This work by Mark Stacy, M.D. and H. James Brownlee, M.D. is a study of "Novel Treatments in Parkinson's Disease". I have permission from Dr. Stacy to reproduce this work here. This work consists of one message. The message, contains the text of "Recognition and Treatment of Early Parkinson's Disease and Other Tremor Disorders". The last part of this message is an uuencoded gif file that contains a diagram composed by Dr. Stacy to illustrate the text. In order to view the diagram, use the Article/extract function of your news reader to turn the message in to a file called TOPD.GIF. Once this is done, you can view the gif with any gif viewer and print it, if you desire. If your newsreader does not support undecoding, a program is available in the public domain called uudecode.exe which will work also. FOCUS: This work is focused toward bringing the partners of your Parkinson's Quest more together, getting everyone on the same page, so to speak. If your family doctor isn't too familiar with your conditions, copy this for them. International members, this is the state of the art from this side of the Atlantic and Pacific oceans. Recognition and Treatment of Early Parkinson's Disease and Other Tremor Disorders By *Mark Stacy. M.D., and #H. James Brownlee, M.D. *Assistant Professor, Division of Neurology, University of Missouri, Columbia, MO and #Professor and Chairman, Department of Family Medicine, University of South Florida, Tampa, FL Word Count: 2200 Abstract: Proper treatment of tremor in any clinical selling is dependent on correct diagnosis. Essential or familial tremor (ET) is symptomatic with movement, and involves the limbs, head and voice. Parkinson's disease (PD) tremor occurs at rest, involves the jaw and limbs, and is associated with bradykinesia, rigidity and falling. Beta--blockers or primidone are used to treat ET, and if no improvement is seen, botulinum toxin injection may be useful. PD is treated with a number of medications, but levodopa is considered most effective. However, the treatment of the early patient may involve levodopa sparing strategies and neuroprotective therapies, and will differ from the more advanced patient. In the moderate patient, polypharmacy is often necessary to minimize or avoid drug side effects. An algorithm addressing these variables is presented in this manuscript. Content Sentence: This paper approaches the diagnosis of tremor disorders (Essential tremor, Parkinson's disease and others) from a clinical perspective. Treatment is outlined in respect to algorithms designed to maximize patient benefit. Abstract: Proper treatment of tremor in any clinical selling is dependent on correct diagnosis. Essential or familial tremor (ET) is symptomatic with movement, and involves the limbs, head and voice. Parkinson's disease (PD) tremor occurs at rest, involves the jaw and limbs, and is associated with bradykinesia, rigidity and falling. Beta--blockers or primidone are used to treat ET, and if no improvement is seen, botulinum toxin injection may be useful. PD is treated with a number of medications, but levodopa is considered most effective. However, the treatment of the early patient may involve levodopa sparing strategies and neuroprotective therapies, and will differ from the more advanced patient. In the moderate patient, polypharmacy is often necessary to minimize or avoid drug side effects. An algorithm addressing these variables is presented in this manuscript. Content Sentence: This paper approaches the diagnosis of tremor disorders (Essential tremor, Parkinson's disease and others) from a clinical perspective. Treatment is outlined in respect to algorithms designed to maximize patient benefit. Introduction: Recognition and treatment of tremor disorders is an important and gratifying component to any clinician's practice. In a managed care setting, the role of the Family Physician in treating these potentially disabling symptoms will become increasingly prominent. Recently, a group of investigators met to develop some consensus in the approach to treating patients with Parkinson's disease (PD), and an algorithm was generated in an effort to improve treatment of this condition [1]. The most common causes of tremor include Essential or Familial Tremor, Parkinson's Disease, and those associated with Cerebellar Disorders. [Figure1] These conditions are characterized by tremor location, frequency, amplitude, type of movement (e.g. pronation-supination