Treatments of Parkinson Disease


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Treatments of Parkinson Disease

  1. 1. NEUROLOGICAL REVIEW SECTION EDITOR: DAVID E. PLEASURE, MD Treatments of Parkinson Disease Circa 2003 Clifford W. Shults, MD P arkinson disease (PD) is a progressive degenerative neurological disorder characterized by resting tremor, bradykinesia, cogwheel rigidity, and postural instability.1 In the later stages, approximately 25% or more of patients develop cognitive compromise. The car- dinal pathological features of PD are degeneration of dopaminergic neurons in the sub- stantia nigra pars compacta and their axons, which project principally to the caudate and puta- men, and the presence of eosinophilic intracytoplasmic inclusions, Lewy bodies.2,3 Although the loss of neurons is most conspicuous in the substantia nigra pars compacta, neuronal loss and/or Lewy bodies are found in other brain regions (eg, the locus coeruleus, entorhinal region, and amyg- dala),2 which suggests that treatments that target only the nigrostriatal dopaminergic system, though they may substantially benefit patients, are unlikely to completely resolve the deficits of PD. Arch Neurol. 2003;60:1680-1684 The neurologist or movement disorders has been proved unequivocally to do so. specialist caring for patients with Par- Selegiline hydrochloride, also referred to kinson disease (PD) often is confronted as deprenyl, which irreversibly inhibits with the following questions: Is there a monoamine oxidase B but may have neu- treatment that slows the progression of roprotective effects independent of mono- PD? Which medication(s) should be amine oxidase B, was the first agent to be used first in the treatment of PD? What evaluated for its ability to slow the clini- should be done for patients who have cal decline in PD. The Parkinson Study begun to have motor fluctuations and/or Group4 found in the Deprenyl and To- dyskinesia? What is the role of surgery copherol Antioxidative Therapy of Par- in the treatment of PD, and which sur- kinsonism study in patients with early PD gical treatment is best? What can be that 5 mg of selegiline twice a day de- done for patients with cognitive com- layed the time until levodopa was re- promise and/or hallucinations? Are new quired by approximately 9 months. How- treatments on the horizon for PD? In ever, improvement in the scores on the this article, I provide a synthesis of the motor portion of the Unified Parkinson available information regarding each of Disease Rating Scale (UPDRS) after be- these questions. ginning selegiline treatment (wash-in) and worsening after withdrawal of selegiline IS THERE A TREATMENT THAT treatment (washout) suggested that the SLOWS THE PROGRESSION OF PD? effect was more likely because of a symp- tomatic effect caused by reduction in the The first goal of PD treatment should be metabolism of dopamine than because of to slow the degeneration of the nigrostria- a neuroprotective effect. Authors of other tal dopaminergic system and functional de- studies have also reported a significant cline in patients with PD, but no therapy wash-in effect, and because of this con- founding symptomatic effect of selegi- From the Department of Neurosciences, University of California, San Diego, La Jolla, line, a neuroprotective effect has not been and the VA San Diego Healthcare System, San Diego. unequivocally demonstrated. (REPRINTED) ARCH NEUROL / VOL 60, DEC 2003 WWW.ARCHNEUROL.COM 1680 Downloaded from on October 18, 2010 ©2003 American Medical Association. All rights reserved.
