Differential progression of motor impairment in levodopa-treated Parkinson's disease.

OBJECTIVE: To monitor comparative progression of clinical impairment over 4 years in patients with Parkinson's disease (PD) who present on levodopa at two different levels of Hoehn and Yahr (HY) stages, II and III. BACKGROUND: The rate of clinical impairment progression in patients with PD being treated with levodopa has not been studied in detail using current, standardized assessment tools. Sample size estimates for all levodopa adjunctive treatment studies and proper definition of study groups require a solid estimate of longitudinal motor impairment progression. DESIGN/METHODS: From our computer database, we identified two groups of patients with PD being treated with levodopa based on their initial HY stage at presentation to our center (II or III). Fifty randomly selected subjects in each stage were monitored in the ON state with annual Unified Parkinson's Disease Rating Scale (UPDRS) motor scores, dyskinesia ratings, and antiparkinsonian medication doses using a repeated measures analysis of variance. RESULTS: The stage II and stage III subjects had similar disease duration. In stage II subjects, parkinsonian impairment was maintained without progression over 4 years, but in association with significantly higher dyskinesia scores and dopaminergic medication doses. In stage III subjects, UPDRS motor scores deteriorated despite more medication and increased dyskinesias. Of the established six factors comprising the UPDRS motor scale, bradykinesia accounted for the increased impairment. Initial UPDRS motor score and disease duration did not influence progression of motor impairment. CONCLUSION: In subjects with similar disease duration, progression of PD motor impairment differs significantly between stage II and stage III subjects over 4 years. Whereas in stage II subjects, parkinsonian impairment can be stabilized at the expense of increased dyskinesia and dopaminergic drugs, once subjects reach stage III, motor impairment progresses. Power estimates and sample size calculations for these groups of patients should be calculated separately.     

Observational study of sleep-related disorders in Italian patients with Parkinson’s disease: usefulness of the Italian version of Parkinson’s disease sleep scale

Sleep disturbances are common in patients with Parkinson's disease (PD). We aimed to evaluate prevalence and severity of nighttime sleep disturbances in Italian PD patients and to validate the Italian version of the Parkinson's disease sleep scale. A total of 221 PD patients and 57 healthy controls participated in a cross-sectional study with retest. PDSS, Epworth Sleepiness Scale (ESS), Hamilton Depression Rating Scale, Unified Parkinson's Disease Rating Scale (UPDRS), and Hoehn and Yahr staging were applied. PDSS total and individual items scores from patients were significantly lower than those in controls. Internal consistency of PDSS scale was satisfactory and intraclass correlation coefficient for test-retest reliability was 0.96 for total PDSS score. A significant negative correlation was found between total PDSS and ESS scores, and between total PDSS and HDRS scores. PDSS scores were also related to UPDRS sections II, III and IV, and H&Y stage. PDSS and ESS scores were not related to levodopa equivalent dose. Daytime sleepiness, depressive symptoms and disease severity correlate with sleep disturbances in Italian PD patients. The PDSS is a valid and reliable tool to evaluate sleep disturbances in Italian patients.     

Bladder symptoms assessed with overactive bladder questionnaire in Parkinson's disease

In Parkinson's disease (PD) the urinary dysfunction manifests primarily with symptoms of overactive bladder (OAB). The OAB questionnaire (OAB‐q) is a measure designed to assess the impact of OAB symptoms on health‐related quality of life. In this study, we quantified the urinary symptoms in a large cohort of PD patients by using the OAB‐q short form. Possible correlations between the OAB‐q and clinical features were tested. Three hundred and two PD patients were enrolled in the study. Correlations between the OAB‐q and sex, age, Unified Parkinson's Disease Rating Scale part III (UPDRS‐III), Hoehn‐Yahr (H‐Y) staging, disease duration, and treatment were analyzed. Data were compared with a large cohort of 303 age‐matched healthy subjects. The OAB‐q yielded significantly higher scores in PD patients than in healthy subjects. In the group of PD patients, all the variables tested were similar between men and women. Pearson's coefficient showed a significant correlation between mean age, disease duration, mean OAB‐q scores, UPDRS‐III scores, and H‐Y staging. A multiple linear regression analysis showed that OAB‐q values were significantly influenced by age and UPDRS‐III. No statistical correlations were found between OAB‐q scores and drug therapy or the equivalent levodopa dose, whilst the items relating to the nocturia symptoms were significantly associated with the equivalent levodopa dose. Our findings suggest that bladder dysfunction assessed by OAB‐q mainly correlates with UPDRS‐III scores for severity of motor impairment, possibly reflecting the known role of the decline in nigrostriatal dopaminergic function in bladder dysfunction associated with PD and patients' age. Our study also suggests that the OAB‐q is a simple, easily administered test that can objectively evaluate bladder function in patients with PD. © 2010 Movement Disorder Society     

