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Current therapy in Parkinson’s disease
Advances in Neurology
Current Therapy in Parkinson’s Disease Melanie M. Brandabur, M.D. Department of Neurology, University of Illinois at Chicago, Chicago, Illinois
Brandabur, M. M. Current therapy in Parkinson’s Disease. Surg Neurol 1999;52:318 –22.
arkinson’s disease is a disorder of movement affecting between 500,000 and 1 million persons in the United States. It is manifested by the “cardinal signs” of bradykinesia, cogwheel rigidity of the extremities, resting tremor, and, later in the disease, postural reflex impairment. Parkinson’s disease (PD) and other parkinsonian disorders present with a general poverty of movement and comprise the “akinetic-rigid” or hypokinetic movement disorders [40]. The diagnosis of these diseases is made by eliciting compatible historical information and examining the patient for clinical signs. The gradual onset of bradykinesia and tremor, often asymmetrical, combined with good clinical response to levodopa therapy are suggestive of idiopathic Parkinson’s disease (IPD). Indifferent response to levodopa therapy, early impairment of gait and balance or the presence of other features, such as definite ataxia, profound orthostatic hypotension, or limitation of extraocular movement, imply another cause of parkinsonism such as olivopontocerebellar atrophy, multiple systems atrophy or progressive supranuclear palsy. These disorders are generally less responsive to treatment and often progress more quickly than does IPD [11,26,31]. Common to all forms of parkinsonism is a relative decrease in dopaminergic tone within the basal ganglia. This can occur for a variety of reasons; in drug-induced parkinsonism, for example, the striatal dopamine receptors are blocked by a neuroleptic or some other dopamine receptor antagonist. In IPD, this decrease in dopaminergic tone is a direct result of a diminished number of dopamineproducing neurons within the substantia nigra. The net result is suppression of the thalamic stimulation of the motor cortex, resulting in difficulty initiating
P
Address reprint requests to: Dr. Brandabur, University of Illinois at Chicago, Department of Neurology (M/C 796), 912 South Wood Street, Chicago, IL 60612, USA. 0090-3019/99/$–see front matter PII S0090-3019(99)00091-9
movement [12]. These neurons die as a normal part of aging in humans but this is not thought to produce symptoms unless at least 80% of these neurons are affected. The rate of attrition of these cells is such that, in the normal aged population, death from some other cause occurs before the development of parkinsonism, that would theoretically occur at around the age of one hundred and ten. In individuals with IPD, the neuron mass in the substantia nigra reaches this critical percentage earlier, resulting in the onset of clinical signs and symptoms of parkinsonism [21]. Proposed mechanisms for this premature loss of dopaminergic neurons include oxidative damage, mitochondrial dysfunction, and apoptosis [34]. Much interest has centered on attempts to identify an exogenous toxin that might trigger this process and, in fact, several studies have linked environmental factors such as pesticides, well-water consumption, or occupational exposure with an increased risk of IPD [35]. This concept was given more credence in recent years by the discovery that MPTP, a byproduct in the manufacture of illicit narcotics, has a specific toxicity for the dopaminergic neurons of the substantia nigra [7]. Recent work with families in which PD is inherited has prompted a renewal of interest into genetic factors in the evolution of PD [4]. The combination of a genetic susceptibility and other host variables with an environmental toxin or toxins is presently considered the most likely explanation [38]. The medical treatment of IPD has advanced tremendously in the past three decades, resulting in a marked improvement in the quality and even the length of life in the majority of patients [5]. That the scope of these treatments remains imperfect is highlighted by the recent revival of interest in various surgical treatments for PD. Several of the surgical techniques used currently for the treatment of PD were developed during the early twentieth century, a time of scant medical therapy. Cortical extirpation and pedunculotomy © 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
Current Therapy in Parkinson’s Disease
were found to reduce tremor, but resulted in hemiparesis. Later, a transventricular approach was used to lesion the caudate nucleus and ansa lenticularis which improved tremor and rigidity, but with an unacceptable risk of complications. The concept of pallidotomy apparently stemmed from an attempted pedunculotomy, during which the anterior choroidal artery was inadvertently destroyed. The pedunculotomy was not performed, but remarkably the patient was tremor-free following surgery, presumably from the resulting lesion of the internal segment of the globus pallidum [17]. The evolution of subcortical procedures for treating parkinsonism was greatly enhanced by the coincidental development of stereotactic methods, that were initially used for treating psychiatric disorders. The most frequently targeted areas at present are the globus pallidus interna and the ventral lateral thalamus. In addition to ablative lesions, it has been noted that electrical stimulation within these regions can also relieve parkinsonian symptoms [14,15]. More recently, the subthalamic nucleus has become an important site for electrical stimulation [23,30]. The accuracy of these procedures has been greatly enhanced by the advent of CT and MRI scanning and, more recently, by the use of neurophysiologic recording techniques such as subcortical electrical stimulation, and microelectrode and semimicroelectrode recording. These techniques enable precise positioning of the lesion and minimize damage to adjacent structures. Within the thalamus, microelectrode recording is used to map the somatotopic representation of the upper and lower extremity. Thalamotomy and thalamic stimulation may be particularly helpful in patients with tremor-predominant PD [15,17]. Stimulation of the subthalamic nucleus appears to reduce akinesia [23,30]. In addition to the beneficial effects on parkinsonian tremor, there is evidence that thalamotomy is also useful in the treatment of essential and even cerebellar and post-traumatic tremor [15]. At present, stereotactic pallidotomy seems especially beneficial in those patients experiencing rigidity and levodopa-induced dyskinesias [6,24]. This apparently works by reducing the overactive pallidal inhibitory action on the thalamus [1,7]. Despite the current level of interest, questions remain as to appropriate patient selection, long-term efficacy and surgical morbidity. Another surgical technique for the treatment of PD is neural transplantation. Because of the relative focality of the neuropathological and neuropharmacologic defects, PD would appear particularly suitable for replacement of dopaminergic neurons with