  2. 2. Two studies compared ropinirole hydrochloride5 ate the development of motor fluctuations; they prefer or pramipexole dihydrochloride 6 with levodopa in to use selegiline, amantadine hydrochloride, an anticho- patients with early PD (see details presented later) and linergic drug, or a dopaminergic agonist. Follow-up in ancillary components of the 2 studies used [18F]fluo- the Deprenyl and Tocopherol Antioxidative Therapy of rodopa positron emission tomography7 or [123I]-2 - Parkinsonism study revealed that patients treated early carbomethoxy-3 -(4-iodophenyl)-tropane (β-CIT) with selegeline were more likely to develop dyskinesias single-photon emission computed tomography,8 respec- but less likely to develop freezing of gait. Amantadine tively, as biological markers of the preservation of has been demonstrated to have a modest but statisti- remaining nigrostriatal dopaminergic axons. Patients cally significant improvement in the clinical assess- treated initially with ropinirole had greater [18F]fluo- ments of PD. Side effects of amantadine can include rodopa accumulation in the striatum than did those peripheral edema, livedo reticularis, rash, and confu- treated with levodopa 2 years after initiation of therapy, sion. Anticholinergic drugs have their most substantial and patients treated initially with pramipexole had benefit in reduction of tremor and modest benefit in greater [123I] -CIT binding in the striatum than did bradykinesia and rigidity, but peripheral and central those treated with levodopa 2 years after study entry. side effects, particularly memory impairment and con- However, the effects of levodopa and dopaminergic ago- fusion, limit their use typically to younger patients with nists on accumulation of [18F]fluorodopa and [123I] - prominent tremor. CIT are not known, and these agents may cause adap- Two prospective, randomized, double-blind studies tive changes in [ 18 F]fluorodopa metabolism and/or assessed the long-term outcome in patients with early [123I] -CIT binding, so the results cannot be unequivo- PD initially treated with ropinirole5 or pramipexole,6 as cally interpreted as indicative of preservation of nigro- compared with the outcome in patients treated with striatal dopaminergic axons.9 levodopa. In both studies, open-label levodopa could be Shults et al10 reported in a phase 2 trial of 3 dosages added after the initial period of titration of levodopa or (300, 600, and 1200 mg/d) of coenzyme Q10 vs placebo agonist if the response to the assigned treatment was no in patients with early untreated PD a positive trend to- longer satisfactory. Results of both studies demonstrated ward slowing functional decline as measured with the that levodopa was significantly more effective in reduc- UPDRS. The authors stress that the results need to be con- ing the score on the UPDRS than was the agonist. Rascol firmed and extended in a definitive phase 3 trial before et al5 reported that after 5 years, 20% of the subjects ini- the recommendation can be made for widespread use of tially assigned to ropinirole developed dyskinesia, while coenzyme Q10 for PD. 45% of the subjects assigned to levodopa developed dys- Recently, Fahn and colleagues in the Parkinson Study kinesia. The Parkinson Study Group6 reported that 10% Group11 compared carbidopa-levodopa (12.5 mg of car- of patients initially randomized to pramipexole devel- bidopa and 50 mg of levodopa, 25 mg of carbidopa and oped dyskinesia, while 31% of patients initially assigned 100 mg of levodopa, or 50 mg of carbidopa and 200 mg to carbidopa-levodopa developed dyskinesia. Also, of levodopa) 3 times a day with placebo and found a dose- patients treated with pramipexole first were less likely to dependent reduction in the total score on the UPDRS. develop any of the 3 motor complications: wearing off, The benefit persisted for 2 weeks after discontinuation on-off, or dyskinesia. of treatment with levodopa, which suggests the possi- A number of conclusions can be drawn from these bility that levodopa slowed the degeneration of the ni- 2 studies. First, treatment with a dopaminergic agonist grostriatal dopaminergic system. However, imaging the or levodopa ameliorated the symptoms of PD to a level dopamine transporter with [123I] -CIT single-photon that the patient and investigator considered satisfactory. emission computed tomography indicated greater reduc- Second, both dopaminergic agonists and levodopa were tion in transporter level with levodopa treatment; this dis- typically well tolerated, but side effects, such as nausea crepancy and the possibility that treatment with le- or hallucinations, were not uncommon and were gener- vodopa may cause adaptive changes in the nigrostriatal ally more common with the agonists than with levo- dopaminergic system make interpretation of a neuro- dopa. Subsequent meta-analysis has indicated that sud- protective effect of levodopa uncertain. Fahn’s study den sleepiness appears to be more common with the should allay concerns that use of levodopa accelerates new agonists. Third, in both studies, levodopa reduced clinical decline in patients with PD. No drug has been the score on the UPDRS more than did the agonist. shown unequivocally to slow the progression of PD. Fourth, initial use of a dopaminergic agonist resulted in a reduced development of dyskinesia. The fourth con- WHICH MEDICATION(S) SHOULD BE USED clusion is somewhat controversial because the groups FIRST IN THE TREATMENT OF PD? were not comparable for the effect of therapy (patients treated with levodopa showed greater improvement in Introduction of levodopa revolutionized treatment of PD.3 UPDRS scores), and the question has been raised Unfortunately, one third to one half of patients treated whether patients treated with an agonist would have had with levodopa develop motor fluctuations (“wearing off” a greater risk of dyskinesia if they had had improvement and sudden “on-off”) and/or dyskinesia within 5 years equivalent to that of the patients treated with levodopa. after beginning treatment.5,6 Studies have been performed to evaluate whether ini- Some clinicians prefer to avoid levodopa as the ini- tial treatment with controlled-release formulations of le- tial treatment because of concerns that levodopa may vodopa could lessen the development of motor fluctua- exacerbate loss of dopaminergic neurons and/or acceler- tions (eg, wearing off or on-off), but they have not (REPRINTED) ARCH NEUROL / VOL 60, DEC 2003 WWW.ARCHNEUROL.COM 1681 Downloaded from on October 18, 2010 ©2003 American Medical Association. All rights reserved.
