For the 99% of the Parkinsn list who were unable to attend or see the recent APDA "Show and Tell", here is a report on similar remarks by Dr. H. James Brownlee and Dr. Ray L. Watts. This report was in a recent issue of Southern Medical Journal. Update on Movement Disorders "with newer strategies involving early combination therapy using adjunctive agents with L-dopa, we aim for 10 to 15 years of good control." Movement disorders was the subject of a special symposium presented in conjunction with the 88th Annual Scientific Assembly of the Southern Medical Association, held in Orlando, Fla. The topics discussed included the differential diagnosis of parkinsonism; the epidemiology, pathology, and treatment of Parkinson's disease (PD); and the diagnosis and treatment of other movement disorders such as essential tremor and dystonia. Classification of Movement Disorders H. James Brownlee, MD, Chairman and Professor of Family Medicine at the University of South Florida College of Medicine in Tampa, Fl, began by pointing out that movement disorders can be classified as bradykinetic (slowed movement) and hyperkinetic, with parkinsonism identified as a bradykinetic movement disorder. The primary type of parkinsonism is idiopathic PD, while secondary types are infectious, drug-induced, toxin-induced, vascular, metabolic, degenerative, and structural, as shown in Fig 1. --------------------------------------------------------- Figure 1 Classification of Parkinsonism Primary (idiopathic, Lewy body) Secondary (symptomatic) Infectious Drug-induced Toxin-induced Vascular Metabolic Structural Degenerative Progressive supranuclear palsy Multiple-System atrophy Corticonigral degeneration with neuronal achromasia Parkinson-dementia complex of Guam Parkinsonism with amyotrophy Alzheimer's disease ------------------------------------------------------------------- Parkinson's Disease: Epidemiology and Pathology Dr. Brownlee went on to explain that the incidence of PD is highest in persons between the ages of 55 and 70, and that it is uncommon in those younger than 40 years of age. The annual incidence is 20/100,000, with an estimated 500,000 patients with PD in the United States. The primary pathology associated with the disease is a selective loss of dopamine-containing neurons, resulting in a severe loss of dopamine input to the striatum. Other factors are the presence of microscopic lewy bodies and a reduced amount of pigmented tissue in the substantia nigra. A genetic predisposition may also exist, but this has not yet been confirmed. Differential Diagnosis of Parkinson's Disease Using a videotape showing various patients, Dr. Brownlee reviewed the primary clinical features of PD--tremor, rigidity, bradykinesia, and postural reflex impairment-- well as secondary features such as autonomic dysfunction and speech abnormality (Fig 2). ----------------------------------------------------------- Figure 2 Parkinson's Disease: Clinical Features Primary Clinical Features Tremor Resting (subsides with action) Slower frequency Starts unilateral, progresses bilateral Increases with anxiety Rigidity Cogwheel (superimposed tremor) Lead-pipe (no superimposed tremor) Bradykinesia--slowness of movement Difficulty arising from chair Masked facies (looks like depression) Difficulty swallowing Micrographia Reptilian stare Postural reflex impairment (fall) Other Clinical Features Autonomic dysfunction Sexual dysfunction (impotence) Constipation Sweating episodes Orthostatic hypotension Increased salivation Urinary incontinence Speech abnormality Low volume Monotonous voice ----------------------------------------------------------- He noted that a characteristic feature is resting tremor, which differs from an action tremor. The tremor is present at rest and dampened or abolished by postural manipulation. "You've got to observe the patients while they're sitting, but also get involved helping them move, such as getting them on the examining table. Then you'll be able to better diagnose movement disorders," said Dr. Brownlee. "You'll also see the tremor end when they're posturing with their hands or holding onto something such as a coffee cup." As part of his discussion of differential diagnosis, Dr. Brownlee reviewed the need to differentiate symptoms of PD from the dyskinetic movements resulting from prolonged treatment with carbidopa-levodopa (L-dopa). Dyskinesias involve hyperkinetic movements rather than the bradykinetic movements of PD. During a review of the staging scale for PD (Fig 3), Dr. Brownlee mentioned that the unilateral involvement of stage I can be confused with partial asymmetric paralysis resulting from a stroke. Patients with stage II have bilateral disease, with little arm movement when walking. Patients with stage III show mild postural