Surg Neurol 319 1999;52:318 –22
grafted tissue. This was attempted initially with autologous transplants from the adrenal medulla. The benefit noted in some patients was assumed to result from innervation of the host brain by the transplanted cells with subsequent restoration of dopaminergic tone. Surprisingly, neuropathological studies of some of these patients failed to demonstrate such findings. In fact, most of the clinically improved patients had no detectable survival of the adrenal cells [36]. The reason for the observed clinical improvement in some patients is therefore not clear. Proposed mechanisms include stimulation of host nerve-terminal sprouting by neurotrophins present in the grafted material, alterations in the blood-brain barrier permitting the passage of systemic dopamine, or simply the previously recognized effects of lesioning the basal ganglia [36]. More recently, attempts at neurotransplantation in PD have focused largely on the implantation of fetal dopaminergic tissue. Although clinical results have varied, it appears that subjects who have parkinsonism on the basis of MPTP toxicity have had more impressive results from fetal transplant than those with IPD [3], presumably because MPTP produces a static lesion while the progressive nature of IPD may mask a certain degree of improvement. One neuropathologic study revealed a higher rate of survival of the implanted dopaminergic cells [19] than that seen in adrenal medullary transplant. Another postmortem study, however, did not demonstrate surviving grafted neurons but did note a marked proliferation of nonneuronal tissue filling and obstructing the ventricular system [9]. This may have been due in part to some variations in surgical technique, but nonetheless highlights questions that have been raised before regarding possible host immune response and potential contamination of the graft with nonneuronal tissue. Additional issues must be also be resolved, not the least of which is the paucity, in some countries, of suitable donor fetal tissue and the legal and ethical issues related to its procurement. In addition, variables in operative technique such as number of grafts used, and storage, age, and processing of the tissue prior to implantation are still being studied. The development of cultured dopaminergic cell lines may provide important answers to some of these issues and make this an important treatment in the future [24]. Juxtaposed between the early and modern eras of surgical treatment for PD was the discovery of levodopa therapy. Because it was introduced into clinical usage in the late 1960’s, this agent, combined with a peripheral decarboxylase inhibitor such as carbidopa, has been the mainstay of therapy for PD.
320 Surg Neurol 1999;52:318 –22
Levodopa crosses the blood-brain barrier and is converted to dopamine, thus temporarily correcting the most profound neurotransmitter deficit. In a majority of patients with IPD, this therapy has a profound impact on clinical function and quality of life. Patients who do not respond to treatment with levodopa are unlikely to have significant benefit from other forms of levodopa therapy and, in fact, may turn out to have a form of parkinsonism other than IPD [18]. Of those who have a brisk response, some will continue to experience these beneficial effects, with minimal modifications in dosing, throughout the course of the disease. The majority of patients, however, will eventually note significant alterations in their response to treatment [39] requiring a larger dose or more frequent dosing to obtain the same relief. Adverse effects are distressingly common and include unpredictable or fluctuating response to medication (motor fluctuations or “on-off phenomenon”), abnormal involuntary movements during peaks in dosage (dyskinesias or dystonia), or psychiatric phenomena (vivid dreams, confusion or hallucinations). It is not clear why this occurs, although some have invoked toxicity of the breakdown products of dopamine itself. Although it is known that dopamine metabolites include free radicals, debate is ongoing as to whether oxidative damage contributes to the changes in levodopa responsiveness during long term therapy for Parkinson’s disease [34]. Meanwhile, several therapeutic agents have been developed to extend the effective life of levodopa and thus to limit the amount needed (“levodopa-sparing”). One of these is Sinemet-CR, a sustained-release preparation of carbidopa/levodopa. Advocates of this product have proposed that the more constant blood levels of levodopa achieved with the time-released dosing are less likely to result in the motor fluctuations associated with chronic levodopa use [13]. The long-acting preparations must usually be given in a higher daily dosage to compensate for incomplete absorption. Selegiline (Eldepryl), a selective monamine oxidase type B inhibitor, is an agent that prevents the breakdown of dopamine, thereby prolonging the effectiveness of carbidopa/levodopa. Preclinical evidence that selegiline could actually slow the progression of IPD, presumably by decreasing the amount of dopamine that is broken down into potentially toxic metabolites [37], has not been convincingly demonstrated in clinical studies. When selegiline is added to levodopa, a decrement in dosage of the latter is often required because deleterious, as well as therapeutic, effects of levodopa therapy may be enhanced in some patients. One of the most useful and rapidly-expanding
Brandabur
category of agents in the treatment of IPD is that of the direct-acting dopamine agonists. These compounds directly stimulate dopamine receptors within the striatum and tend to have a longer halflife than standard levodopa preparations. Dopamine agonists are advantageous for patients who are beginning to require increased doses of levodopa and are particularly useful for those who have developed motor fluctuations [16]. Like selegiline, these drugs can be used as levodopa-sparing agents and may afford some degree of neuroprotection. This is postulated to be due to inherent anti-oxidant properties of the dopamine agonists [16,41,42] and may have important clinical implications. Dopamine agonists are most commonly used as adjuncts to levodopa treatment, however, monotherapy can be effective, especially in patients who are unable to tolerate levodopa due to nausea [41]. Until recently, the only agonists available in the United States were bromocriptine (Parlodel) and pergolide (Permax). Both are ergot derivatives acting directly on postsynaptic dopamine receptors and both have a longer half-life than levodopa [28]. Dopamine agonists have several advantages compared with levodopa therapy in that they do not depend on conversion into an active agent by a