or flexion-extension), and activity of occurrence (such as at rest or with movement). Other causes of tremor are drug-induced, dystonic, post-traumatic and exaggerated physiologic tremors. Common medications reported to produce tremor include: corticosteroids, Beta-agonists, theophylline, caffeine, thyroid hormone, valproic acid, lithium, and some tricyclic antidepressants. Essential or Familial Tremor (ET) ET is an autosomal dominant disorder occurring in approximately 5 percent of the population [2]. The tremor occurs with movement and may produce difficulty holding the newspaper, writing or eating. ET is usually characterized by head, voice, trunk and leg tremor, but is not associated with tremor of the tongue, chin, or face. The arm tremor is most often symmetric, flexion-extension in nature, and has a frequency of 8 - 10 Hz. The tremor is also seen when the arms are held in an extended posture or with finger-to-nose maneuvers, but absent at rest. Treatment of ET in younger patients with no history of asthma, smoking, diabetes, bradycardia, hypotension. or congestive heart failure, is best achieved with propranolol (or other Beta-blocker) 60 - 80 mg per day [3]. In older patients primidone 25 mg at bedtime is initiated, and titrated to tremor improvement up to 150 mg a day. All patients should be cautioned about the risk of depression with these drugs. Primidone incurs the additional risk of confusion, urinary retention, and memory difficulties [4] If neither drug produces improvement, combination therapy is sometimes effective. Benzodiazepines (clonazepam 0.5 - 1.0 mg bid or lorazepam 0.5 - 1.0 mg on a pm basis) are also useful in some patients [5]. In addition, one alcoholic beverage may reduce tremor for several hours, but may cause a "rebound" tremor with withdrawal [6]. If a patient is unable to take medication for tremor, wrist weights during eating may dampen the tremor amplitude Finally, botulinum toxin type-A (BOTOX), a paralytic protein injected directly into the muscle may produce satisfactory improvement of tremor for 3-5 months [7]. Cerebellar Tremor Cerebellar or action (intention) tremor, differs in presentation and neurologic findings from ET or PD. Patients exhibit "cerebellar signs" of dysanthria, incoordination and walking difficulty. The tremor is higher in amplitude, and involves more proximal muscles of the limb. On examination a past-pointing type oscillation is seen with finger-to-nose testing. Treatment with primidone, Beta-blockers, benzodiazepines, or acetazolamide is occasionally beneficial. Injection with botulinum toxin is sometimes helpful. Parkinson's Disease In contrast to the head and limb tremor of ET, PD tremor occurs at rest, involves the face, tongue, and limbs, and is often asymmetric. It is usually 5-7 Hz in frequency, and pronating-supinating in the forearms with "pill rolling" in the hands. The tremor of PD is associated with bradykinesia (slow movement), postural instability, and rigidity [8]. Patients may report nightmares, depression, excessive salivation, difficulty turning over in bed, buttoning buttons or cutting food, and problems with walking. Other features of PD include autonomic difficulties such as orthostatic hypotensi0n, constipation, micrographia, hypophonia, urinary incontinence, and impotence. Pharmacological intervention in PD is dependent on the severity of patient symptoms and preferences of the treating physician. However, if a patient is only bothered by tremor of the non-dominant hand, both the patient and physician may be comfortable avoiding medications. It is important to stress an exercise program in all PD patients. Protein intake interferes with levodopa absorption in only a small percentage of PD patients, and in these patients diet alteration must be pursued. Educational materials are readily available from the four PD organizations: the American Parkinson's Disease Association (APDA), National Parkinson's Disease Foundation (NPF), Parkinson's Disease Foundation (PDF) or United Parkinson's Foundation (UPF). In most communities one of these organizations is easily accessible. Finally, support groups offer an opportunity to learn of coping strategies beneficial to patients. However, in the early patient these strategies are usually not necessary, and occasionally, observation of patients with advanced disease is not helpful to the newly diagnosed PD patient. COGNITIVE IMPAIRMENT: Treatment of PD can be extremely