Table 1. Medications available for Parkinson s disease A.Dopaminergic agents Dopamine precursor : Decarboxylase inhibitor : Dopamine agonists : Catech

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1 Treatment of Parkinson s Disease Joo-Hyuk Im, M.D., Ji Hoon Kang, M.D., Myoung Chong Lee, M.D. Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center Joo-Hyuk Im, M.D. Copyright 2001 by the Korean Neurological Association 315

2 Table 1. Medications available for Parkinson s disease A.Dopaminergic agents Dopamine precursor : Decarboxylase inhibitor : Dopamine agonists : Catechol-O-methyltransferase inhibitors : Dopamine receptor blocker : Monoamine oxidase B inhibitors : Monoamine oxidase A & B inhibitors : B.Non-dopaminergic agents Antimuscarinics : Antihistaminics : Antiglutamatergics : Antidepressants : Antipsychotics : Anti-stress : Anti-orthostasis : Muscle relaxants : Antioxidant vitamins : Mitochondrial enhancer : Adenosine A 2A receptor antagonists Neutrophins : levodopa carbidopa, benserazide bromocriptine, pergolide, ropinirole, pramipexole, cabergoline, lisuride, piribedil, apomorphine entacapone, tolcapone domperidone selegiline, lazabemide, rasagiline tranylcypromine, phenelzine trihexyphenidyl, benztropine, ethopropazine, biperiden, etc. diphenhydramine, orphenadrine amantadine, riluzole, dextromethorphan selective serotonin reuptake inhibitors, tricyclics clozapine, olanzapine, quetiapine benzodiazepines; diazepam, lorazepam, alprazolam fluodrocortisone, midodrine cyclobenzaprine, diazepam, baclofen ascorbate, tocopherol coenzyme Q10 neuroimmunophilins, GDNF Table 2. Dopamine agonists and dopamine receptors Agonist D1 D2 D3 D4 D5 Bromocriptine Lisuride - +++??? Pergolide ? + Cabergoline + +++??? Ropinirole ? Pramipexole ? +=Agonist (low affinity); ++=agonist (medium affinity); +++= agonist (high affinity); ++++=very high affinity; -=antagonist; 0=no affinity;?=unknown 316 J Korean Neurol Assoc / Volume 19 / July, 2001

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6 Table 3. Major fluctuations and dyskinesias as complications of levodopa Fluctuations (offs) Sensory and behavioural offs Dyskinesias wearing off pain peak-dose chorea, ballism and dystonia sudden off akathisia diphasic chorea and dystonia random off depression off dystonia yo-yo-ing anxiety myoclonus episodic failure to respond dysphoria simultaneous dyskinesia and parkinsonism delayed on panic weak response at end of day response varies in relationship to meals sudden transient freezing 320 J Korean Neurol Assoc / Volume 19 / July, 2001

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10 Table 4. Summary of results of surgical treatment for Parkinson s disease Indication Thalamotomy Vim DBS Pallidotomy Gpi DBS STN DBS Brain grafts* Bradykinesia 0 ++~ Tremor Rigidity + ++~ PIGD - 0~+ 0~++ - Freezing Dyskinesia 0~ =deterioration; 0= no improvement; + =mild improvement; ++ =moderate improvement; +++ =marked improvement *Based on a double blind study (Freed CR, et al, 2001), Some patients experienced dyskinesia even without levodopa. Vim; ventrointermediate thalamic nucleus, GPi; internal segment of glubus pallidus, STN; subthalamic nucleus DBS; deep brain stimulation, PIGD; postural impairment and gait disturbance 324 J Korean Neurol Assoc / Volume 19 / July, 2001

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14 Table 8. Advantages and disadvantages of DBS Advantages -lmmediate symptomatic and functional improvement -Stimulation is suitable and can be customized -Lower risk of lesion-related complications -Lower risk with bilateral procedures Disadvantages -Long-term outcome unclear -Replacement of batteries -lmplantation of a foreign body (hardware) -Cost to the patient and the neurologist 328 J Korean Neurol Assoc / Volume 19 / July, 2001