diminishing supply of nigral decarboxylase, nor are they broken down into toxic metabolites or free radicals [28]. Bromocriptine stimulates primarily the D2 receptor and acts as a weak D1 antagonist, while pergolide stimulates both D1 and D2 receptors. In some studies, pergolide has demonstrated a greater efficacy than bromocriptine, possibly because of the effect on the D1 receptors [2,29,33]. The side-effect profile of dopamine agonists overlaps to a great extent with that for levodopa. In addition to dyskinesias, confusion and hallucinations, these agents can cause significant orthostatic hypotension in patients who may already be predisposed to this problem because of their IPD. Therefore, it is important to start agonist therapy with a very small dose, to increase gradually to a therapeutic dose, and to decrease the levodopa dose as necessary to avoid side effects. Less common adverse effects include vascular effects such as edema and Raynaud’s phenomenon, rare instances of pulmonary or retroperitoneal fibrosis [28], and hepatic toxicity [22]. Lisuride, a semisynthetic ergot alkaloid, has been available in Europe for some time. This agonist has an oral half-life of only 1.5 to 2 h, however, the solubility of lisuride makes it ideal for potential administration via intravenous or subcutaneous pumps [10]. Two new dopamine agonists, ropinirole and
Current Therapy in Parkinson’s Disease
pramipexole, have recently become available in the United States. Ropinirole, a non-ergoline agonist with a strong affinity for the D2 family of dopamine receptors is well-tolerated and may improve motor fluctuations [20]. Pramipexole, which is also a nonergot agonist, has activity at the D3 subclass of dopamine receptors which may benefit psychiatric conditions as well as IPD [27]. Both have already proven to be useful agents, both as monotherapy in early disease and as adjunctive therapy along with levodopa. A new category of anti-parkinsonian drug therapy was recently introduced with the availability of the first catechol-O-methyltransferase (COMT) inhibitor, talcapone (Tasmar). Because of the risk of hepatic toxicity, patients taking this medication must agree to stringent monitoring of liver function studies mandated by the FDA [32]. Talcapone affects the metabolism of levodopa, allowing more to cross the blood-brain barrier and be converted to dopamine. Although not a true “dopamine sparing” agent, COMT inhibitors do present the brain with a more consistent level of levodopa, that may provide a more physiologic exposure. Whereas treatment of IPD remains far from ideal, the expanding options for both surgical and medical therapy portend a more optimistic future for those afflicted with this relentless condition. The author wishes to thank Dr. Richard Penn for his suggestions regarding this manuscript.
Surg Neurol 321 1999;52:318 –22
7.
8.
9.
10. 11. 12. 13. 14. 15.
16. 17.
REFERENCES 1. Benabid AL, Pollack P, Hoffman D, Le Bas JF, Ming GD. Chronic high frequency thalamic stimulation in Parkinson’s disease. In: Koller, WC, Paulson, G, eds. Therapy of Parkinson’s Disease, 2nd Edition. Marcel Dekker, Inc., 1995. 2. Bonnet AM, Serre I, Marconi R, Agid Y, DuBois B. A “combined” levodopa test as a useful method for evaluating the efficacy of dopamine agonists: application to pergolide and bromocriptine. Movement Disorders 1995;10(5):668 –71. 3. Collier TJ, Kordower JH. Fetal nigral transplants: a preclinical and clinical prospectus. In: Koller WC, Paulson G. Therapy of Parkinson’s disease, 2nd Edition. Marcel Dekker, Inc., 1995. 4. Denson MA, Wszolek ZK. Familial parkinsonism: our experience and review. Parkinsonism and Related Disorders. 1995;1(1):35– 46. 5. Di Rocca A, Molinari SP, Kollmeier B, Yahr MD. Parkinson’s disease: progression and mortality in the L-DOPA era. In: Battistin L, Scarlato G, Caraceni T, Ruggieri S, eds. Advances in Neurology Volume 69, Lippincott–Raven Publishers, Philadelphia, 1996. 6. Dogali M, Sterio D, Fazzini E, Kolodny E, Eidelberg E, Beric A. Effects of posteroventral pallidotomy on Parkinson’s disease. Battistin L, Scarlato G, Caraceni T,
18. 19.
20.
21. 22.
23.
Ruggieri S. Advances in neurology, Volume 69 Lippencott–Raven, 1996. Eidelberg D, Moeller VR, Ishikawa T, Dhawan V, Spetsieris P, Silbersweig D, Stern E, Woods RP, Fazzini E, Dogali M, Beric A. Regional metabolic correlates of surgical outcome following unilateral pallidotomy for Parkinson’s disease. Annals of Neurology 1996;39: 450 –9. Ellenberg, Joseph H, Koller, William C, Langston J, William. Etiology of Parkinson’s disease. Marcel Dekker 1995. Folkerth RD, Durso R. Survival and proliferation of nonneural tissues, with obstruction of cerebral ventricles, in a parkinsonian patient treated with fetal allografts. Neurology 1996;46:1219 –25. Goetz CG, Diederich NJ. Dopaminergic agonists in the treatment of Parkinson’s disease. In: Neurologic Clinics; Parkinson’s Disease 10(2)May 1992. Golbe L. Epidemiology. In: Litvan I, Agid, Yves. Progressive Supranuclear Palsy; Clinical and Research Approaches. Oxford University Press, 1992. Hallett M. Physiology of basal ganglia disorders. Le Journal Canadien des Sciences Neurologiques 1993; 20:177– 83. Hutton JT, Morris JL. Long-acting levodopa preparations. In: Koller WC, Paulson G. Therapy of Parkinson’s disease, 2nd Edition. Marcel Dekker, Inc., 1995. Iacono RP, Lonser RR, Mandubur G, Yamada S. Stimulation of the globus pallidus in Parkinson’s disease. Br J Neurosurg 1995;9:505–10. Jancovic J, Cardoso F, Grossman RG, Hamilton WJ. Outcome after stereotactic thalamotomy for parkinsonism, essential, and other types of tremor. Neurosurgery 1995 Oct;37(4):680 – 6. Jenner P. The Rationale for the Use of Dopamine Agonists in Parkinson’s Disease. Neurology 45 (suppl. 3) March 1995;S6 –S11. Kelly PJ. Stereotactic thalamotomy. In: Koller WC, Paulson G, eds. Therapy of Parkinson’s Disease, 2nd Edition. Marcel Dekker, Inc., 1995. Koller WC, Silver DE, Lieberman A. An algorhythm for the management of Parkinson’s disease. Neurology 1994;44(suppl. 10):S5–S52. Kordower JH, Freeman TB, Snow BJ, Vingerhoets FJ, Mufson EJ, Sanberg PR, Hauser RA, Smith DA, Nauert GM, Perl DP, Olanow CW. Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson’s disease. N Engl J Med 1995; 332:1118 –24. Kreider MS, Knox S, Gardiner D, Wheadon DE. The Efficacy of Ropinirole, a non-ergoline agonist, as an adjunct to L-Dopa (DCI) in patients with Parkinson’s disease. Movement Disorders, 11;(suppl. 1) 1996. Langston JW. Predicting Parkinson’s disease. Neurology 40 (suppl. 3) October 1990. LeWitt PA, Ward CD, Larsen TA, Raphaelson MI, Newman RP, Foster N, Dambrosia JM, Calne DM. Comparison of pergolide and bromocriptine therapy in parkinsonism. Neurology 1983;33:1009 –14. Limousin P, Pollak P, Benazzouz A, Hoffman D, Brousolle E, Perret JE, Benabid AL. Bilateral subthalamic nucleus stimulation for severe Parkinson’s disease. Movement Disorders 1995;10(5):672– 4.