A favorable response to antiparkinsonian treatment in juvenile neuronal ceroid lipofuscinosis

To study the effect of dopaminergic drugs on the parkinsonism in juvenile neuronal ceroid lipofuscinosis, the authors conducted an open study of 21 patients. According to the motor Unified PD Rating Scale (UPDRS) score, treatment was initiated with either levodopa (n = 10) or selegiline (n = 6). Five patients served as a control group. The UPDRS score after 1 year was compared with the score at onset. Both in the control group and in the selegiline group, the mean UPDRS score increased, whereas in the levodopa group, the mean UPDRS score decreased. The difference between the levodopa group and the control group was significant.     

Medication dose reductions after pallidal versus subthalamic stimulation in patients with Parkinson's disease

Evidente VGH, Premkumar AP, Adler CH, Caviness JN, Driver‐Dunckley E, Lyons MK. Medication dose reductions after pallidal versus subthalamic stimulation in patients with Parkinson’s disease.
Acta Neurol Scand: 2011: 124: 211–214.
© 2010 John Wiley & Sons A/S. Objective – To compare the medication dose reduction between deep brain stimulation (DBS) of the globus pallidus interna (GPi) vs subthalamic nucleus (STN) in matched patients with Parkinson’s disease (PD). Materials and methods – Records of 12 patients with PD who underwent GPi‐DBS at our institution from 2002 to 2008 were matched by pre‐operative PD medication doses and pre‐operative motor Unified Parkinson’s Disease Rating Scale (UPDRS) scores to 12 cases of STN‐DBS. PD medication doses were converted to levodopa equivalent doses (LEDs). Results – GPi and STN groups had similar mean pre‐operative LEDs and motor UPDRS scores. At 6 months post‐DBS, there was no significant difference in percent reduction in LEDs between the GPi (47.95%) and STN (37.47%) groups (P = 0.52). The mean post‐operative ‘medication off/stimulation on’ motor UPDRS scores did not differ significantly between GPi (15.33) and STN (16.25) groups (P = 0.74). The mean percent reduction in motor UPDRS scores was also similar between GPi (58.44%) and STN (58.98%) patients (P = 0.94). Conclusions – We conclude that in disease‐matched patients with PD undergoing DBS, both GPi and STN may result in similar reduction in PD medication doses.     

Anxious and depressive symptoms in Parkinson's disease: The French cross‐sectionnal DoPaMiP study

Anxiety has been less extensively studied than depression in Parkinson's disease (PD). The DoPaMiP survey allowed assessing simultaneously anxiety and depressive symptoms in PD and comparing correlations of both symptoms with clinical and therapeutic features of the disease. Cross sectional survey conducted prospectively in 450 ambulatory nondemented PD patients and 98 patients with other disorders than PD. Anxiety and depressive symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS), parkinsonism using the Unified Parkinson's Disease Rating Scale (UPDRS). Other clinical factors were measured using a structured standardized examination/questionnaire. The mean HADS‐A (anxiety) subscore was higher in PD patients than in the others (8.2 ± 3.9 vs. 6.5 ± 3.2, P < 10^?4) as was the HADS‐D (depressive) subscore (6.6 ± 3.8 vs. 3.9 ± 3.2, P < 10^?4). Patients with possible/probable anxious signs (HADS‐A ≥ 8) were more prevalent in PD (51% vs. 29%, P < 10^?4) as were those with depressive symptoms (40% vs. 10%, P < 10^?4). Conversely, anxiolytic and antidepressant medications consumption was not different between the 2 groups. Patients with anxious symptoms were more frequently female and younger than those without such symptoms, while those with depressive symptoms had more severe indices of parkinsonism, more comorbidities and lower cognitive function (Mini Mental State Exam). The logistic regression model revealed that patients with depressive symptoms received more frequently levodopa and less frequently a dopamine agonist. Anxiety and depressive symptoms were more frequent in PD patients than in medical control group. Both symptoms were commonly associated in the same PD patients, but were correlated with different clinical/therapeutic features, suggesting different underlying pathophysiological mechanisms. © 2009 Movement Disorder Society     

Intravenous amantadine improves levadopa-induced dyskinesias: an acute double-blind placebo-controlled study.