15 Figure 1. The management of Parkinson s disease J Korean Neurol Assoc / Volume 19 / July,

16 CH, Fahn S, et al. A multicenter trial of ropinirole as adjunct to treatment for Parkinson s disease. N e u r o l o g y 1998;51: Pinter MM, Pogarell O, Oertel WH. Efficacy, safety, and 11. Hornykiewicz O. Dopamine (3-hydroxytyramine) and brain function. Pharmacol Rev 1966;18: Perachon S, Schwartz JC, Sokoloff P. Functional potencies of new antiparkinsonian drugs at recombinant human dopamine D-1, D-2 and D-3 receptors. Eur J Pharmacol 1999;366: Poewe W. Adjuncts to levodopa therapy; dopamine agonists. Neurology 1998;(Suppl 6):S23-S Watts RL. The role of dopamine agonists in early Parkinson s disease. N e u r o l o g y 1997;49(Suppl 1):S34- S Schrag AE, Brooks DJ, Brunt E, Fuell D, Korczyn A, Poewe W et al. The safety of ropinirole, a selective nonergoline dopamine agonist, in patients with Parkinson s disease. Clin Neuropharmacol 1998;21: Im JH, Ha JH, Cho IS, Lee MC. Ropinirole as an adjunct to levodopa in the treatment of Parkinson s disease. J Kor Neurol Assoc 2001;19(2): Lieberman A, Olanow CW, Sethi K, Swanson P, Waters tolerance of non-ergoline dopamine agonist pramipexole in the treatment of advanced Parkinson s disease: a double blind, placebo controlled, randomised, multicenter study. J Neurol Neurosurg Psychiat 1999;66: Kieburtz K, Shoulson I, McDermott M, Fahn S, Lang AE, et al. Parkinson Study Group. Safety and efficacy of pramipexole in early Parkinson s disease: a randomized dose-ranging study. JAMA 1997;278: Brooks DJ, Abbott RJ, Lees AJ, Martignoni E, Philcox DV, Rascol O. A placebo-controlled evaluation of ropinirole, a novel D-2 agonist, as sole dopaminergic therapy in Parkinson s disease. Clin Neuropharmacol ; 2 1 : Sethi KD, O Brien CF, Hammerstad JP, Adler CH, Davis TL, Taylor RL, et al. Ropinirole for the treatment of early Parkinson s disease: A 12-month experience. Arch Neurol 1998;55: Rinne UK, Bracco F, Chouza C, Dupont E, Gershanik O, Masso JFM, et al. Cabergoline in the treatment of early Parkinson s disease: results of the first year treatment in a double-blind comparison of cabergoline and levodopa. Neurology 1997;48: Kulisevsky J, Lopez-Villegas D, Garcia-Sanchez C, Barbanoj M, Giornell A, Pascual-Sedano B. A six-month study of pergolide and levodopa in de novo Parkinson s disease patients. Clin Neuropharmacol 1998;21: Frucht S, Rogers JD, Greene PE, Gordon MF, Fahn S. Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole. N e u r o l o g y ; 5 2 : Hoehn MM. Falling asleep at the wheel: motor vehicle mishaps in people taking pramipexole and ropinirole. Neurology 2000;54: Schapira AHV. Sleep attacks (sleep episodes) with pergolide. Lancet 2000;355: Ferreira JJ, Galitzky M, Montastruc JL, Rascol O. Sleep attacks and Parkinson s disease treatment. Lancet ; : Parkinson Study Group. Impact of deprenyl and tocopherol treatment on Parkinson s disease in DATATOP subjects not requiring levodopa. Ann Neurol ; 3 9 : Parkinson Study Group. Impact of deprenyl and tocopherol treatment on Parkinson s disease in DATATOP patients requiring levodopa. Ann Neurol 1996;39: Golbe LI, Lieberman AN, Muenter MD, Ahlskog JE, Gopinathan G, Neophytides AN, et al. Deprenyl in the treatment of symptom fluctuations in advanced Parkinson s disease. Clin Neuropharmacol 1988;11: Parkinson Study Group. A controlled trial of lazabemide (RO ) in untreated Parkinson s disease. A n n 330 J Korean Neurol Assoc / Volume 19 / July, 2001