complicated [Figure 2], but with a systematic approach, most patients will benefit. In the patient with dementia, dopaminergic medications are more likely to produce hallucinations or psychosis, as well as symptoms of toxic delirium (agitation, confusion, and worsening of PD symptoms) [10-12]. Thus, it is best avoid amantadine, selegiline, and dopamine agonists, and conservative use of levodopa is recommended. Before 1990, the development of hallucinations. agitation and psychosis were treated by reducing levodopa. The use of anti-psychotic drugs are contraindicated because of dramatic, often prolonged worsening of symptoms of parkinsonism. However, in some instances, low doses of low- potency neuroleptic drugs are appropriate, and molindone (Moban) or mesoridizine (Serentil) are suggested; if these drugs worsen symptoms of PD, clozapine may be used although weekly lab monitoring is initially time- consuming [13]. FUNCTIONAL IMPAIRMENT WITH COGNITIVE IMPAIRMENT: Treatment of PD is based on restoring the dopaminergic (DA) function lost with substantia nigra cell drop-out in the extrapyramidal pathway. [Figure 3] Because levodopa is the most effective symptomatic medication in PD, conservative use of this amino acid maximizes the potential for treatment benefit, while the potential for delirium or psychosis remains less than with other drugs used individually or in combination. Levodopa is metabolized to dopamine in the blood-stream (peripherally) and the brain (centrally). Because "peripheral" dopamine often causes nausea, vomiting, and orthostatic hypotension, it is combined with carbidopa, a peripheral dopa-decarboxylase inhibitor. A minimum of 75 mg per day of carbidopa is suggested to inhibit levodopa metabolism outside the blood-brain barrier [14]. Individualization of anti-PD therapy requires a thorough understanding of patient response to each dose of levodopa (e.g. when does a patient "kick-in," develop dyskinesias, and "turn-off" in relation to each carbidopa/levodopa) [15]. [Table 1] Patients treated with immediate-release carbidopa/levodopa often will notice an improvement of symptoms within 30 minutes of dosing, and experience improved mobility for 2 to 4 hours before requiring a second dose. Patients treated with controlled release carbidopa/levodopa (Sinemet CR) usually require less frequent dosing (5 hour intervals), but the "kick-in" time associated with the CR preparation may be delayed [16]. This is easily overcome by adding one-half to one immediate-release carbidopa/levodopa 25/100 with the first controlled- release dose in the morning. The prolonged therapeutic benefit from CR carbidopa/levodopa is advantageous as patients develop end-of-dose "wearing-off" in more advanced stages of PD [17]. The CR preparation can be adjusted by increasing the dose per interval or the interval may be shortened without changing the dose. Carbidopa/levodopa 10/100 should be reserved for patients with advanced motor fluctuations not responding well to the CR preparation. Furthermore, the development of hallucinations on Sinemet CR, should be treated by dosage reduction, especially in the evening, and conversion to the immediate release 25/100 or 10/100 preparations. NEUROPROTECTION: The most vigorously debated clinical and pathological question in Parkinson's disease for the past 30 years has centered on the pathogenesis of PD and whether levodopa hastens disease progression [18,19]. In the late 1980's investigators reported slowing the rate of patient decline with selegiline, a monoamine oxidase-B (MAO-B) inhibitor [20]. In 1989 the preliminary analysis of the Deprenyl and Tocopherol Antioxidative Trial of Parkinson's Disease (DATATOP), a randomized, placebo-controlled evaluation of 800 patients, concluded that selegiline 10 mg per day significantly delayed the progression of disability in PD [21]. Although these findings have met with controversy, the DATATOP investigators and others now report that selegiline will delay the need for levodopa for almost nine months, but were unable to determine whether the benefit was from symptomatic or "neuroprotective" response [22-25]. However, selegiline has been shown to delay the use of levodopa in the early patient, and when used with levodopa, may reduce the total levodopa requirements. In addition, one retrospective autopsy study has reported fewer Lewy bodies (the pathologic hallmark of PD) in patients treated with selegiline when compared