Experimental evidence suggests that glutamatergic receptor blockade may improve the motor response complications associated with long-term levodopa treatment in Parkinson's disease (PD) patients. Our objective was to evaluate the acute effect of amantadine, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, on levodopa-induced dyskinesias, and to gain further insights into the antidyskinetic mechanism of this drug. Nine PD patients with motor fluctuations and severely disabling peak of dose dyskinesias received their first morning levodopa dose, followed by a 2-hour intravenous amantadine (200 mg) or placebo infusion, on two different days. Parkinsonian symptoms and dyskinesias were assessed every 15 minutes during the infusion and for 3 hours thereafter, while patients were taking their usual oral antiparkinsonian therapy, by means of Unified Parkinson's Disease Rating Scale (UPDRS, motor examination), tapping test, and a modified Abnormal Involuntary Movement Scale (AIMS). Intravenous amantadine acutely improved levodopa-induced dyskinesias by 50%without any loss of the anti-parkinsonian benefit from levodopa. This study confirms the antidyskinetic effect of amantadine and strengthens the rationale for using antiglutamatergic drugs in the treatment of parkinsonian motor fluctuations.     

Motor features and response to oral levodopa in patients with Parkinson’s disease under continuous dopaminergic infusion or deep brain stimulation

Background: Subthalamic nucleus deep brain stimulation (STN DBS) and continuous dopaminergic infusions (jejunal levodopa or subcutaneous apomorphine) are indicated in complicated Parkinson’s disease (PD), although it remains unsettled how they compare to each other. Methods: We investigated the daytime motor condition in patients with advanced PD under monotherapy with jejunal levodopa, subcutaneous apomorphine, or STN DBS and also measured the motor changes produced by an additional standard morning dose of levodopa. Motor performance was assessed with the UPDRS‐III, hand taps, the AIMS dyskinesia score and patients’ diaries. Outcome measures were time to best motor ‘on’ after start of morning treatment, daytime variability of motor condition, motor scores. Results: The time to ‘on’ was longest in the jejunal levodopa group. DBS and jejunal levodopa treatments produced stable motor conditions without appreciable ‘off’ episodes. Continuous apomorphine infusion was associated with the worst motor scores (UPDRS‐III and taps) and the most frequent off‐states. Jejunal levodopa infusion was associated with the highest AIMS scores. Addition of a levodopa dose produced shortening of time to ‘on’ and a transient motor improvement in the jejunal levodopa group without increase in dyskinesias; in the DBS and apomorphine groups, there was an increase in dyskinesias without changes in UPDRS‐III or taps. Conclusions: STN DBS provided adequate trade‐off between motor improvement and dyskinesia control, although dyskinesias could be elicited by adding oral levodopa. Jejunal levodopa infusion produced adequate motor improvement with slow time to ‘on’ and moderate dyskinesias. Apomorphine infusion produced insufficient motor control and negligible dyskinesias.     

Subthalamic DBS replaces levodopa in Parkinson's disease: two-year follow-up

BACKGROUND: Subthalamic nucleus (STN) deep brain stimulation (DBS) of patients with PD allows reduction of antiparkinsonian medication but has only a mild direct effect on dyskinesia. Since antiparkinsonian medication has short- and long-term effects that may prevent an estimate of the maximal possible impact of STN DBS, such medication was used at the lowest possible dosage after DBS implantation. OBJECTIVE: To study the maximal and long-term effects of STN DBS using the lowest dose of medication. METHODS: Twenty consecutive patients with PD with motor fluctuations and dyskinesia underwent bilateral implantation under stereotactic guidance, microrecording, and clinical control. All medications were stopped before implantation and reintroduced, at the lowest dosage needed, only if the postoperative motor score did not reach the baseline level. Unified PD Rating Scale (UPDRS) motor (subscale III) scores were measured at baseline and after 3, 6, 12, and 24 months. RESULTS: After 21 plus minus 8 months, the UPDRS III "off-medication" score was decreased by 45% and was similar to the preoperative UPDRS III "on" score. Overall, medication was reduced by 79%, being completely withdrawn in 10 patients. Fluctuations and dyskinesia showed an overall reduction of >90%, disappearing completely in patients without medication. These improvements were maintained for 2 years. CONCLUSIONS: These results show that STN DBS could replace levodopa and allowed all antiparkinsonian medication to be discontinued in 50% of patients with PD. Fluctuations and dyskinesia disappeared completely in these patients but persisted in those still on medication. These improvements were maintained for 2 years.     