322 Surg Neurol 1999;52:318 –22
24. Lindvall O. Neural transplantation. In: Cell Transplantation. Elsevier Science Ltd.; 1995;4(4):393– 400. 25. Lozano AM, Lang AE, Galvez-Jimenez N, Miyasaki J, Duff J, Hutchinson WD, Dostrovsky JO. Effect of GPI pallidotomy on motor function in Parkinson’s disease. Lancet 1995;346:1383– 87. 26. Marsden CD, Fahn S. Problems in Parkinson’s disease and other akinetic-rigid syndromes. Movement Disorders 2. Marsden CD, Fahn S, eds. Butterworth & Co. Ltd, 1987. 27. Mierau J, Schneider FJ, Ensinger HA, Chio CL, Lajiness ME, Huff RM. Pramipexole Binding and Activation of Cloned and Expressed Dopamine D2, D3, and D4 Receptors. Eur J Pharmacol, Mol Pharmacol Sec 1995; 290:29 –36. 28. Montastruc JL, Rascol O, Senard JM. Current status of dopamine agonists in Parkinson’s disease. Drugs 1993;46(3):384 –393. 29. Pezzoli G, Martignoni E, Pachetti C, Angeleri V, Lamberti P, Muratorio A, Bonuccelli U, DeMari M, Foschi N, Cossutta E, Nicoletti F, Giammona G, Canesi M, Scarlato G, Caraceni T, Moscarelli E. A crossover, controlled study comparing pergolide with bromocriptine as an adjunct to levodopa for the treatment of Parkinson’s disease. Neurology 1995; 45(suppl 3):S22–S27. 30. Pollak P, Benabid AL, Gross C, Gao DM, Laurent A, Benazzouz A, Hoffman D, Gentil M, Perret J. Effets de la stimulation du noyau sous-thalamique dans la maladie de Parkinson. Revue Neurologique (Paris), 1993;149(3):175–176. 31. Quinn N. Multiple systems atrophy. In: Movement Disorders 3. Marsden CD, Fahn S, eds. Butterworth– Heinemann Ltd, 1994. 32. Roche Laboratories Inc. Revised Tasmar (tolcapone) Package Insert, November, 1998.
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33. Sage JI, Duvoisin RC. Pergolide. In: Koller WC, Paulson G. Therapy of Parkinson’s disease, 2nd Edition. Marcel Dekker, Inc., 1995. 34. Schapira AHV. Neurotoxicity and the mechanisms of cell death in Parkinson’s disease. In: Advances in Neurology Volume 69, Battistin L, Scarlato G, Caraceni T, Ruggieri S, eds. Lippincott–Raven Publishers, Philadelphia, 1996. 35. Seidler A, Hellebrand W, Robra B-P, Vieregge P, Nischan P, Joerg J, Oertel WH, Ulm G, Schneider E. Possible environmental, occupational, and other etiologic factors for Parkinson’s disease: a case-control study in Germany. Neurology 1996;46:1275– 84. 36. Shannon KM, Goetz CG. Transplantation of adrenal medullary tissue to Parkinson’s disease. In: Koller WC, Paulson G, eds. Therapy of Parkinson’s Disease, 2nd Edition. Marcel Dekker, Inc., 1995. 37. Shinotoh H, Calne S, Calne DB. Does selegiline afford neuroprotection? In: Koller WC, Paulson G, eds. Therapy of Parkinson’s disease, 2nd Edition. Marcel Dekker, Inc., 1995. 38. Tanner CM. Epidemiologic clues to the cause of Parkinson’s disease. In: Marsden CD, Fahn S, eds. Movement Disorders 3. Butterworth–Heinemann, Ltd., 1994. 39. Tolosa ES, Valldeoriola F, Marti MJ. New and emerging strategies for improving levodopa treatment. Neurology 1994;44(suppl 6):S35– 44. 40. Weiner WJ, Lang AE. Movement disorders: a comprehensive survey. Futura 1989:2–3. 41. Wolters EC, Tissingh G, Bergmans PLM, Kuiper MA. Dopamine agonists in Parkinson’s disease. Neurology 1995;45(suppl 3):S28 –S34. 42. Yoshikawa T, Minamiyama Y, Naito Y, Kondo M. Antioxidant properties of bromocriptine, a dopamine agonist. J Neurochem 1994;62:1034 – 8.
When purchasing health care, people do not have the sense that they are spending their own money.” Ninety-five percent of all costs incurred during hospitalizations and 81% of physician’s fees are paid by someone (government or private insurance) other than the person seeking medical care. As a result, patients do not have an incentive to reduce costs; market forces are lacking in the health care delivery system. The end result is that costs continue to escalate. More government and more bureaucracy is not the answer.