17 Neurol 1993;33: Fahn S, Chouinard S. Experience with tranylcypromine in early Parkinson s disease. J Neural Transmis 1998;S52: Friedman JH, Lannon MC. Clozapine in idiopathic Parkinson s disease. Neurology 1990;40: Pfeiffer RF, Kang J, Graber B, Hofman R, Wilson J. Clozapine for psychosis in Parkinson s disease. M o v Disord 1990;5: Kahn N, Freeman A, Juncos JL, Manning D, Watts RL. Clozapine is beneficial for psychosis in Parkinson s disease. Neurology 1991;41: Factor SA, Brown D. Clozapine prevents recurrence of psychosis in Parkinson s disease. Mov Disord ; 7 : Greene P, Cote L, Fahn S. Treatment of drug-induced psychosis in Parkinson s disease with clozapine. Adv Neurol 1993;60: Pinter MM, Helscher RJ. Therapeutic effect of clozapine in psychotic decompensation in idiopathic Parkinson s disease. J Neural Transm 1993;5: Factor SA Brown D, Molho ES, Podskalny GD. Clozapine: a 2-year open trial in Parkinson s disease patietns with psychosis. Neurology 1994;44: Rabey JM, Treves TA, Neufeld MY, Orlov E, Korczyn AD. Low-dose clozapine in the treatment of levodopainduced mental disturbances in Parkinson s disease. Neurology 1995;45: Ruggieri S, Depandis MF, Bonamartini A, Vacca L, Stocchi F. Low dose of clozapine in the treatment of dopaminergic psychosis in Parkinson s disease. C l i n Neuropharmacol 1997;20: Factor SA, Friedman JH. The emerging role of clozapine in the treatment of movement disorders. Mov Disord ; 1 2 : Safferman AZ, Lieberman JA, Pollack S, Kane JM. Akathisia and clozapine treatment. J Clin Psychopharmacol ; 1 3 : Friedman JH. Akathisia and clozapine. Biol Psychiatry 1993;33: Kastrup O, Gastpar M, Schwarz M. Acute dystonia due to clozapine. J Neurol Neurosurg Psychiatry 1994;57: Thomas P, Lalaux N, Viava G, Goudemand M. Dosedependent stuttering and dystonia in a patient taking clozapine. Am J Psychiatry 1994;151: Dave M. Clozapine-related tardive dyskinesia. B i o l Psychiatry 1994;35: Jimenez-Jimenez FJ, Tallon-Barranco A, Ortipareja M, Zurdo M, Porta J, Molina JA. Olanzapine can worsen parkinsonism. Neurology 1998;50: Fahn S. Parkinson s disease, the effect of levodopa, and the ELLDOPA trial. Arch Neurol 1999;56: Felten DL, Felten SY, Fuller RW, Romano TD, Smaltstig EB, Wong DT, et al. Chronic dietary pergolide preserves nigrostriatal neuronal integrity in aged-fischer-344 rats. Neurobiol Aging 1992;13: Carvey PM, Pieri S, Ling ZD. Attenuation of levodopainduced toxicity in mesencephalic cultures by pramipexole. J Neural Transm 1997;104: Gassen M, Gross A, Youdim MBH. Apomorphin enantiomers protect cultured pheochromocytoma (PC12) cells from oxidative stress induced by H 2 O 2 and 6-hydroxydopamine. Mov Disord 1998;13: Sawada H, Ibi M, Kihara T, Urushitani M, Akaike A, Kimura J, et al. Dopamine D2-type agonists protect mesencephalic neurons from glutamate neurotoxicity: mechanisms of neuroprotective treatment against oxidative stress. Ann Neurol 1998;44: Zou LL, Jankovic J, Rowe DB, Xie WJ, Appel SH, Le WD. Neuroprotection by pramipexole against dopamineand levodopa-induced cytotoxicity. Life Sci 1999;64: Iida M, Mitazaki I, Tanaka K, Kabuto H, Iwata IE, Ogawa N, et al. Dopamine D2 receptor-mediated antioxidant and neuroprotective effects of ropinirole, a dopamine agonist. Brain Res 1999;838: Vu TQ, Ling ZD, Ma SY, Robie HC, Tong CW, Chen EY, et al. Pramipexole attenuates the dopaminergic cell loss induced by intraventricular 6-hydroxydopaine. J Neural Transm 2000;107: Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson s disease. N Eng J Med 1989;321: Yoshikawa T. Free radicals and their scavengers in Parkinson s disease. Eur Neurol 1993;33: Fahn S. A pilot trial of high-dose alpha-tocopherol and ascorbate in early Parkinson s disease. Ann Neurol ; 3 2 : S S Quinn N, Critchley P, Marsden CD. Young onset Parkinson s disease. Mov Dosord 1987;2: Kostic V, Przedborski S, Flaster E, Sternic N. Early development of levodopa-induced dyskinesias and response fluctuations in young-onet Parkinson s disease. Neurology 1991;41: Gershanik OS. Early-onset Parkinson s disease. In: Jankovic J, Tolosa E, eds: Parkinson s disease and movement disorders, 2nd edition. Baltimore: Williams & Wilkins, 1993; Wagner ML, fedak MN, Sage JI, Mark MH. Complication of disease and therapy: a comparison of younger and older patients with Parkinson s disease. Ann Clin Lab Sci ; 2 6 : Montastruc JL, Rascol O, Senard JM, Rascol A. A randomised controlled study comparing bromocriptine to which levodopa was later added, with levodopa alone in previously untreated patients with Parkinson s disease: A five year follow up. J Neurol Neurosurg Psychiatry 1994;57: Weiner WJ, Factor SA, Sanchez-Ramos JR, Singer C, J Korean Neurol Assoc / Volume 19 / July,