Levodopa withdrawal after bilateral subthalamic nucleus stimulation in advanced Parkinson disease

CONTEXT: Subthalamic nucleus (STN) stimulation may be effective in ameliorating parkinsonian symptoms even to the extent to permit levodopa withdrawal. OBJECTIVES: To analyze the efficacy of STN stimulation in patients with Parkinson disease (PD) and to determine if levodopa may be withdrawn after surgery. DESIGN: Before-after trial. SETTING: Referral center, hospitalized care. PATIENTS: Fifteen patients with advanced PD. INTERVENTIONS: Microelectrode-guided bilateral STN high-frequency stimulation. OUTCOME MEASURES: Before surgery patients were evaluated in off-medication and on-medication conditions. Dopaminergic drug dosages were reduced after surgery, aiming for complete withdrawal. Six months after surgery, patients were reeavaluated in off- and on-medication conditions, with the stimulation turned on and off. RESULTS: Total Unified Parkinson's Disease Rating Scale (UPDRS) motor score in the off-medication condition improved by 65.9%; and axial symptoms, bradykinesia, rigidity, and tremor improved by 65.8%, 60.4%, 66.1%, and 81.1%, respectively. UPDRS part II scores were reduced by 71.8% and Schwab and England scores improved by 45.3%. Levodopa was withdrawn in 8 patients and the overall levodopa dose was reduced 80.4%. "Off" time was reduced 89.7% and the severity of dyskinesias decreased 80.6% after surgery. All results reached significance (P<.001). Stimulation of the STN achieved antiparkinsonian effect similar to that of treatment with levodopa. No life-threatening adverse effects occurred. CONCLUSIONS: Bilateral STN stimulation safely improves all parkinsonian symptoms, decreases or eliminates the need for levodopa, and ameliorates motor fluctuations and dyskinesias. Complete withdrawal of levodopa is feasible with this technique and the overall motor effect of STN stimulation is quantitatively comparable to that obtained with levodopa.     

重复经颅磁刺激治疗帕金森病2年随访

目的随访观察重复经颅磁刺激(r TMS)治疗帕金森病(PD)患者的疗效。方法应用统一PD评分量表第Ⅲ部分(UPDRSⅢ)、Hoehn-Yahr(H-Y)分级、PD非运动症状(NMS)筛查问卷(NMSQ)、PD睡眠量表(PDSS)、汉密尔顿抑郁量表(HAMD)、汉密尔顿焦虑量表(HAMA)和简易智能量表(MMSE)对37例应用药物和r TMS治疗的PD患者(r TMS+药物组)及45例单纯药物治疗的PD患者(药物组)在基线和2年随访末的运动症状(MS)和非运动症状(NMS)进行评估,对比分析两组患者病情进展。结果 r TMS+药物组2年随访末H-Y分级较基线显著升高(P 0.05);药物组2年随访末UPDRSⅢ、H-Y分级、HAMD、HAMA评分及左旋多巴等效剂量(LED)较基线均显著升高(P 0.05);对两组2年随访末的症状进行比较,药物组的UPDRSⅢ、H-Y分级、HAMD评分及LED较r TMS+药物组升高显著(P 0.05)。结论规律的r TMS辅助常规抗PD药物治疗可减缓PD进展,优于单纯抗PD药物治疗。     

Effect of impulse control disorders on disability and quality of life in Parkinson’s disease patients