“
—Miguel A. Faria, Jr., M.D. “Vandals at the Gates of Medicine: Historic Perspectives on the Battle Over Health Care Reform” (1994)
Current Therapy in Parkinson’s Disease Melanie M. Brandabur, M.D. Department of Neurology, University of Illinois at Chicago, Chicago, Illinois
Brandabur, M. M. Current therapy in Parkinson’s Disease. Surg Neurol 1999;52:318 –22.
arkinson’s disease is a disorder of movement affecting between 500,000 and 1 million persons in the United States. It is manifested by the “cardinal signs” of bradykinesia, cogwheel rigidity of the extremities, resting tremor, and, later in the disease, postural reflex impairment. Parkinson’s disease (PD) and other parkinsonian disorders present with a general poverty of movement and comprise the “akinetic-rigid” or hypokinetic movement disorders [40]. The diagnosis of these diseases is made by eliciting compatible historical information and examining the patient for clinical signs. The gradual onset of bradykinesia and tremor, often asymmetrical, combined with good clinical response to levodopa therapy are suggestive of idiopathic Parkinson’s disease (IPD). Indifferent response to levodopa therapy, early impairment of gait and balance or the presence of other features, such as definite ataxia, profound orthostatic hypotension, or limitation of extraocular movement, imply another cause of parkinsonism such as olivopontocerebellar atrophy, multiple systems atrophy or progressive supranuclear palsy. These disorders are generally less responsive to treatment and often progress more quickly than does IPD [11,26,31]. Common to all forms of parkinsonism is a relative decrease in dopaminergic tone within the basal ganglia. This can occur for a variety of reasons; in drug-induced parkinsonism, for example, the striatal dopamine receptors are blocked by a neuroleptic or some other dopamine receptor antagonist. In IPD, this decrease in dopaminergic tone is a direct result of a diminished number of dopamineproducing neurons within the substantia nigra. The net result is suppression of the thalamic stimulation of the motor cortex, resulting in difficulty initiating
P
Address reprint requests to: Dr. Brandabur, University of Illinois at Chicago, Department of Neurology (M/C 796), 912 South Wood Street, Chicago, IL 60612, USA. 0090-3019/99/$–see front matter PII S0090-3019(99)00091-9
movement [12]. These neurons die as a normal part of aging in humans but this is not thought to produce symptoms unless at least 80% of these neurons are affected. The rate of attrition of these cells is such that, in the normal aged population, death from some other cause occurs before the development of parkinsonism, that would theoretically occur at around the age of one hundred and ten. In individuals with IPD, the neuron mass in the substantia nigra reaches this critical percentage earlier, resulting in the onset of clinical signs and symptoms of parkinsonism [21]. Proposed mechanisms for this premature loss of dopaminergic neurons include oxidative damage, mitochondrial dysfunction, and apoptosis [34]. Much interest has centered on attempts to identify an exogenous toxin that might trigger this process and, in fact, several studies have linked environmental factors such as pesticides, well-water consumption, or occupational exposure with an increased risk of IPD [35]. This concept was given more credence in recent years by the discovery that MPTP, a byproduct in the manufacture of illicit narcotics, has a specific toxicity for the dopaminergic neurons of the substantia nigra [7]. Recent work with families in which PD is inherited has prompted a renewal of interest into genetic factors in the evolution of PD [4]. The combination of a genetic susceptibility and other host variables with an environmental toxin or toxins is presently considered the most likely explanation [38]. The medical treatment of IPD has advanced tremendously in the past three decades, resulting in a marked improvement in the quality and even the length of life in the majority of patients [5]. That the scope of these treatments remains imperfect is highlighted by the recent revival of interest in various surgical treatments for PD. Several of the surgical techniques used currently for the treatment of PD were developed during the early twentieth century, a time of scant medical therapy. Cortical extirpation and pedunculotomy © 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
Current Therapy in Parkinson’s Disease
were found to reduce tremor, but resulted in hemiparesis. Later, a transventricular approach was used to lesion the caudate nucleus and ansa lenticularis which improved tremor and rigidity, but with an unacceptable risk of complications. The concept of pallidotomy apparently stemmed from an attempted pedunculotomy, during which the anterior choroidal artery was inadvertently destroyed. The pedunculotomy was not performed, but remarkably the patient was tremor-free following surgery, presumably from the resulting lesion of the internal segment of the globus pallidum [17]. The evolution of subcortical procedures for treating parkinsonism was greatly enhanced by the coincidental development of stereotactic methods, that were initially used for treating psychiatric disorders. The most frequently targeted areas at present are the globus pallidus interna and the ventral lateral thalamus. In addition to ablative lesions, it has been noted that electrical stimulation within these regions can also relieve parkinsonian symptoms [14,15]. More recently, the subthalamic nucleus has become an important site for electrical stimulation [23,30]. The accuracy of these procedures has been greatly enhanced by the advent of CT and MRI scanning and, more recently, by the use of neurophysiologic recording techniques such as subcortical electrical stimulation, and microelectrode and semimicroelectrode recording. These techniques enable precise positioning of the lesion and minimize damage to adjacent structures. Within the thalamus, microelectrode recording is used to map the somatotopic representation of the upper and lower extremity. Thalamotomy and thalamic stimulation may be particularly helpful in patients with tremor-predominant PD [15,17]. Stimulation of the subthalamic nucleus appears to reduce akinesia [23,30]. In addition to the beneficial effects on parkinsonian tremor, there is evidence that thalamotomy is also useful in the treatment of essential and even cerebellar and post-traumatic tremor [15]. At present, stereotactic pallidotomy seems especially beneficial in those patients experiencing rigidity and levodopa-induced dyskinesias [6,24]. This apparently works by reducing the overactive pallidal inhibitory action on the thalamus [1,7]. Despite the current level of interest, questions remain as to appropriate patient selection, long-term efficacy and surgical morbidity. Another surgical technique for the treatment of PD is neural transplantation. Because of the relative focality of the neuropathological and neuropharmacologic defects, PD would appear particularly suitable for replacement of dopaminergic neurons with