  3. 3. demonstrated a decrease in the development of fluctua- Results of the study by Metman et al16 and other tions. Thus, there is no reason to use controlled-release more recent studies showed that treatment with aman- levodopa for the initial treatment of PD.12 tadine (up to 300 or 400 mg/d) reduced dyskinesia Because no treatment has been proved to slow the induced by intravenous or oral levodopa or as measured progression of PD, there is no compelling reason to be- as cumulative dyskinesia recorded in diaries. Selegiline gin using this medication until the patient’s disability war- has been found to improve motor function in patients rants it. Levels of disability that warrant medication vary receiving levodopa, but the improvement has typically among patients with PD; for example, the level of ac- been modest. ceptable slowness may differ between patients with PD In patients with wearing off, addition of a dopamin- who are working and those who are retired. Although ergic agonist, controlled-release levodopa, or a COMT selegiline, amantadine, and anticholinergic drugs can ame- inhibitor can reduce off time. In patients with dyskine- liorate the disability in early PD, the benefit is typically sia, addition of amantadine can substantially reduce dys- modest, and most patients soon need treatment with le- kinesia. vodopa or a dopaminergic agonist. Use of an agonist as the initial treatment will reduce but not eliminate the in- WHAT IS THE ROLE OF SURGERY cidence of dyskinesia, and this benefit should be weighed IN THE TREATMENT OF PD, AND against the greater reduction in symptoms and signs of WHICH SURGICAL TREATMENT IS BEST? PD and lower cost of levodopa. Both dopaminergic ago- nists and levodopa are acceptable and appropriate ini- Three regions in the brain have been targeted for surgi- tial treatments for PD. cal intervention in PD: the thalamus, globus pallidus in- terna (GPi), and subthalamic nucleus (STN). Ablative pro- WHAT SHOULD BE DONE FOR PATIENTS cedures (eg, thalamotomy or pallidotomy) were initially WHO HAVE BEGUN TO HAVE MOTOR used but recently have been largely supplanted by deep FLUCTUATIONS AND/OR DYSKINESIA? brain stimulation (DBS). A number of excellent re- views, such as the one by Lang,17 provide a more de- Controlled-release formulations of levodopa reduce the tailed discussion. number of doses needed, but, surprisingly, the increase Thalamotomy and DBS of the thalamus can both in the on time with controlled-release levodopa is rela- markedly reduce tremor in the contralateral arm but have tively modest.13 Dopaminergic agonists are often added little effect on rigidity and bradykinesia; DBS has been to levodopa to treat PD, and results from a number of reported to have fewer adverse effects and result in greater studies have demonstrated improvement. Addition of functional improvement. However, bilateral thala- bromocriptine mesylate, pramipexole, or placebo in motomy and DBS lead to impairment in speech and swal- patients treated with levodopa who had motor fluctua- lowing and should be avoided. tions has been studied, and both bromocriptine and In the 1990s, there was a renewal of interest and ac- pramipexole significantly improved scores on the tivity in pallidotomy and later advancing to DBS. Most UPDRS part II (activities of daily living) and part III of the reports on pallidotomy for PD have not been pro- (motor score), as compared with placebo; pramipexole, spective, randomized, or blinded. However, de Bie et al18 but not bromocriptine, caused a significant reduction in conducted a prospective randomized trial of unilateral the time spent in the off state.14 The agonists initially pallidotomy vs medical therapy and found significant ben- introduced, bromocriptine and pergolide mesylate, are efit as assessed with the motor portion of the UPDRS dur- ergot derivatives and rarely are associated with fibrosis, ing a clinically defined off period and with measures of such as in the pleura or heart. The more recently intro- activities of daily living and dyskinesia. Vitek et al19 re- duced agonists, such as pramipexole and ropinirole, cently confirmed this finding. Patients