to those not receiving this drug [26]. Side effects are infrequent with selegiline, but include insomnia, lightheadedness, nausea, skin rash, headache, and constipation. The importance of "levodopa sparing" strategies in PD has not been adequately determined, and often leads to confusion for both the clinician and patient. Currently, selegiline is the only MAO-B inhibitor available in this country, but lazabemide, may be available in the near future [27]. The use of selegiline as a neuroprotective agent in PD is a decision best decided jointly by a patient and a physician. It is important to consider the age, lifestyle, disability and resources of the patient when considering this therapy. FUNCTIONAL IMPAIRMENT WITHOUT COGNITIVE IMPAIRMENT: An arbitrary age cut-off of 60 years has been suggested, but duration of symptoms, and relative activity of the individual patient may be more important. In the mildly symptomatic or tremor-dominant patient, levodopa-sparing strategies may be used. [Table 2) This treatment rationale is based on clinical and scientific data suggesting that both endogenous and exogenous dopamine hastens the progression of symptoms in this disease. However, the potential long range benefit of prolonged mobility must be carefully weighed against the potential loss of function in the short term (e.g. can the patient continue to work if not treated with levodopa). The tremor dominant patient may respond dramatically to anticholinergic medications (e.g. trihexyphenidyl 2-12 mg per day), but most patients report benefit for only three to four months [1]. These drugs are believed to restore an "imbalance" between reduced dopamine and uninhibited cholinergic interneurons in the striatum [Figure 3]. The exact mechanism of tremor suppression is unknown, but recent data suggests these cells discharge rhythmically at 2-10 Hz, and anticholinergic drugs may alter the delay of firing associated with nigrostriatal destruction [28]. Amitriptyline is another anticholinergic drug useful in PD, especially in patients with sleep difficulty and excessive salivation. Side effects of the anticholinergics include dry mouth, urinary retention, constipation, visual problems, confusion and psychosis [29]. Amantadine (100 mg; 1-4 tablets per day) is a highly effective drug that can be used in monotherapy, or as an adjunctive medication, particularly when patients report wearing-off difficulties or problems sleeping [30]. Although its mechanism of action is unknown, it does act on both presynaptic and postsynaptic dopamine receptors, and has some anticholinergic properties. Side effects are similar to the anticholinergic drugs, and also include ankle edema and livedo reticularis [1]. There are only two dopamine agonists currently available in this country. Pergolide and bromocriptine act at the post-synaptic membrane and both have been shown to be useful in conjunction with levodopa. Bromocriptine (at 10 - 20 mg per day) is a potent D2 dopamine agonist, while pergolide, a Dl and D2 agonist, may be used as a monotherapeutic agent at I - 4 mg per day [31,32]. Cabergoline is a D2 dopamine agonist currently in clinical trial in this country, and may soon be available [33]. Side effects are more common in this class of anti-PD drugs and include: confusion, hallucinations, orthostatic hypotension, nausea, and depression. Long term therapy is associated with shortness of breath secondary to pulmonary fibrosis. Erythromelalgia, headache and back pain are also reported [1]. The remainder of this PD algorithm is an attempt to catalogue symptoms commonly seen in patients with advancing disease. Although some of these symptoms are resistant to any treatment, in most cases viable therapeutic options exist. Recognition of the head and postural tremor of ET and the chin and resting tremor of PD is necessary to produce symptomatic benefit in patients with these problems. Conclusion: Treatment of the early patient with either of these conditions is often quite gratifying, because of the tangible improvement patients achieve in their daily routines. However, if a patient does not respond adequately to these initial treatment algorithms, or these treatments become less effective, referral to a Neurologist or Movement Disorders Center may be beneficial. References: 1. Pahwa R, KolIer WC. A rational polypharmacy approach to Parkinson's disease. Int Med 1994;15:53-64. 