when there will be frequent placements of deep brain stimulators in PD patients. This is similar to a cardiac pacemaker, but the electrodes are placed deep in brain structures such as the globus pallidus and subthalamic nucleus. These can be placed on one or both sides and the response can, on occasion, be nothing short of amazing. Dr. Ajay Ananda and I are developing a deep brain stimulation (DBS) program here at Cedars-Sinai.

The deep brain stimulator is not something for all PD patients. The best patients for this treatment option are ones who are relatively young and free of other medical problems, and who still respond well to levodopa, albeit briefly. Patients with significant dyskinesia are often dramatically helped by DBS. In addition, the patient should be emotionally balanced as there is some evidence that DBS can occasionally cause psychological problems such as depression, mania, and apathy. The placement of the electrodes also can occasionally cause bleeding and strokes, and after the placement, it is often time consuming to achieve the proper electrical settings. The stimulator can be turned on and off by the patient. Many Parkinson's patients will turn off the stimulator when they sleep to preserve battery function.

Another treatment in the early stage of development is the use of neuro-stem cells, either from fetal stem cells grown in the laboratory or from the patient's own stem cells, which can be derived from various tissue including brain, skin or mucosa. Thus far, patients who have had fetal cells implanted in the brain have not done all that well and there is a current moratorium on this procedure.

In my opinion, the future of PD therapy will be in two areas. One is in determining persons at risk for developing PD and then applying neuroprotective treatments to "head it off." The second will be replacement therapy (i.e., replacing dopamine-producing cells that survive and rewiring the intricate motor control systems in the brain). Stem cell research should come to the forefront over the next 10 to 20 years.

There is some exciting research going on in PD, both in the area of genetics and in neurochemistry. An increasing number of gene defects have been identified that are associated with familial PD. The role of genetics in typical idiopathic PD, however, is still somewhat controversial.

In the realm of neurochemistry, pathologists have known for years that brain cells in PD patients contain red circular bodies called Lewy bodies. Techniques are being developed to analyze and define the composition of these curious cellular structures. It is hoped that learning the chemical make-up of these structures will lead to further understanding of the cause of PD.

Because of the rapidly changing developments in this disease, I would recommend that PD patients be at least in part managed by a neurologist with an expertise in movement disorders. Cedars-Sinai Medical Center is an American Parkinson's Disease Association Information and Referral Center. The Parkinson's Center is staffed by Dr. Stefan Pulst and myself along with our social worker, Linda O'Connor, and our nurse, Cathy Tucker. Information concerning the Cedars-Sinai Parkinson's Center can be obtained by calling Ms. Tucker at (310) 423-0934 or Ms. O'Connor at (310) 423-1065. The center is prepared to evaluate and treat patients with Parkinson's disease or related conditions. Patients can be followed there or simply to get second opinions at this center.

As you can see, things are changing rapidly in the treatment of PD. We at the Parkinson's Center would be happy to assist patients and families in any way that we can.