18 Sheldon C, Cornelius L, et al. Early combination therapy (bromocriptine and levodopa) does not prevent motor fluctuations in Parkinson s disease. Neurology 1993;43: Rinne UK, Bracco F, Chouza C, Dupont E, Gershanik O, Masso JFM, et al. Early treatment of Parkinson s disease with cabergoline delays the onset of motor complications: Results of a double-blind levodopa controlled trial. Drugs 1998;55: Rascol O, Brooks DJ, Korczyn AD, DeDeyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson s disease who were treated with ropinirole or levodopa. N Engl J Med 2000;342: Holloway R, Parkinson Study Group. Pramipexole versus levodopa in early parkinson s disease: A randomized clinical trial. Neurology 2000;54(Suppl 3):A Oertel WH. Pergolide vs. L-dopa (PELMOPET) M o v Disord 2000;15(Suppl 3): Poewe W. Adjuncts to levodopa therapy: Dopamine agonists. 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19 84. Muenter MD, Sharpless NS, Tyce GM. Plasma 3-Omethyldopa in L-dopa therapy of Parkinson s disease. Mayo Clin Proc 1972;47: Nutt JG, Woodward WR, Hammerstad JP, Carter JH, Anderson JL. The on-off phenomenon in Parkinson s disease. N Engl J Med 1984;310: Horstink MWIM, Zijlmans JCM, Pasman JW, Berger HJC, Vanthof MA. Severity of Parkinson s disease is a risk factor for peak-dose dyskinesia. J Neurol Neurosurg Psychiatry 1990;53: Fahn S. The spectrum of levodopa-induced dyskinesias. Ann Neurol 2000;47(Suppl 1):S2-S Nutt JG, Woodward WR, Anderson JL. The effect of carbidopa on the pharmacokinetics of intravenously administered levodopa: The mechanism of action in the treatment of parkinsonism. Ann Neurol 1985;18: Sassin JF, Taub S, Weitzman ED. Hyperkinesia and changes in behavior produced in normal monkeys by L- dopa. Neurology 1972;22: Metman LV, Del Dotto P, LePoole K, Konitsiotis S, Fang J, Chase TN. Amantadine for levodopa-induced dyskinesias A 1 year follow-up study. Arch Neurol 1999;56: Snow BJ, Macdonald L, Mcauley D, Wallis W. The effect of amantadine on levodopa-induced dyskinesias in Parkinson s disease: A double-blind, placebo-controlled study. Clin Neuropharmacol 2000;23: Metman LV, Del Dotto P, Natte R, van den Munckhof P, Chase TN. Dextromethorphan improves levodopa-induced dyskinesias in Parkinson s disease. N e u r o l o g y ; 5 1 : Metman LV, Del Dotto P, Blanchet PJ, van den Munckhof P, Chase TN. Blockade of glutamatergic transmission as treatment for dyskinesias and motor fluctuations in Parkinson s disease. Amino Acids 1998;14: Merims D, Ziv I, Djaldetti R, Melamed E. Riluzole for levodopa-induced dyskinesias in advanced Parkinson s disease. Lancet 1999;353: Bennett JP, Landow ER, Schuh LA. Suppression of dyskinesias in advanced Parkinson s disease. 2. increasing daily clozapine doses suppress dyskinesias and improve parkinsonism symptoms. Neurology 1993;43: Bennett JP, Landow ER, Dietrich S, Schuh LA. Suppression of dyskinesias in advanced Parkinson s disease: moderate daily clozapine doses provide long-term dyskinesia reduction. Mov Disord 1994;9: Durif F, Vidailhet M, Assal F, Roche C, Bonnet AM, Agid Y. Low-dose clozapine improves dyskinesias in Parkinson s disease. Neurology 1997;48: Pierelli F, Adipietro A, Soldati G, Fattapposta F, Pozzessere G, Scoppetta C. Low dosage clozapine effects on L-dopa induced dyskinesias in parkinsonian patients. Acta Neurol Scand 1998;97: Durif F, Vidailhet