Advances In The Treatment Of Parkinson's Disease

Jill Marjama-Lyons, M.D.
Jill Marjama-Lyons, M.D. is an Assistant Professor Department of Neurology,
Shands Jacksonville and Director of The Parkinson and Movement Disorder Center.

Historical Perspective

Since James Parkinson's publication on The Shaking Palsy in 1817, the treatment of Parkinson's disease has undergone several transformations. Over a century elapsed devoid of any effective treatments for this devastating disease and Parkinson's disease was considered to be a terminal illness. In the 1940's and 1950's neurosurgical treatments of Parkinson's disease emerged. Neurosurgery of the basal ganglia was performed as early as 1939 by Meyers with notable improvement in the motor symptoms of Parkinson's disease, but with a high mortality rate of 12%.1 The development of the stereotactic frame in 1947 allowed for more precise lesioning of the brain and over tens of thousands of thalamotomies and pallidotomies were performed in Europe and the United States for the treatment of Parkinson's disease.2,3

Pharmacotherapy during the 1940's and 1950's consisted primarily of the use of amantadine and cogentin.4,5 These drugs reduced the motor symptoms of Parkinson's disease, but were clearly less efficacious as the disease progressed. The 1967 discovery of levodopa by Cotzias revolutionized the treatment of Parkinson's disease.6 The dramatic improvement in the motor symptoms of Parkinson's disease with carbidopa/levodopa (Sinemet®) gave birth to the levodopa era and a near complete halt to the neuro-surgical treatments of the prior two decades. Introduction of the dopamine agonists, bromocriptine (Parlodel®) and pergolide (Permax®) occurred in the 1970's. The dopamine agonists were clearly beneficial in reducing tremor, rigidity and bradykinesia, but were less efficacious and had a greater side effect profile than carbidopa/levodopa and were primarily were used as adjunctive therapy to carbidopa/levodopa.7,8 The addition of selegiline and controlled release carbidopa/levodopa (Sinemet CR®) in the early 1990's had minimal impact on clinical treatment of Parkinson's disease.

Today, levodopa remains the gold standard for the treatment of Parkinson's disease. However, long-term use of levodopa over 5 to 10 years is often associated with the development of motor complications in as high as 80% of Parkinson patients.9,10,11 These include wearing off of the levodopa dose prior to taking the next dose(requiring frequent dosing of the medication sometimes as often as every 1 to 2 hours throughout the day), dose failures, rapid changes in motor symptoms so called "on/off" phenomena, and disabling dyskinesias (involuntary chorea and dystonia).

The limitations of long-term levodopa therapy has led to the study and development of alternative and adjunctive medications for the treatment of Parkinson's disease. In the last two years, four new medications have been FDA approved and are currently available for the treatment of Parkinson's patients. These include two dopamine agonists, pramipexole (Mirapex®) and ropinerole (Requip®) and two comt (catecholamine-o-methyl transferase) inhibitors, tolcapone (Tasmar®) and entacapone (Comtan®). A brief description and potential uses of these medications will be described below.

In addition to the development of new medications, a renewed interest in the neurosurgical treatment of Parkinson's disease has emerged in the last decade. An understanding of the neuroanatomy and physiology of the basal ganglia coupled with recent advances in the technology of stereotactic surgery has led to effective neurosurgical procedures for Parkinson's disease. Some of these techniques will be discussed later in this article.

New Medications For Parkinson's Disease

Dopamine Agonists

The role of dopamine agonists as solely adjunctive medications to levodopa is changing. Recent studies of the new dopamine agonists clearly demonstrate they are effective in reducing the motor symptoms (tremor, rigidity, bradykinesia) of Parkinson's disease as monotherapy as well as when added to levodopa.12,13 Off time decreases by 30% to56%, less on/off fluctuations occur and a recent 5 year study showed a markedly lower incidence of dyskinesia in the patients on monotherapy ropinerole of 5% when compared to the monotherapy levodopa rate of 46%.14 Similar data has been reported in MPTP-treated monkeys for bromocriptine and ropinerole.15, 16 There is also evidence that dopamine agonists may be neuroprotective of dopaminergic neurons.17-20 Taken together, these findings support the use of dopamine agonists as monotherapy in newly diagnosed, early and mild to moderate Parkinson's disease and adding levodopa therapy when the patients motor symptoms are not adequately controlled by dopamine agonists alone or intolerable side effects develop.