Surg Neurol 319 1999;52:318 –22
grafted tissue. This was attempted initially with autologous transplants from the adrenal medulla. The benefit noted in some patients was assumed to result from innervation of the host brain by the transplanted cells with subsequent restoration of dopaminergic tone. Surprisingly, neuropathological studies of some of these patients failed to demonstrate such findings. In fact, most of the clinically improved patients had no detectable survival of the adrenal cells [36]. The reason for the observed clinical improvement in some patients is therefore not clear. Proposed mechanisms include stimulation of host nerve-terminal sprouting by neurotrophins present in the grafted material, alterations in the blood-brain barrier permitting the passage of systemic dopamine, or simply the previously recognized effects of lesioning the basal ganglia [36]. More recently, attempts at neurotransplantation in PD have focused largely on the implantation of fetal dopaminergic tissue. Although clinical results have varied, it appears that subjects who have parkinsonism on the basis of MPTP toxicity have had more impressive results from fetal transplant than those with IPD [3], presumably because MPTP produces a static lesion while the progressive nature of IPD may mask a certain degree of improvement. One neuropathologic study revealed a higher rate of survival of the implanted dopaminergic cells [19] than that seen in adrenal medullary transplant. Another postmortem study, however, did not demonstrate surviving grafted neurons but did note a marked proliferation of nonneuronal tissue filling and obstructing the ventricular system [9]. This may have been due in part to some variations in surgical technique, but nonetheless highlights questions that have been raised before regarding possible host immune response and potential contamination of the graft with nonneuronal tissue. Additional issues must be also be resolved, not the least of which is the paucity, in some countries, of suitable donor fetal tissue and the legal and ethical issues related to its procurement. In addition, variables in operative technique such as number of grafts used, and storage, age, and processing of the tissue prior to implantation are still being studied. The development of cultured dopaminergic cell lines may provide important answers to some of these issues and make this an important treatment in the future [24]. Juxtaposed between the early and modern eras of surgical treatment for PD was the discovery of levodopa therapy. Because it was introduced into clinical usage in the late 1960’s, this agent, combined with a peripheral decarboxylase inhibitor such as carbidopa, has been the mainstay of therapy for PD.
320 Surg Neurol 1999;52:318 –22
Levodopa crosses the blood-brain barrier and is converted to dopamine, thus temporarily correcting the most profound neurotransmitter deficit. In a majority of patients with IPD, this therapy has a profound impact on clinical function and quality of life. Patients who do not respond to treatment with levodopa are unlikely to have significant benefit from other forms of levodopa therapy and, in fact, may turn out to have a form of parkinsonism other than IPD [18]. Of those who have a brisk response, some will continue to experience these beneficial effects, with minimal modifications in dosing, throughout the course of the disease. The majority of patients, however, will eventually note significant alterations in their response to treatment [39] requiring a larger dose or more frequent dosing to obtain the same relief. Adverse effects are distressingly common and include unpredictable or fluctuating response to medication (motor fluctuations or “on-off phenomenon”), abnormal involuntary movements during peaks in dosage (dyskinesias or dystonia), or psychiatric phenomena (vivid dreams, confusion or hallucinations). It is not clear why this occurs, although some have invoked toxicity of the breakdown products of dopamine itself. Although it is known that dopamine metabolites include free radicals, debate is ongoing as to whether oxidative damage contributes to the changes in levodopa responsiveness during long term therapy for Parkinson’s disease [34]. Meanwhile, several therapeutic agents have been developed to extend the effective life of levodopa and thus to limit the amount needed (“levodopa-sparing”). One of these is Sinemet-CR, a sustained-release preparation of carbidopa/levodopa. Advocates of this product have proposed that the more constant blood levels of levodopa achieved with the time-released dosing are less likely to result in the motor fluctuations associated with chronic levodopa use [13]. The long-acting preparations must usually be given in a higher daily dosage to compensate for incomplete absorption. Selegiline (Eldepryl), a selective monamine oxidase type B inhibitor, is an agent that prevents the breakdown of dopamine, thereby prolonging the effectiveness of carbidopa/levodopa. Preclinical evidence that selegiline could actually slow the progression of IPD, presumably by decreasing the amount of dopamine that is broken down into potentially toxic metabolites [37], has not been convincingly demonstrated in clinical studies. When selegiline is added to levodopa, a decrement in dosage of the latter is often required because deleterious, as well as therapeutic, effects of levodopa therapy may be enhanced in some patients. One of the most useful and rapidly-expanding
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category of agents in the treatment of IPD is that of the direct-acting dopamine agonists. These compounds directly stimulate dopamine receptors within the striatum and tend to have a longer halflife than standard levodopa preparations. Dopamine agonists are advantageous for patients who are beginning to require increased doses of levodopa and are particularly useful for those who have developed motor fluctuations [16]. Like selegiline, these drugs can be used as levodopa-sparing agents and may afford some degree of neuroprotection. This is postulated to be due to inherent anti-oxidant properties of the dopamine agonists [16,41,42] and may have important clinical implications. Dopamine agonists are most commonly used as adjuncts to levodopa treatment, however, monotherapy can be effective, especially in patients who are unable to tolerate levodopa due to nausea [41]. Until recently, the only agonists available in the United States were bromocriptine (Parlodel) and pergolide (Permax). Both are ergot derivatives acting directly on postsynaptic dopamine receptors and both have a longer half-life than levodopa [28]. Dopamine agonists have several advantages compared with levodopa therapy in that they do not depend on conversion into an active agent