M, Bonnet AM, Blin J, Agid Y. Levodopa-induced dyskinesias are improved by fluoxetine. Neurology 1995;45: Carpentier AF, Bonnet AM, Vidailhet M, Agid Y. Improvement of levodopa-induced dyskinesia by propranolol in Parkinson s disease. N e u r o l o g y ; 4 6 : Bonifati V, Fabrizio E, Cipriani R, Vanacore N, Meco G. Buspirone in levodopa-induced dyskinesias. C l i n Neuropharmacol 1994;17: Muenter MD, Sharpless NS, Tyce GM, Darley FL. Patterns of dystonia (I-D-I and D-I-D ) in response it L- dopa therapy of Parkinson s disease. Mayo Clin Proc 1977;52: Luquin MR, Scipioni O, Vaamonde J, Gershanik O, Obeso JA. Levodopa-induced dyskinesias in Parkinson s disease: clinical and pharmacological classification. Mov Disord 1992;7: Melamed E. Early-morning dystonia: A late side effect of long-term levodopa therapy in Parkinson s disease. A r c h Neurol 1979;36: Metman LV, Hoff J, Mouradian MM, Chase TN. Fluctuations in plasma levodopa and motor responses with liquid and tablet levodopa/carbidopa. Mov Disord ; 9 : Sage JI, McHale DM, Sonsalla P, Vitagliano D, Heikkila RE. Continuous levodopa infusions to treat complex dystonia in Parkinson s disease. N e u r o l o g y a ; 3 9 : Sage JI, Trooskin S, Sonsalla PK, Heikkila RM. Experience with contnuous enteral levodopa infusions in the treatment of 9 patients with advanced Parkinson s disease. Neurology 1989b;39(Suppl 2): Nilsson D, Hansson LE, Johansson K, Nystrom C, Paalzow L, Aquilonius SM, Long-term intraduodenal infusion of a water based levodopa-carbidopa dispersion in very advanced Parkinson s disease. Acta Neurol Scand 1998;97: Colzi A, Turner K, Lees AJ. Continuous subcutaneous waking day apomorphine in the long term treatment of levodopa induced interdose dyskinesias in Parkinson s disease. J Neurol Neurosurg Psychiatry 1998;64: Miyawaki E, Meah Y, Koller WC. Serotonin, dopamine, and motor effects in Parkinson s disease. Clin Neuropharmacol ; 2 0 : Richard IH, Kurlan R, Tanner C, Factor S, Hubble J, Suchowersky O, et al. Serotonin syndrome and the combined use of deprenyl and an antidepressant in Parkinson s disease. Neurology 1997;48: Sanchez-Ramos JR, Ortoll R, Paulson GW. Visual hallucinations associated with Parkinson s disease. Arch Neurol 1996;53: Fernandez HH, Friedman JH, Jacques C, Rosenfeld M. Quetiapine for the treatment of drug-induced psychosis in Parkinson s disease. Mov Disord 1999;14: J Korean Neurol Assoc / Volume 19 / July,

20 114.Brown RG, Marsden CD. How common is dementia in Parkinson s disease? Lancet. 1984;2: Biggins CA, Boyd JL, Harrop FM, Madeley P, Mindham RH, Randall JI, et al. A controlled, longitudinal study of dementia in Parkinson s disease. J Neurol Neurosurg Psychiatry 1992;55: Mayeux R, Chen J, Mirabello E, Marder K, Bell K, Dooneief G, et al. An estimate of the incidence of dementia in idiopathic Parkinson s disease. N e u r o l o g y ; 4 0 : Hughes TA, Ross HF, Musa S, Bhattacherjee S, Nathan RN, Mindham RH, et al. A 10-year study of the incidence of and factors predicting dementia in Parkinson s disease. Neurology 2000;54: McKeith IG, Perry EK, Perry RH. Report of the second dementia with Lewy body international workshop: diagnosis and treatment. Consortium on Dementia with Lewy Bodies. Neurology 1999;53:3: McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, et al. 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