Impulse control and related disorders (ICRD) are not uncommon in patients with idiopathic Parkinson’s disease (PD). The present study aimed to investigate the effects of ICRD on quality of life (QoL) and disability in PD. From two movement disorder clinics in Sydney, Australia, 100 consecutive patients with PD were included in the trial. The Unified Parkinson’s Disease Rating Scale (UPDRS), Mini Mental State Examination and the Parkinson’s Disease Questionnaire-39 were used to measure disease severity, cognition and disease-specific QoL. The diagnosis of ICRD was based on face-to-face structured clinical interviews by three psychiatrists with experience in ICRD using the Expanded Structured Clinical Interview for the Diagnostic and Statistical Manual IV for Obsessive-Compulsive Disorder Related/Spectrum Disorders. ICRD were present in 15% of our patient population, and had a negative impact on QoL and Activity of Daily Living (ADL) scores. After adjusting for the presence of major depressive disorders and PD duration, the effect on emotional wellbeing remained statistically significant (p < 0.004). Disease duration also correlated with worse QoL and ADL scores. Major depression disorders reduced QoL but not ADL. Patients with ICRD tended to suffer more from depression than those without ICRD. There were no statistically significant differences in age, sex, major depressive disorders, PD duration, total levodopa equivalent daily dose, use of dopamine agonists, or UPDRS motor score between patients with and without ICDR.     

Effects of gabapentin on the motor response to levodopa: a double-blind, placebo-controlled, crossover study in patients with complicated Parkinson disease

BACKGROUND: Motor fluctuations and dyskinesias affect many parkinsonian patients chronically treated with levodopa. Imbalance between gabaergic direct and indirect striatopallidal pathways may originate them. Manipulating GABA neurotransmission may be effective in the treatment of these patients. Gabapentin is an antiepileptic drug that increases the synthesis and release of GABA. Previous studies suggest that gabapentin may be useful in Parkinson disease (PD). OBJECTIVE: To know the effects of gabapentin on the motor response to levodopa in PD patients with motor complications. DESIGN: A randomized double-blind, placebo-controlled, cross-over trial with four weeks of treatment. SETTING: A tertiary referral center. PARTICIPANTS: Twenty subjects with PD and motor fluctuations and dyskinesias on stable antiparkinsonian treatment, took gabapentin up to a maximum dose of 2.400 mg/d in three doses and placebo. METHODS: Three levodopa challenges were performed: at the beginning of the study and at the end of each period of treatment (4 weeks). Basal (off) and best (on) motor status were assessed by the UPDRS III. Latency to peak effect, magnitude of motor response (difference between "on" and "off" scores in the UPDRS III), duration of motor response and severity and duration of dyskinesias after each levodopa challenge were assessed. Patients' diaries were administered. RESULTS:: Fifteen patients completed the study. A significant improvement in the basal UPDRS III resulting in a significant reduction in the magnitude of the motor response after gabapentin was obtained (P < 0.001). No other changes were observed, either on pharmacological parameters or in levodopa-induced dyskinesias. Number of daily hours spent in "on," "on with dyskinesias" and "off" also remained unchanged. Tolerance was good, dizziness being the most common side effect. CONCLUSION: Gabapentin improved parkinsonian symptoms (basal UPDRS III and magnitude of the motor response) following levodopa. This improvement was not reflected in the daily motor situation of patients. Dyskinesias remained unchanged. Gabapentin was well tolerated. Further studies are needed to know the impact of these results in the long-term.     

Impact of Subthalamic Nucleus Stimulation on Young‐Onset Parkinson's Disease

Objective. To clarify the efficacy of subthalamic nucleus (STN) stimulation in young‐onset Parkinson's disease (PD), we compared the effects of STN stimulation on the motor symptoms between young‐onset PD (YOPD) and late‐onset PD (LOPD). Methods. We analyzed the effects of STN stimulation on motor function and motor fluctuations in 15 patients with YOPD, and 113 patients with LOPD who underwent STN stimulation during the same period. The Unified Parkinson's Disease Rating Scale (UPDRS) was evaluated during the on‐period and off‐period, which are defined as the times at which the motor symptoms are the best and worst during the daily active time with sustaining anti‐parkinsonian drugs. The dyskinesia severity rating scale (DSRS) also was employed to assess the severity of peak‐dose dyskinesia. We analyzed the changes in levodopa equivalent daily dose (LED), motor fluctuations, DSRS, and UPDRS part 3 score after STN stimulation, and compared the changes in each score between the two groups (YOPD vs. LOPD). Results. The LED was reduced, and the on‐off motor fluctuation index, dyskinesia rating scale score (on‐period), and UPDRS part 3 score (on‐ and off‐periods) were improved in both the YOPD and LOPD groups. The improvement rates of the UPDRS part 3 scores in both the on‐ and off‐periods in the YOPD group were superior to those in the LOPD group. The results of multivariate logistic regression analysis demonstrated that YOPD itself is the best responder to STN stimulation. Conclusions. STN stimulation can reduce the LED and improve motor fluctuations in patients with YOPD. The effects of STN stimulation on the motor symptoms of YOPD patients are superior to those in LOPD. The present findings suggest that YOPD patients suffering from several problems related to pharmacological therapy are probably good candidates for STN stimulation.     