by a diminishing supply of nigral decarboxylase, nor are they broken down into toxic metabolites or free radicals [28]. Bromocriptine stimulates primarily the D2 receptor and acts as a weak D1 antagonist, while pergolide stimulates both D1 and D2 receptors. In some studies, pergolide has demonstrated a greater efficacy than bromocriptine, possibly because of the effect on the D1 receptors [2,29,33]. The side-effect profile of dopamine agonists overlaps to a great extent with that for levodopa. In addition to dyskinesias, confusion and hallucinations, these agents can cause significant orthostatic hypotension in patients who may already be predisposed to this problem because of their IPD. Therefore, it is important to start agonist therapy with a very small dose, to increase gradually to a therapeutic dose, and to decrease the levodopa dose as necessary to avoid side effects. Less common adverse effects include vascular effects such as edema and Raynaud’s phenomenon, rare instances of pulmonary or retroperitoneal fibrosis [28], and hepatic toxicity [22]. Lisuride, a semisynthetic ergot alkaloid, has been available in Europe for some time. This agonist has an oral half-life of only 1.5 to 2 h, however, the solubility of lisuride makes it ideal for potential administration via intravenous or subcutaneous pumps [10]. Two new dopamine agonists, ropinirole and
Current Therapy in Parkinson’s Disease
pramipexole, have recently become available in the United States. Ropinirole, a non-ergoline agonist with a strong affinity for the D2 family of dopamine receptors is well-tolerated and may improve motor fluctuations [20]. Pramipexole, which is also a nonergot agonist, has activity at the D3 subclass of dopamine receptors which may benefit psychiatric conditions as well as IPD [27]. Both have already proven to be useful agents, both as monotherapy in early disease and as adjunctive therapy along with levodopa. A new category of anti-parkinsonian drug therapy was recently introduced with the availability of the first catechol-O-methyltransferase (COMT) inhibitor, talcapone (Tasmar). Because of the risk of hepatic toxicity, patients taking this medication must agree to stringent monitoring of liver function studies mandated by the FDA [32]. Talcapone affects the metabolism of levodopa, allowing more to cross the blood-brain barrier and be converted to dopamine. Although not a true “dopamine sparing” agent, COMT inhibitors do present the brain with a more consistent level of levodopa, that may provide a more physiologic exposure. Whereas treatment of IPD remains far from ideal, the expanding options for both surgical and medical therapy portend a more optimistic future for those afflicted with this relentless condition. The author wishes to thank Dr. Richard Penn for his suggestions regarding this manuscript.
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7.
8.
9.
10. 11. 12. 13. 14. 15.
16. 17.
REFERENCES 1. Benabid AL, Pollack P, Hoffman D, Le Bas JF, Ming GD. Chronic high frequency thalamic stimulation in Parkinson’s disease. In: Koller, WC, Paulson, G, eds. Therapy of Parkinson’s Disease, 2nd Edition. Marcel Dekker, Inc., 1995. 2. Bonnet AM, Serre I, Marconi R, Agid Y, DuBois B. A “combined” levodopa test as a useful method for evaluating the efficacy of dopamine agonists: application to pergolide and bromocriptine. Movement Disorders 1995;10(5):668 –71. 3. Collier TJ, Kordower JH. Fetal nigral transplants: a preclinical and clinical prospectus. In: Koller WC, Paulson G. Therapy of Parkinson’s disease, 2nd Edition. Marcel Dekker, Inc., 1995. 4. Denson MA, Wszolek ZK. Familial parkinsonism: our experience and review. Parkinsonism and Related Disorders. 1995;1(1):35– 46. 5. Di Rocca A, Molinari SP, Kollmeier B, Yahr MD. Parkinson’s disease: progression and mortality in the L-DOPA era. In: Battistin L, Scarlato G, Caraceni T, Ruggieri S, eds. Advances in Neurology Volume 69, Lippincott–Raven Publishers, Philadelphia, 1996. 6. Dogali M, Sterio D, Fazzini E, Kolodny E, Eidelberg E, Beric A. Effects of posteroventral pallidotomy on Parkinson’s disease. Battistin L, Scarlato G, Caraceni T,
18. 19.
20.
21. 22.
23.
Ruggieri S. Advances in neurology, Volume 69 Lippencott–Raven, 1996. Eidelberg D, Moeller VR, Ishikawa T, Dhawan V, Spetsieris P, Silbersweig D, Stern E, Woods RP, Fazzini E, Dogali M, Beric A. Regional metabolic correlates of surgical outcome following unilateral pallidotomy for Parkinson’s disease. Annals of Neurology 1996;39: 450 –9. Ellenberg, Joseph H, Koller, William C, Langston J, William. Etiology of Parkinson’s disease. Marcel Dekker 1995. Folkerth RD, Durso R. Survival and proliferation of nonneural tissues, with obstruction of cerebral ventricles, in a parkinsonian patient treated with fetal allografts. Neurology 1996;46:1219 –25. Goetz CG, Diederich NJ. Dopaminergic agonists in the treatment of Parkinson’s disease. In: Neurologic Clinics; Parkinson’s Disease 10(2)May 1992. Golbe L. Epidemiology. In: Litvan I, Agid, Yves. Progressive Supranuclear Palsy; Clinical and Research Approaches. Oxford University Press, 1992. Hallett M. Physiology of basal ganglia disorders. Le Journal Canadien des Sciences Neurologiques 1993; 20:177– 83. Hutton JT, Morris JL. Long-acting levodopa preparations. In: Koller WC, Paulson G. Therapy of Parkinson’s disease, 2nd Edition. Marcel Dekker, Inc., 1995. Iacono RP, Lonser RR, Mandubur G, Yamada S. Stimulation of the globus pallidus in Parkinson’s disease. Br J Neurosurg 1995;9:505–10. Jancovic J, Cardoso F, Grossman RG, Hamilton WJ. Outcome after stereotactic thalamotomy for parkinsonism, essential, and other types of tremor. Neurosurgery 1995 Oct;37(4):680 – 6. Jenner P. The Rationale for the Use of Dopamine Agonists in Parkinson’s Disease. Neurology 45 (suppl. 3) March 1995;S6 –S11. Kelly PJ. Stereotactic thalamotomy. In: Koller WC, Paulson G, eds. Therapy of Parkinson’s Disease, 2nd Edition. Marcel Dekker, Inc., 1995. Koller WC, Silver DE, Lieberman A. An algorhythm for the management of Parkinson’s disease. Neurology 1994;44(suppl. 10):S5–S52. Kordower JH, Freeman TB, Snow BJ, Vingerhoets FJ, Mufson EJ, Sanberg PR, Hauser RA, Smith DA, Nauert GM, Perl DP, Olanow CW. Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson’s disease. N Engl J Med 1995; 332:1118 –24. Kreider MS, Knox S, Gardiner D, Wheadon DE. The Efficacy of Ropinirole, a non-ergoline agonist, as an adjunct to L-Dopa (DCI) in patients with Parkinson’s disease. Movement Disorders, 11;(suppl. 1) 1996. Langston JW. Predicting Parkinson’s disease. Neurology 40 (suppl. 3) October 1990. LeWitt PA, Ward CD, Larsen TA, Raphaelson MI, Newman RP, Foster N, Dambrosia JM, Calne DM. Comparison of pergolide and bromocriptine therapy in parkinsonism. Neurology 1983;33:1009 –14. Limousin P, Pollak P, Benazzouz A, Hoffman D, Brousolle E, Perret JE, Benabid AL. Bilateral subthalamic nucleus stimulation for severe Parkinson’s disease. Movement Disorders 1995;10(5):672– 4.
