丘脑底核脑深部电刺激术在改善帕金森病核心症状中的应用

目的探讨丘脑底核脑深部电刺激术在改善帕金森病(PD)核心症状中的疗效。方法选取行双侧丘脑底核脑深部电刺激术PD患者20例,采用自身前后对照法在基线和随访结束时(术后12个月)对患者运动症状、认知功能进行评估,观察患者术后不良反应,比较术前、术后日左旋多巴等效计量。结果术前及术后12个月时,服药状态下帕金森病评定量表第3部分(UPDRSⅢ)评分及各亚相评分均明显低于未服药状态(P0.05);术后12个月时,未服药及服药状态下的UPDRSⅢ评分及各亚相评分均明显低于术前(P0.05),服药后各个评分项目的改善率均明显高于术前(P0.05),VFT评分明显低于术前(P0.05),CDT评分明显高于术前(P0.05);术后1年日左旋多巴等效计量均较术前明显减少(P0.01);术后未见颅内出血、电极位置不当、脑脊液漏等并发症。结论双侧丘脑底核脑深部电刺激术能显著改善PD患者运动及认知功能,有效减少药物用量,手术安全性高,治疗效果显著。     

Sensory abnormalities and pain in Parkinson disease and its modulation by treatment of motor symptoms

Pain and sensory abnormalities are present in a large proportion of Parkinson disease (PD) patients and have a significant negative impact in quality of life. It remains undetermined whether pain occurs secondary to motor impairment and to which extent it can be relieved by improvement of motor symptoms. The aim of this review was to examine the current knowledge on the mechanisms behind sensory changes and pain in PD and to assess the modulatory effects of motor treatment on these sensory abnormalities. A comprehensive literature search was performed. We selected studies investigating sensory changes and pain in PD and the effects of levodopa administration and deep brain stimulation (DBS) on these symptoms. PD patients have altered sensory and pain thresholds in the off‐medication state. Both levodopa and DBS improve motor symptoms (i.e.: bradykinesia, tremor) and change sensory abnormalities towards normal levels. However, there is no direct correlation between sensory/pain changes and motor improvement, suggesting that motor and non‐motor symptoms do not necessarily share the same mechanisms. Whether dopamine and DBS have a real antinociceptive effect or simply a modulatory effect in pain perception remain uncertain. These data may provide useful insights into a mechanism‐based approach to pain in PD, pointing out the role of the dopaminergic system in pain perception and the importance of the characterization of different pain syndromes related to PD before specific treatment can be instituted.     

Citicoline as Adjuvant Therapy in Parkinson's Disease: A Systematic Review

PurposeParkinson disease (PD) medications are not readily available in all countries. Citicoline increases dopamine synthesis and inhibits dopamine uptake. This systematic review aims to synthesize current existing evidence on the efficacy of citicoline adjunctive therapy in improving PD symptoms.MethodsAn extensive literature search of Scopus, Embase, PubMed, Cochrane Library, and Google Scholar was conducted for articles published on or before December 31, 2019. The studies were screened and selected by 2 independent reviewers. We included all studies that explored the efficacy of citicoline as an adjunct therapy in PD.FindingsA total of 7 studies (2 crossover, 3 randomized controlled, and 2 open prospective studies) were included. Despite the varied outcome tools, this review found that patients with PD who were taking citicoline had significant improvement in rigidity, akinesia, tremor, handwriting, and speech. Citicoline allowed effective reduction of levodopa by up to 50%. Significant improvement in cognitive status evaluation was also noted with citicoline adjunctive therapy.ImplicationsCiticoline adjuvant therapy has beneficial effects as an adjuvant therapy in patients with PD. However, due to the heterogeneity of the studies, there is a need for more high-quality studies.     

Rasagiline: defining the role of a novel therapy in the treatment of Parkinson's disease

Parkinson's disease (PD) is a therapy area with considerable unmet needs. The current key targets for PD treatment include the slowing of disease progression, improved control of motor fluctuations in advanced disease and the treatment of non-motor symptoms. In view of such major requirements, it is important to consider how new drug treatments fit into the context of PD therapy, and the practical advantages that they may offer in the management of PD in clinical practice. Rasagiline is a novel, second-generation, irreversible, selective monoamine oxidase type B inhibitor that is indicated for the treatment of idiopathic PD, either as initial monotherapy or as adjunct therapy (with levodopa) for patients experiencing end-of-dose motor fluctuations. This review assesses the outcome from several large-scale clinical studies that have investigated the use of rasagiline in early and advanced PD patient populations and discusses the role of rasagiline within the current scope of PD therapy.     