imbalance, but they are able to lead an independent life. By stage IV, patients are unable to perform activities of daily living without help from someone else. Patients with stage V disease are usually rigid and frozen, and exhibit severe postural instability, usually being restricted to bed and chair in a nursing home. Referring to patients in stage IV, Dr. Brownlee stated, "If we as primary care physicians have to get to this point with patients before we can diagnose then we are playing catch-up ball. We need to be diagnosing a lot earlier." In the past, when there were few viable treatments for the disease, an early diagnosis was less important however, he said that this is no longer true due to recent advances in the treatment of neurologic disorders. ----------------------------------------------------------- Figure 3 Staging of Parkinson's Disease Stage I Unilateral involvement Stage II Bilateral involvement, but no postural abnormalities Stage III Bilateral involvement with mild postural imbalance; patient leads an independent life Stage IV Bilateral involvement with postural instability; patient requires substantial help Stage V Severe, fully developed disease, patient is restricted to bed and chair ---------------------------------------------------------- Hohn and Yahr (1967) Parkinson's Disease: Symptomatic Therapy, Neuroprotective Therapy, and Surgical Options Symptomatic therapy, in which the treatment agent is specifically aimed at certain symptoms, was discussed by Ray L. Watts, MD, Chief of the Movement Disorders Center at Emory Medical School in Atlanta,Ga. Physicians should avoid designing a treatment strategy without first questioning their patients about what symptoms are most troubling to them. The degree to which symptoms interfere with function and employability is the guidepost used for determining when to introduce L-dopa, the most potent treatment available for PD. However, the agent does not alter the progressive natural history of the disease and is associated with a number of troublesome side effects such as nausea, confusion, and involuntary movements (dyskinesia). Until recently, physicians treating newly diagnosed patients would immediately start them on L-dopa and proceed to relatively high doses within a few years. "Five years later the patients would be showing signs of involuntary movements, and by 6 or 7 years they might be as disabled from the side effects as from the disease itself," said Dr. Watts. "With newer strategies involving early combination therapy using adjunctive agents with L-dopa, we aim for 10 to 15 years of good control." In patients with mild, early-onset PD who are in their fifties or early sixties, symptoms may be alleviated with one of the older drugs such as amantadine, which increases dopamine release and its anticholinergic properties (Fig 4). Since this agent can induce memory or confusional problems, it is used less commonly in patients in their late sixties or seventies. For those needing a higher rate of improvement, small amounts of L-dopa can be used. Restricting the dose initially is important because patients will need higher doses as the disease progresses. "and more is not always better when you get to the side effects region. So, we use as much as needed, but no more," said Dr. Watts. "We know that most early patients need about 100 mg of L-dopa three times a day to get a dramatic improvement in symptoms," stated Dr. Watts. But over a few years, signs gradually increase of the drug wearing off in between doses. In the past, higher doses of L-dopa were then given, but this resulted in periods of involuntary movements that gradually became unpredictable after about 7 to 8 years. The advent of slow-release L-dopa administered twice daily has helped maintain more stable blood and brain levels of L-dopa, and thus has led to less dyskinesia and on-off fluctuations of PD symptoms. Recently, two new adjunctive drug therapies have been added earlier in the course of therapy selegiline and the dopamine agonists. Selegiline blocks the major metabolic enzyme monoamine oxidase type B (MAO-B) in the brain that normally breaks down dopamine, thus extending dopamine's duration at active brain sites. The addition of selegiline to L-dopa therapy allows physicians to use 20% to 30% less L-dopa than before. In addition to blocking MAO-B, Dr. Watts reported that a large clinical study has shown that selegiline slows the progression of PD by 40% to 50% when used as monotherapy. He added, "1 think the best early strategy for the treatment of PD, both from a practical and long-term planning standpoint, is L-dopa combined with selegiline for the first 3 to 5 years. Two dopamine agonists are currently used to treat PD: bromocriptine and pergolide. Although dopamine agonists act like