undergoing uni- appear not to have this side effect and are used more lateral pallidotomy may experience major persistent ad- commonly. verse events, and bilateral pallidotomy is also often In the periphery, levodopa is metabolized by aro- accompanied by serious adverse events, most fre- matic–amino acid–decarboxylase and catechol O- quently impairments of speech and cognition.17 methyltransferase (COMT). Two COMT inhibitors, en- Deep brain stimulation of the GPi or STN has largely tacapone and tolcapone, are currently marketed. Results supplanted unilateral pallidotomy because of the ability of some studies have indicated that addition of tolca- to manipulate the circuitry bilaterally and a reduced like- pone in patients receiving levodopa who have fluctua- lihood of permanent adverse events. The Deep-Brain tions can decrease the percentage of off time by 2 to 3 Stimulation for Parkinson’s Disease Study Group20 per- hours. However, approximately 3% to 4% of patients formed a study in which 18 centers enrolled 143 pa- treated with tolcapone developed abnormalities in liver tients with PD and implanted bilateral electrodes in ei- function tests, and 3 deaths from liver failure occurred. ther the STN (n = 96) or GPi (n = 38) in 134 patients, The hepatotoxicity led to a ban of tolcapone in the Eu- according to the experience and preference of the inves- ropean Union and to stringent controls of its use in the tigators at each site. After 3 months, the patients were United States. In patients with wearing off, addition of assessed with the motor portion of the UPDRS after over- entacapone caused a 5% increase in the on time of ap- night discontinuation of medication and stimulation. Sig- proximately 1 hour and reduction in levodopa dose by nificant improvement was reported in both groups of pa- approximately 12%.15 The COMT inhibitors can be ben- tients—STN stimulation (49%) and GPi stimulation eficial in patients with PD with wearing off. (37%). Home diaries indicated increase in the on time (REPRINTED) ARCH NEUROL / VOL 60, DEC 2003 WWW.ARCHNEUROL.COM 1682 Downloaded from on October 18, 2010 ©2003 American Medical Association. All rights reserved.
  4. 4. without dyskinesia. However, 7 intracranial hemor- regeneration of the nigrostriatal dopaminergic system in rhages and 2 infections requiring removal of electrodes PD. Much of the work has focused on trophic factors, occurred in the 143 patients. with the most promising being glial cell line–derived The data suggest that in patients with advanced PD neurotrophic factors (GDNF). Nutt et al24 conducted a that cannot be managed satisfactorily with medication, multicenter, randomized, double-blind, placebo- DBS of either the GPi or STN can improve motor func- controlled, sequential cohort study to compare the tion and reduce dyskinesia. As with pallidotomy, there effects of monthly intracerebroventricular administra- is the risk of intracranial hemorrhage and neuropsycho- tion of placebo and escalating doses of GDNF in 50 logical changes and the additional risks of infection and subjects with PD. The total score and the score on the hardware failure. The superior site for DBS—GPi or motor portion of the UPDRS during clinically defined STN—remains uncertain, but the Department of Veter- on and off periods did not improve with GDNF. Com- ans Affairs (Washington, DC) and National Institute of mon adverse events included nausea, anorexia, vomit- Neurological Disorders and Stroke (Bethesda, Md) are ing, weight loss, paresthesia, and hyponatremia. Nutt et performing a prospective randomized trial to address this al24 hypothesized that GDNF did not improve parkin- question. sonism, possibly because it did not reach the target tis- sues, the putamen and substantia nigra pars compacta. WHAT CAN BE DONE FOR PATIENTS The results of their study underscore the need for WITH COGNITIVE COMPROMISE delivery of the trophic factor to the appropriate target AND/OR HALLUCINATIONS? (eg, the striatum) and for delivery of the trophic factor in a controlled fashion. Results of a recent pilot study The prevalence of dementia in patients with PD is ap- suggest that