A Phase I Study of Aromatic -Amino Acid Decarboxylase Gene Therapy for Parkinson's Disease

Gene transfer of dopamine-synthesizing enzymes into the striatal neurons has led to behavioral recovery in animal models of Parkinson''s disease (PD). We evaluated the safety, tolerability, and potential efficacy of adeno-associated virus (AAV) vector–mediated gene delivery of aromatic -amino acid decarboxylase (AADC) into the putamen of PD patients. Six PD patients were evaluated at baseline and at 6 months, using multiple measures, including the Unified Parkinson''s Disease Rating Scale (UPDRS), motor state diaries, and positron emission tomography (PET) with 6-[¹⁸F]fluoro--m-tyrosine (FMT), a tracer for AADC. The short-duration response to levodopa was measured in three patients. The procedure was well tolerated. Six months after surgery, motor functions in the OFF-medication state improved an average of 46% based on the UPDRS scores, without apparent changes in the short-duration response to levodopa. PET revealed a 56% increase in FMT activity, which persisted up to 96 weeks. Our findings provide class IV evidence regarding the safety and efficacy of AADC gene therapy and warrant further evaluation in a randomized, controlled, phase 2 setting.     

Cost-utility model of rasagiline in the treatment of advanced Parkinson's disease in Finland

BACKGROUND: The economic burden of Parkinson's disease (PD) is high, especially in patients experiencing motor fluctuations. Rasagiline has demonstrated efficacy against symptoms of PD in early and advanced stages of the disease. OBJECTIVE: To assess the cost-utility of rasagiline and entacapone as adjunctive therapies to levodopa versus standard levodopa care in PD patients with motor fluctuations in Finland. METHODS: A 2 year probabilistic Markov model with 3 health states: "25% or less off-time/day," "greater than 25% off-time/day," and "dead" was used. Off-time represents time awake with poor or absent motor function. Model inputs included transition probabilities from randomized clinical trials, utilities from a preference measurement study, and costs and resources from a Finnish cost-of-illness study. Effectiveness measures were quality-adjusted life years (QALYs) and number of months spent with 25% or less off-time/day. Uncertainty around parameters was taken into account by Monte Carlo simulations. RESULTS: Over 2 years from a societal perspective, rasagiline or entacapone as adjunctive therapies to levodopa showed greater effectiveness than levodopa alone at no additional costs. Benefits after 2 years were 0.13 (95% CI 0.08 to 0.17) additional QALYs and 5.2 (3.6 to 6.7) additional months for rasagiline and 0.12 (0.08 to 0.17) QALYs and 5.1 (3.5 to 6.6) months for entacapone, both in adjunct to levodopa compared with levodopa alone. CONCLUSIONS: The results of this study support the use of rasagiline and entacapone as adjunctive cost-effective alternatives to levodopa alone in PD patients with motor fluctuations in Finland. With a different mode of action, rasagiline is a valuable therapeutic alternative to entacapone at no additional charge to society.     

Reliability of measurements obtained with the Timed "Up & Go" test in people with Parkinson disease

BACKGROUND AND PURPOSE: The Timed "Up & Go" Test (TUG) is used to measure the ability of patients to perform sequential locomotor tasks that incorporate walking and turning. This study investigated the retest reliability, interrater reliability, and sensitivity of scores obtained with the TUG in detecting changes in mobility in subjects with idiopathic Parkinson disease (PD). SUBJECTS: The performance of 12 people with PD was compared with that of 12 age-matched comparison subjects without PD. METHODS: The subjects with PD completed 5 trials of the TUG after withdrawal of levodopa for 12 hours ("off" phase of the medication cycle) as well as an additional 5 trials 1 hour after levodopa was administered ("on" phase of the medication cycle). They were scored on the Modified Webster Scale at both sessions. The comparison subjects also performed 5 TUG trials. All trials were videotaped and timed by 2 experienced raters. The videotape was later rated by 3 experienced clinicians and 3 inexperienced clinicians. RESULTS: For the subjects with PD, within-session performance was highly consistent, with correlations (r) ranging from.80 to.98 for the "off" phase and from.73 to.99 for the "on" phase. The performance of the comparison subjects across the 5 trials was also highly consistent (r=.90-.97). Comparisons showed differences between trials 1 and 2 on the TUG for both groups. Removal of data for trial 1 (the practice trial) further enhanced retest reliability. There was close agreement in TUG scores among raters despite different levels of experience (intraclass correlation coefficient [3,1]=.87-.99). Mean TUG scores were different between the "on" and "off" phases of the levodopa cycle and between subjects with PD and comparison subjects during the "on" phase. CONCLUSION AND DISCUSSION: Retest reliability and interrater reliability of the TUG measurements were high, and the measurements reflected changes in performance according to levodopa use. The TUG can also be used to detect differences in performance between people with PD and elderly people without PD.     