322 Surg Neurol 1999;52:318 –22
24. Lindvall O. Neural transplantation. In: Cell Transplantation. Elsevier Science Ltd.; 1995;4(4):393– 400. 25. Lozano AM, Lang AE, Galvez-Jimenez N, Miyasaki J, Duff J, Hutchinson WD, Dostrovsky JO. Effect of GPI pallidotomy on motor function in Parkinson’s disease. Lancet 1995;346:1383– 87. 26. Marsden CD, Fahn S. Problems in Parkinson’s disease and other akinetic-rigid syndromes. Movement Disorders 2. Marsden CD, Fahn S, eds. Butterworth & Co. Ltd, 1987. 27. Mierau J, Schneider FJ, Ensinger HA, Chio CL, Lajiness ME, Huff RM. Pramipexole Binding and Activation of Cloned and Expressed Dopamine D2, D3, and D4 Receptors. Eur J Pharmacol, Mol Pharmacol Sec 1995; 290:29 –36. 28. Montastruc JL, Rascol O, Senard JM. Current status of dopamine agonists in Parkinson’s disease. Drugs 1993;46(3):384 –393. 29. Pezzoli G, Martignoni E, Pachetti C, Angeleri V, Lamberti P, Muratorio A, Bonuccelli U, DeMari M, Foschi N, Cossutta E, Nicoletti F, Giammona G, Canesi M, Scarlato G, Caraceni T, Moscarelli E. A crossover, controlled study comparing pergolide with bromocriptine as an adjunct to levodopa for the treatment of Parkinson’s disease. Neurology 1995; 45(suppl 3):S22–S27. 30. Pollak P, Benabid AL, Gross C, Gao DM, Laurent A, Benazzouz A, Hoffman D, Gentil M, Perret J. Effets de la stimulation du noyau sous-thalamique dans la maladie de Parkinson. Revue Neurologique (Paris), 1993;149(3):175–176. 31. Quinn N. Multiple systems atrophy. In: Movement Disorders 3. Marsden CD, Fahn S, eds. Butterworth– Heinemann Ltd, 1994. 32. Roche Laboratories Inc. Revised Tasmar (tolcapone) Package Insert, November, 1998.
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33. Sage JI, Duvoisin RC. Pergolide. In: Koller WC, Paulson G. Therapy of Parkinson’s disease, 2nd Edition. Marcel Dekker, Inc., 1995. 34. Schapira AHV. Neurotoxicity and the mechanisms of cell death in Parkinson’s disease. In: Advances in Neurology Volume 69, Battistin L, Scarlato G, Caraceni T, Ruggieri S, eds. Lippincott–Raven Publishers, Philadelphia, 1996. 35. Seidler A, Hellebrand W, Robra B-P, Vieregge P, Nischan P, Joerg J, Oertel WH, Ulm G, Schneider E. Possible environmental, occupational, and other etiologic factors for Parkinson’s disease: a case-control study in Germany. Neurology 1996;46:1275– 84. 36. Shannon KM, Goetz CG. Transplantation of adrenal medullary tissue to Parkinson’s disease. In: Koller WC, Paulson G, eds. Therapy of Parkinson’s Disease, 2nd Edition. Marcel Dekker, Inc., 1995. 37. Shinotoh H, Calne S, Calne DB. Does selegiline afford neuroprotection? In: Koller WC, Paulson G, eds. Therapy of Parkinson’s disease, 2nd Edition. Marcel Dekker, Inc., 1995. 38. Tanner CM. Epidemiologic clues to the cause of Parkinson’s disease. In: Marsden CD, Fahn S, eds. Movement Disorders 3. Butterworth–Heinemann, Ltd., 1994. 39. Tolosa ES, Valldeoriola F, Marti MJ. New and emerging strategies for improving levodopa treatment. Neurology 1994;44(suppl 6):S35– 44. 40. Weiner WJ, Lang AE. Movement disorders: a comprehensive survey. Futura 1989:2–3. 41. Wolters EC, Tissingh G, Bergmans PLM, Kuiper MA. Dopamine agonists in Parkinson’s disease. Neurology 1995;45(suppl 3):S28 –S34. 42. Yoshikawa T, Minamiyama Y, Naito Y, Kondo M. Antioxidant properties of bromocriptine, a dopamine agonist. J Neurochem 1994;62:1034 – 8.
When purchasing health care, people do not have the sense that they are spending their own money.” Ninety-five percent of all costs incurred during hospitalizations and 81% of physician’s fees are paid by someone (government or private insurance) other than the person seeking medical care. As a result, patients do not have an incentive to reduce costs; market forces are lacking in the health care delivery system. The end result is that costs continue to escalate. More government and more bureaucracy is not the answer.
“
—Miguel A. Faria, Jr., M.D. “Vandals at the Gates of Medicine: Historic Perspectives on the Battle Over Health Care Reform” (1994)