Motor complications in Parkinson's disease: Ten year follow‐up study

Parkinson's disease (PD) can be symptomatically controlled with standard treatments; however, after a few years, this response typically declines and most patients develop motor complications. We carried out a prospective practice‐based study to evaluate the evolution appearance and evolution of motor complications in 64 de novo PD patients over 5 years and in 38 PD patients over 10 years. We studied untreated patients from initial assessment at basal conditions and evaluated every 6 months thereafter with treatment (levodopa versus other drugs). The follow‐up assessments were performed with the Unified Parkinson's Disease Rating Scale (UPDRS). At each assessment, patients were monitored regarding the development of dyskinesias, motor fluctuations, freezing, loss of postural reflexes, and cognitive impairment. We observed a significant improvement in UPDRS scores during the first year, then a progressive decline, more evident after the third year. Motor complications increased after the third year, and at the end of the survey (tenth year); drug‐induced dyskinesias and motor fluctuations were experienced (71.1 and 94.7%, respectively). After the first decade, many complications arose from the non‐levodopa–responsive features of the disease (cognitive impairment was present in 52.6% and gait freezing in 71.1%). Initial medication may influence medium‐term complications but not long‐term problems. Most long‐term disabling problems of PD were related to non‐levodopa‐responsive features. © 2010 Movement Disorder Society.     

SSRIs do not worsen Parkinson's disease: evidence from an open-label, prospective study

Selective serotonin reuptake inhibitors (SSRIs) have been reported to be useful in the treatment of depression in patients with Parkinson's disease (PD). However, a few reports have suggested that SSRIs may worsen parkinsonian motor symptomatology and extrapyramidal side effects have been reported in depressed patients treated with SSRIs. So far, no prospective trial comparing the effects of different SSRIs in depressed patients with PD has been performed. The aim of the present study was to assess the effects of four SSRIs (citalopram, fluoxetine, fluvoxamine, and sertraline) on motor performance and their efficacy on depression in a group of patients with PD. Sixty-two consecutive nondemented, nonfluctuating, depressed patients with PD were included in four treatment groups (15 patiens received citalopram, 16 fluoxetine, 16 fluvoxamine, and 15 sertraline). The evaluation of extrapyramidal and depressive symptomatology was performed with use of the Unified Parkinson's Disease Rating Scale (UPDRS), Beck Depression Inventory, and Hamilton Depression Rating Scale at baseline and after 1, 3, and 6 months. Fifty-two patients completed the study. UPDRS scores were not significantly modified by the add-on therapy with each of the SSRIs studied. A significant improvement in depressive symptoms from baseline to the end of the trial was obtained with all SSRIs (Beck and Hamilton scores improving; p < 0.05 according to an analysis of variance). Our findings suggest that SSRIs do not significantly worsen extrapyramidal symptomatology and may ameliorate depression in patients with PD.     

Predictors of effective bilateral subthalamic nucleus stimulation for PD

To identify factors predictive of effective bilateral subthalamic nucleus (STN) stimulation for PD with severe motor complications, pre- and postoperative Unified PD Rating Scale (UPDRS) scores were analyzed in a series of 54 patients who received bilateral STN stimulation. Younger age and levodopa responsiveness predict a favorable response to bilateral STN stimulation. For individual PD symptoms, those that improve with a suprathreshold dose levodopa challenge are likely to improve with stimulation.     