Four dopamine agonists are available in the United States and include bromocriptine, pergolide, mirapex and ropinerole. The new, second generation agonists, mirapex andropinerole are structurally more similar to the dopamine molecule, lack the ergot structure of the first generation agonists, are potent D-2 agonists similar to pergolide, and have little or no binding to alpha, beta, and serotonin receptors. Despite these differences, no one dopamine agonist has been shown to be superior to another in the treatment of the motor symptoms of Parkinson's disease.21,22 They all may produce similar side effects of nausea/vomiting, light headedness, orthostasis, peripheral edema, sedation and confusion/hallucinations. The ergot agonists have rarely been reported to cause retroperitoneal and pulmonary fibrosis, erythromelalgia and Raynaud's like syndrome.23 In the authors experience ropinerole has a lower CNS side effect profile and maybe a more appropriate agonist for an elderly Parkinson's patient with preexisting confusion or dementia. Recent reports in the literature have implicated sudden sleep attacks in Parkinson's patients taking mirapex and in only one patient taking ropinerole with some of these attacks occurring while the patient was driving.24

Given all of the above factors, it may be difficult to decide which dopamine agonist to use in a Parkinson's patient. Some general rules to consider are outlined below:

  1. Use only one dopamine agonist at a time as monotherapy or adjunctive to levodopa;
  2. Begin with the lowest dose (bromocriptine 2.5mg, pergolide 0.05mg, mirapex 0.125mg, ropinerole 0.25mg);
  3. Always dose three times daily evenly spaced throughout the day;
  4. Slowly titrate the dosage by doubling the lowest dose no faster than every 1-2 weeks until an intolerable side effect occurs or clinical benefit is achieved. Be aware of the potency differences among the different agonists ( pergolide and mirapex are roughly equivalent; for example 0.5mg of pergolide could be substituted for 0.5mg of mirapex, bromocriptine is 1/10 as potent as pergolide and mirapex such that 5mg of bromocriptine could be substituted for 0.5mg of pergolide and mirapex, and ropinerole is more potent than bromocriptine but less than pergolide and mirapex and may need to be given at single doses of 4-6mg to achieve a clinical benefit.
  5. If a patient has preexisting dementia or confusion, consider using ropinerole.

COMT Inhibitors

COMT inhibitors act by inhibiting the enzyme catecholamine-o-methyltransferase which is responsible for metabolizing levodopa to3-O-methyldopa in the peripheral bloodstream. By inhibiting COMT, these drugs result in an increase in the half-life of levodopa and an increase in the bioavailability of levodopa such that a more continuous and greater amount of levodopa crosses the blood brain barrier to act directly on dopaminergic neurons. Tolcapone was released in March of 1998 and Entacapone was just released in November of 1999. Both result in a decrease in the "off" time by 1 to 3 hours per day, a decrease in motor fluctuations and allowed for a reduction in the total levodopa daily dose by 10 to 30%.25-28 COMT inhibitors are indicated for use as adjunctive therapy to levodopa in Parkinson's disease patients who experience wearing "off" and motor fluctuations.

Both drugs may cause levodopa side effects of dyskinesias, nausea, confusion and sedation that are easily controlled by lowering the levodopa dose. Non levodopa side effects include diarrhea (3 to 4%) and urine discoloration. Tolcapone results in an increase in liver enzymes in only 1 to 3% of patients. Three cases of fatal liver failure out of 60,000 patient years have been reported with the use of tolcapone and the FDA has mandated that patients on tolcapone have frequent liver function testing.29 Patients taking tolcapone must have their liver function checked every 2 weeks for the first year, followed by one a month for the next 6 months and then every 2 months there-after. No cases of elevated liver enzymes or hepatotoxicity have been reported with entacapone to date.