synthetic dopamine, they are not as potent. However, their long half-life in the 10- to 15-hour range helps provide more stable drug levels in patients with more advanced PD. The biggest shift in strategy in recent years has been to add dopamine agonists once patients are on 400 to 600 mg of L-dopa per day rather than waiting until "on-off" fluctuations become pronounced. Most patients in the 5- to 10-year range of disease will benefit from a combination of L-dopa, selegiline, and a dopamine agonist, according to Dr. Watts. Many of these individuals will be able to keep functioning for over a decade, able to work and remain independent. By keeping the dosage of L-dopa at shout 50% of what was once thought necessary, physicians are now able to avoid the involuntary movements such as dyskinesia that are so debilitating. "The most important message I can leave with you is their strategic application early in treatment," said Dr. Watts. Treatment of Parkinson's Disease: The Future ---------------------------------------------------------- Figure 4 Treatment for Parkinson's Disease Present Treatments Amantadine Carbidopa-levodopa (L-dopa) Combination therapy: L-dopa and selegiline L-dopa, selegiline, and a dopamine agonist (bromocriptine, Pergolide) Future Treatments New dopamine agonists New MAO-B inhibitors COMT inhibitors Neurotropic factors Sterotaxic surgery (pallidotomy) Dopamine cell transplantion ---------------------------------------------------------- Dr. Watts next turned his attention to possible treatment approaches in the future (Fig 4). In addition to the development of new dopamine agonists and MAO-B inhibitors, a new class of compounds looks very promising--the COMT inhibitors, which block another enzyme that breaks down dopamine and thus greatly prolong the effectiveness of L-dopa. Another potential therapeutic area in the treatment of neurodegenerative diseases (including Lou Gehrig's disease and Alzheimer's disease) involves neurotrophic--factors, particularly brain-derived neurotrophic factor. Research is currently underway to determine how to move this complex molecule across the blood-brain barrier so to see if it will help slow disease progression. Another advance in treatment includes stereotaxic surgery (pallidotomy and thalamotomy) in patients with refractory tremor. During stereotaxic surgery, a radiofrequency lesion is created in a part of the brain that has become overactive because of dopamine deficiencies; the lesion may permanently stop the related tremor. Research in animal models and humans has shown that different types of dopamine cells, particularly young brain cells, can be successfully implanted in the brain, where they will make new connections. For example, human fetal mesencephalic tissue transplantation into the striatum of patients with idiopathic PD and MPTP-induced parkinsonism has shown substantial long-term functional improvement in these patients. These investigational techniques offer promise for patients with advanced PD. Diagnosis and Treatment of Other Movement Disorders During the second part of the program, Dr. Brownlee explored other movement disorders such as kinetic/postural (essential), intention, hysterical, drug-induced, and task-specific tremors. Unlike parkinsonism, which is a bradykinetic disorder, these disorders are hyperkinetic disorders. Essential tremor, unlike PD, affects all parts of the body, including the larynx, and is an action tremor that occurs when the individual is moving or holding on to something. The rigidity, bradykinesia, and postural reflex impairment of PD is missing. Essential tremor is lessened under the influence of alcohol. Because this type of tremor does not respond to treatment with L-dopa, differentiating the condition from PD is important. First-line treatment includes propranolol or the anticonvulsant agent primidone in low doses. Dr. Watts then presented an overview of dystonia, a syndrome characterized by involuntary sustained or spasmodic muscle contractions that frequently cause twisting abnormal postures, or repetitive movements. The condition can usually be improved by treatment with injections of botulinum A toxin. He also reviewed tardive dyskinesia, tic disorder, and myoclonus. In closing, Dr. Brownlee pointed out, "In the past, treatments for movement disorders weren't that good, so the question was, 'Is diagnosis all that important?' Now that we have a variety of viable treatments, we have more of a mandate as primary care physicians to correctly diagnose these conditions, since we now can treat them more effectively." The Southern Medical Association acknowledges Allergan and Sandoz Pharmaceuticals Corporation for unrestricted educational grants in support of this symposium. John Cottingham [log in to unmask] OR [log in to unmask]