Entacapone in the treatment of Parkinson's disease

BACKGROUND: The development of fluctuations in motor response and involuntary movements commonly complicate the treatment of Parkinson's disease (PD). Catechol-O-methyltransferase (COMT) inhibitors delay the breakdown of levodopa, which leads to an increase in levodopa bioavailability and more stable concentrations of plasma levodopa. The addition of a COMT inhibitor therefore combines the rapid onset of levodopa with prolonged efficacy, and theoretically provides a more continuous stimulation of dopamine receptors with reduced risk of motor complications. Randomised, controlled trials have shown that in patients with PD who have motor fluctuations, the addition of the COMT-inhibitor entacapone results in an improvement in motor fluctuations, particularly of the "wearing-off" type, with about 1.0-1.7 h more on-time and less off-time per day, reduced required levodopa dose, modest improvement in motor and disability scores (mean total unified PD rating scale [UPDRS] scores of about 4.5), and in some but not all studies improvement of health-related quality of life [HRQOL] scores. RECENT DEVELOPMENTS: Patients with stable PD, without motor fluctuations, also have improved HRQOL scores on treatment with entacapone in addition to levodopa with a dopa-decarboxylase inhibitor. However, in a recent large multicentre study, UPDRS motor and disability scores were not improved despite significant improvements in HRQOL scores. The disparity between results on clinical rating scales and HRQOL scores suggests that these scales give different and potentially complementary information on health status changes in PD, and that entacapone provides benefit that may not be captured with standard clinical rating scales. Whether entacapone combined with levodopa can delay dyskinesia or motor fluctuations in patients with untreated PD is unknown; however, in animal studies, a decrease in motor complications has been reported in drug-naive animals given frequent doses of levodopa combined with entacapone. WHERE NEXT?: Clinical studies are underway to address the hypothesis that motor complications in PD can be delayed if entacapone is given from the start of treatment. Until the results of these trials are available, entacapone is indicated as a useful adjunct to levodopa in the symptomatic treatment of patients with PD with and without motor fluctuations. In addition, future trials should specifically assess the effect of entacapone on HRQOL in PD.     

Initial treatment of early Parkinson’s disease: A review of recent, randomized controlled trials

Many studies have shown dopamine agonists to significantly improve parkinsonian symptoms compared with placebo in early Parkinson’s disease (PD), but how do agonists compare with the standard treatment of levodopa? Recently, three large, multicenter, randomized controlled studies directly comparing a dopamine agonist with levodopa as initial therapy in early PD have been published. These studies suggest that although both agents effectively ameliorate parkinsonian symptoms, levodopa was superior to dopamine agonists as measured by improvement in Unified Parkinson’s Disease Rating Scale (UPDRS) scores. However, levodopa was more frequently associated with dopaminergic motor complications, and the dopamine agonists were more commonly associated with adverse events. Until further studies clearly demonstrate the beneficial effects of one therapeutic strategy over another, the decision to initiate treatment in early PD with either an agonist or levodopa will be based on the favorable motor complication profile of agonists versus the more potent antiparkinsonian effects and the favorable side-effect profile of levodopa.     

Deep Brain Stimulation for Early-Stage Parkinson’s Disease: An Illustrative Case

Objectives: Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective intervention in advanced Parkinson's disease (PD), but its efficacy and safety in early PD are unknown. We are conducting a randomized pilot trial investigating DBS in early PD. This report describes one participant who received bilateral STN‐DBS. Materials and Methods: Thirty subjects have been randomized to either optimal drug therapy (ODT) or DBS + ODT. Microelectrode recordings from the STN and substantia nigra are collected at implantation. The Unified Parkinson's Disease Rating Scale Motor Subscale (UPDRS‐III) is administered in the ON and OFF states semi‐annually and neuropsychological function and quality of life are assessed annually. We describe a 54‐year‐old man with a two‐year history of PD who was randomized to DBS + ODT and followed for two years. Results: The subject showed a lower STN to substantia nigra ratio of neuronal activity than advanced PD patients, and higher firing rate than non‐PD patients. The subject's total UPDRS and UPDRS‐III scores improved during the two‐year follow‐up, while his OFF UPDRS‐III score and levodopa equivalent daily dose increased. Quality of life, verbal fluency, and verbal learning improved. He did not experience any serious adverse events. Conclusions: This report details the first successful application of bilateral STN‐DBS for early‐stage PD during a clinical trial.