2. Findley LJ. Tremor: Differential diagnosis and pharmacology. In: Jankovic J, Tolosa E, eds. Parkinson's disease and movement disorders. Baltimore: Williams and Wilkens, pp. 293-314, 1993. 3. Koller WC. Dose-response relationship of essential tremor. Arch Neurol 1986;43:42-3. 4. Findley LJ, Cleeves L, Calzett S. Primidone in essential tremor of the hands and head. J Neurol Neurosurg Psychiatry 1985;48:911-5. 5. Heilman KM. Orthostatic tremor. Arch Neurol 1984;41:880-1. 6. Koller WC, Biary N. Effect of alcohol on tremors. Neurology 1984;34:221-2. 7. Jankovic J, Schwartz K. Botulinum toxin in the treatment of tremors. Neurology 1991;41:1185-B8. 8. Stacy M, Jankovic J. Differential diagnosis of Parkinson's disease and the parkinsonism-plus syndromes. Neurol Clin 1992;10:341-59. 9. Stacy M, Jankovic J. Advances in the treatment of Parkinson's disease. Ann Rev Med 1993;44:431-40. 10. Mayeux R, Mirabello E, Marder K, et al. An estimate of the incidence of dementia in idiopathic Parkinson's disease patients. Neurology 1990;40:1513-7. 11. Biggins CA, Boyd JL, Harrop FA, et al. A controlled, longitudinal study of dementia in Parkinson's disease. J Neurol Neurosurg Psychiatry 1992:55;566-72 12. Saint-Cyr JA, Taylor AE, Lang AE. Neuropsychological and psychiatric side effects in treatment of Parkinson's disease. Neurology 1993(suppl 43):547-52. 13. Friedman JH, Lannon MC. Clozapine in the treatment of psychosis of Parkinson's disease. Neurology 1989;39:1 219-21. 14. Calne DB. Treatment of Parkinson's disease. N Eng J Med 1993;329:1021-7. 15. Nun JG. Levodopa-induced dyskinesia: review, observations, and speculations. Neurology 1989;40:340-5. 16. Markham CH, Diamond SG. Evidence to support early levodopa therapy in Parkinson's disease. Neurology 1981;31:125-31. 19. Rajput AN, Rozdilsku B, Rajput A. Levodopa efficacy and pathological basis of parkinson syndrome. Clin Neuropharm 1990;13:553-58. 20. Tetrud JW, Langston JW. The effect of deprenyl (selegiline) on the natural history of Parkinson's disease. Science 1989;245:519-22. 21. The Parkinson study group. Effect of deprenyl on the progression of disability in early Parkinson's disease. N Eng J Med 1989;321:1364-71. 22. The Parkinson study group. Effects of tocopherol deprenyl on the progression of disability in early Parkinson's disease. N Eng J Med 1993;328:176-83. 23. Landau WM. Clinical neuromythology IX. Pyramid sale in a bucket shop. DATATOP bottoms out. Neurology 199Q;40:1337-9. 24. Myllyla VV, Sotaniemi KA, Vuorinen JA. Selegiline as initial treatment in de novo Parkinson's disease patients. Neurology 1992;42:339-43. 25. Schulzer M, Mak E, Calne DB. The antiparkinson efficacy of deprenyl derives from transient improvement is likely to be symptomatic. Ann Neurol 1992;32:795-98 26. Rinne JO. Nigral degeneration in Parkinson's disease in relation to clinical features. Acta Neurol Scand 1991;316(suppl):87-90. 27. Lewitt PA, Segel SA, Mistura KL, Schork MA. Symptomatic anti- parkinsonian effects of monoamine oxidase-B inhibition: comparison of selegiline and lazabemide. Clin Neuropharm 1993;16:332-337. 28. Graybiel AM, Aosaki T, Flaherty AW, Kimura M. The basal ganglia and adaptive motor control. Science 1994;265:1826-31. 29. Fitzgerald PM, Jankovic J. Nondopaminergic therapy in Parkinson's disease. In: Koller WC, Paulson G, eds. Therapy of Parkinson's disease. New York: Marcel Dekker, pp. 369-97, 1990. 30. Jankovic J, Marsden CD. Therapeutic strategies in Parkinson's disease. In: Jankovic J, Tolosa E, eds. Parkinson's disease and Movement Disorders. Baltimore: Williams and Wilkens, pp. 115-37, 1993. 31. Nakanishi T, Mizuno Y, Goto I, et al. A nationwide collaborative study on the long-term effects of bromocriptine in patients with Parkinson's disease. Eur Neurol 1991;31:3-16. 32. Olanow CW, Fahn S, Muenter M, et al. A multicenter double-blind placebo-controlled trial of pergolide as an adjunct to sinemet in Parkinson's disease. Mov Disord 1994;9:40-7. 