Dosing of the COMT inhibitors varies between the two drugs. Tolcapone should be started at 100 mg three times a day separated by 6 to 8 hours and if no significant benefit is noted by 2 to 3 weeks one should either discontinue the drug or consider increasing the dosage to 200 mg t.i.d. If however at the higher dosage no significant clinical improvement is observed the drug should be stopped. Entacapone comes only in 200 mg pills and it is recommended that the patient take one pill each time they take levodopa up to a maximum of 8 total pills per day. As with tolcapone if no clinical benefit is noted one should consider stopping the drug. Due to the relatively little time entacapone has been available it is difficult to comment on it's true clinical impact on the treatment of Parkinson's disease. Tolcapone, on the other hand, has been used worldwide for over a year and a half and in the author's personal experience, it is clearly miraculous in a select group of patients suffering from motor fluctuations. Three patients I personally treated had such severe motor fluctuations that all three were candidates for neurosurgical treatments and all three dramatically improved with the addition of tolcapone such that we were able to lower their levodopa doses and avoid pursuing neurosurgical therapies.

Neurosurgical Procedures

A greater understanding of the neuroanatomy and physiology of the basal ganglia coupled with recent advances in the technology of stereotactic surgery has led to effective and safer neurosurgical procedures for Parkinson's disease. These include tissue transplants (human and porcein fetal midbrain), direct lesioning of the brain (pallidotomy, thalamotomy) and placement of an electrode deep into the brain and then stimulating the brain with high frequencies (deep brain stimulation). Due to the limited scope of this article, a description of the most effective and widely used procedures of pallidotomy and deep brain stimulation will follow.

Pallidotomy

Pallidotomy involves placing a small lesion into the medial segment of the globus pallidus with thermocoagulation. Despite its long history, patients undergoing pallidotomy have not been studied carefully until recently. Current data suggests that patients may experience a reduction in rigidity, bradykinesia, off time, dyskinesia and tremor up to 50% which may persist between 6 months and 4 years.25-27 Mortality is less than 1%, a significant improvement from the 12% rate of the 1950's. Morbidity occurs in 1 to 8% of patients and may include hemiparesis, visual field defects, depression, hypophonia, dysarthria, and seizures. Bilateral pallidotomy is generally not recommended due to the higher morbidity rate.

Deep Brain Stimulation

Deep brain stimulation involves placing a small quadripolar electrode into the brain at a specific site and then continuously stimulating the brain at frequencies between 100 and 180 hertz. This technique has been applied to the ventral intermediate nucleus (VIM) of the thalamus, the subthalamic nucleus (STN) and the globus pallidus intermedius (GPI). Stimulation of the VIM causes a significant reduction in tremor in 92% of Parkinson's disease patients that persists past 8 years.28 However, VIM stimulation does not result in marked reduction of rigidity or bradykinesia. Recent studies with STN stimulation have reported an 80% reduction in the Unified Parkinson's Disease Rating Scale (UPDRS) tremor score as well as a 65% reduction in rigidity and a 51% reduction in bradykinesia. Similar, although less dramatic, findings occur with deep brain stimulation of the GPI.29-31 Deep brain stimulation when compared to ablative procedures, has a much lower morbidity rate especially with bilateral procedures. Overall morbidity has been estimated at 2% for permanent neurological deficits and minor side effects are often reversible with electrode reprogramming. Current studies comparing pallidotomy to deep brain stimulation are underway in an effort to decide if one of these procedures is more effective in the treatment of Parkinson's disease and which patients seem to benefit most. Deciding to refer a Parkinson's patient for neurosurgical treatment may be a difficult task. Neurosurgery is generally recommended for patients who have severe motor fluctuations, disabling dyskinesia, and are classified as a stage III or higher on the Hoehn and Yahr scale. Evaluation for a neurosurgical procedure should be done at a center with a neurologist who specializes in Parkinson's disease and a neurosurgeon with stereotactic training.

Conclusion

The spectrum of treatments for Parkinson's disease has dramatically changed in the last decade. The advances in pharmacotherapy and neurosurgery afford today's practicing neurologist a greater opportunity to better manage the motor symptoms of Parkinson's patients and allow for a higher quality of daily life in those suffering from this sometimes cruel and unpredictable disease. As we enter the 21st century, future research will undoubtedly lead to more effective treatments and new discoveries in the area of neuroprotective agents and restorative cell transplants (neurostem cells) may eventually lead to a cure for Parkinson's disease.

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Jacksonville Medicine / August, 2000

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