direct infusion into the putamen may be proximately 25% and increases with advancing disease; beneficial. approximately 15% develop hallucinations. Aarsland et Neuroimmunophilin ligands (eg, GPI-1046) have al21 reported that treatment with donepezil modestly but also been reported to promote regeneration of the statistically significantly improved the score on the Mini- injured nigrostriatal dopaminergic system, but this Mental State Examination in patients with PD with cog- finding is controversial. Neuroimmunophilin ligand-A nitive impairment. (GPI-1485) has been studied in patients with PD in 1 Typical antipsychotic drugs cause worsening of trial, but the results were disappointing.25 Neuroim- parkinsonian features and should be avoided in patients munophilin ligands are still considered deserving of with PD. Clozapine has been shown to improve drug- further study in PD,26 and an additional trial is under induced psychosis significantly in patients with PD way. without worsening of parkinsonism. However, patients Research in PD has recently elucidated a number receiving clozapine can develop agranulocytosis, as well of processes that appear to contribute to degeneration as seizures and myocarditis, and the complete blood and to identify interventions in these processes. These cell count must be monitored closely. pathogenic mechanisms include mitochondrial dys- Other atypical antipsychotic drugs have been stud- function, oxidative stress, impaired protein degrada- ied in PD. However, olanzapine worsens parkinsonism. tion, abnormal protein aggregation, inflammation, and Risperidone has recently been reported to be associated apoptosis. An encouraging development has been the with an increase in the incidence of stroke when used in National Institute of Neurological Disorders and Stroke elderly patients with dementia. Although controlled pro- Neuroprotection Exploratory Trials in PD, which has spective studies of quetiapine for the treatment of psy- the mandate to identify agents with the potential to chosis in PD have not been reported, it has been de- slow the progression of PD and then conduct clinical scribed as reducing psychosis in patients with PD without trials with the most promising agents.26 Neurologists worsening parkinsonism. should encourage patients with PD to consider partici- pating in clinical trials supported both by federal agen- ARE NEW TREATMENTS cies, such as National Institute of Neurological Disor- ON THE HORIZON FOR PD? ders and Stroke and the Department of Veterans Affairs, and pharmaceutical firms because only through pro- Transplantation of fetal mesencephalic cells in patients spective, randomized placebo-controlled trials will neu- with PD has been studied in 2 prospective, randomized, rologists and patients develop better treatments for PD. sham operation-controlled trials by Freed et al22 and Olanow et al23 in patients with PD. Results of [18F]fluoro- Accepted for publication May 29, 2003. dopa positron emission tomography in these patients Dr Shults is a coinventor in a pending patent appli- indicated that the implanted cells survived and were bio- cation for use of coenzyme Q10 in neurodegenerative dis- chemically functional. In both studies, the primary eases. The application is jointly owned by Enzymatic analysis indicated that the procedure did not lead to Therapy, Inc, Green Bay, Wis (owner of Vitaline Corp, functional improvement in patients who had fetal dopa- Ashland, Ore), and The Regents of the University of Cali- minergic cells implanted. Some of the patients with fornia. transplanted cells developed disabling dyskinesia that Corresponding author and reprints: Clifford W. could not be controlled with medication adjustment. Shults, MD, Neurology Service 127, VA San Diego Health- In the past decade, extensive research has been care System, 3350 La Jolla Village Dr, San Diego, CA directed to the development of therapies to induce 92161 (e-mail: (REPRINTED) ARCH NEUROL / VOL 60, DEC 2003 WWW.ARCHNEUROL.COM 1683 Downloaded from on October 18, 2010 ©2003 American Medical Association. All rights reserved.
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