33. Jori MC, Franceschi MC, Giusti MC, et al. Clinical experience with cabergoline, a new ergoline derivative, in the treatment of Parkinson's disease. Adv Neurol 1990;53:539-44. TABLE I Treatment of Parkinson's Disease Immediate-release carbidopa/levodopa Medication: Indications Dosage 25/100 Early to Advanced 2-10 per day 25/250 Moderate to Advanced 2-10 per day 10/100 Advanced As needed Side effects: nausea, hypotension Controlled-release carbidopa/levodopa hallucinations Medication: Indications Dosage dyskinesias CR 25/100 Early to Advanced 1 qd - 2 tid CR 50/200 most useful with at 5 hour motor fluctuations intervals TABLE 2 ADJUNCTIVE TREATMENT OF PARKINSON'S DISEASE Medication: Indications Dosage Side Effects Amantadine Night time myoclonus 100 mg hallucinations, dry freezing/dystonia 3-4/d mouth, 5% insomnia Amitriptyline Early morning dystonia 20-50 mg at HS early morning (e.g. foot cramping) lethargy, dry mouth, hallucinations Baclofen useful for levodopa- 10 - 20 mg with sleepiness related dystonia levodopa dose Bromocriptine improvement of 2.5-30 mg'd somnolence, PD symptoms back pain, hallucinations, reduction in levodopa confusion Lorazepam anxiety 1-3 mg'd sieepiness,confusion Pergolide see bromocriptine 1-3 mg'd see bromocriptine Selegiline ? protective 5 mg ' 7-12 insomnia may improve PD symptoms may allow 10-30% reduction in levodopa Clozapine hallucinations, 6.25 - 200 mg'd fatal neutropenia psychosis CBC checked weekly Legends: Figure 1: There are 3 major types of tremor subtypes in clinical practice; essential tremor (ET), Parkinson's disease (PD) tremor and cerebellar tremor. In addition, drug-induced tremor has features of both PD and ET. Correct recognition of these tremors increases the likelihood of therapeutic response to the options listed in this algorithm. Figure 2: This algorithm is an attempt to organize the extremely complicated decisions involved in treating the Parkinson's disease (PD) patient. The Early PD patient may be treated with emphasis on function and relief of disabling symptoms. Treatment of the advanced patient is concerned with recognition of later manifestations of the disease and palliation of drug- related side effects. Figure 3: This diagrammatic representation of the substantia nigra and the striatum is a highly theoretical model of the sites of action for medications used in the treatment of Parkinson's disease. LEVEDOPA, metabolized to dopamine, increases the concentration of this neurotransmitter in the brain, and is taken up by the nigrostriatal neuron. AMANTADINE enhances the release of dopamine in the striatum, and has some anticholinergic effects. TRIHEXYPHENIDYL and AMITRIPTYLINE also act on the acetylcholine interneuron. SELEGILINE indirectly increases dopamine concentration in the synapse, by reducing the rate of dopamine metabolism in glial and neuronal cells. DOPAMINE AGONISTS such as PERGOLIDE or BROMOCRIPTINE improve dopaminergic tone by acting at the post-synaptic membrane. BACLOFEN alters GABA-ergic tone in the striatum, pallidum, subthalamic nucleus, thalamus and spinal cord. Table 1; There are 5 different formulations of carbidopa/levodopa. Of the traditional preparations 25/100 should be the initial therapy (one-half tablet daily for one week, then bid for one yveek. then tid for one week, and then one tablet tid). If subtherapeutic response develops, the 25/250 preparation may be used. The 10/100 should be saved for only the most advanced patient. Controlled release carbidopa/levodopa may be started at one tablet every morning for one week, then one tablet bid. If the patient develops difficulty toward the end of the day. a third tablet can be added. Table 2: These medications may be used as adjunctive or primary therapies in Parkinson's disease. Biographic Sketch Dr. Mark Stacy obtained his medical degree at the University of Missouri, and completed his Neurology training at Hahnemann University in Philadelphia. After completing a fellowship at Baylor College of Medicine in Houston, he returned to his alma mater, where he is currently an assistant professor of Neurology. His wife is also a faculty member in the Department of Electrical Engineering, and they have two children. Dr. H. James Brownlee obtained his medical degree at the Health Sciences Center - Syracuse, and completed his Family Practice Residency training at the Williamsport Hospital in Williamsport, Pennsylvania. After completing a faculty development fellowship at the University of Miami, Dr. Brownlee spent three years as a faculty member at the Carswell AFB Regional Hospital Family Practice Residency Program. Dr. Brownlee joined the faculty of the University of South Florida College of Medicine in 1983, completed a part-time Geriatric Fellowship in 1987, and served as Residency Director at Bayfront Medical Center until 1994. He was recently named Chairman of the Department of Family Practice University of South Florida College of Medicine. 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