Adding a dopamine agonist to preexisting levodopa therapy vs. levodopa therapy alone in advanced Parkinson’s disease: a meta analysis

Background: To perform a meta analysis of randomised placebo‐controlled trials evaluating the use of dopamine agonist (DA) or placebo to preexisting levodopa therapy for the treatment of advanced Parkinson’s disease (PD). We focused on clinically important efficacy [Unified Parkinson’s Disease Rating Scale (UPDRS) activities of daily living (ADL) and motor scores as well as change in ‘off’ time and levodopa dose] and safety outcomes (withdrawal because of adverse drug events (ADEs), dyskinesias, hallucinations and mortality). Methods: A systematic literature search was performed between January 1990 and July 2007. The primary outcome measures assessed were the reduction in scores of Unified Parkinson’s Disease Rating Scale (UPDRS) activities of daily living (ADL) and motor scores as well as reduction in ‘off’ time and reductions in levodopa dose from baseline. Safety end‐points were also evaluated. Results: A total of 15 trials (n = 4380 subjects) were included in the meta analysis. Adjunctive DA use resulted in greater improvement as measured by the UPDRS ADL [weighted mean difference (WMD) ?2.20, 95% confidence interval (CI) ?2.64 to ?1.76; p < 0.0001] and motor score reduction (WMD ?5.56, 95% CI ?6.82 to ?4.31; p < 0.0001) as well as reduction in ‘off’ time measured in hours/day (WMD ?1.20, 95% CI ?1.78 to ?0.62; p < 0.0001) and reduction in levodopa dose (WMD ?128.5 mg, 95% CI ?175.0 to ?82.1; p < 0.0001) vs. placebo. Incidence of dyskinesia and hallucinations was higher with DAs [odds ratio (OR) 3.27, 95% CI 2.65–4.03; p < 0.0001] and (OR 3.34, 95% CI 2.44–4.58; p < 0.0001). Non‐ergot DAs were qualitatively better, although both ergot and non‐ergot DAs showed statistically significant improvements in all UPDRS scores. Conclusion: Adjunctive DA use to levodopa is superior to levodopa alone in reducing PD symptoms in patients not controlled with monotherapy. DAs seem especially useful amongst PD patients with wearing‐off phenomenon from levodopa therapy, but can cause some adverse events.     

Possible zoophilia associated with dopaminergic therapy in Parkinson disease

OBJECTIVE: To report a patient with Parkinson disease (PD) who developed zoophilia as a possible complication of dopaminergic therapy. CASE SUMMARY: A 74-year-old man with advanced PD, who had wearing-off motor fluctuations, with a marked disability during the off periods and severe peak-of-dose choreiform dyskinesias, developed hypersexuality with zoophilia 5 days after standard levodopa was substituted for controlled-release levodopa and the dose of bromocriptine was increased. The abnormal sexual behavior disappeared 2 days after the doses of standard levodopa and of bromocriptine were reduced. DISCUSSION: Hypersexuality is a known complication in PD patients undergoing dopaminergic therapy. However, the possible development of zoophilia due to these drugs, as was the case in our patient, is exceptional. CONCLUSIONS: Zoophilia should be considered as a possible behavioral complication of dopaminergic therapy in PD patients.     

New, selective catechol-O-methyltransferase inhibitors as therapeutic agents in Parkinson's disease

Levodopa remains the most effective drug for Parkinson's disease (PD). However, its benefits are limited owing to extensive metabolism by catechol-O-methyltransferase (COMT), especially if levodopa is used in combination with peripheral dopa-decarboxylase inhibitors. A new generation of potent, orally active, selective, and reversible COMT inhibitors has become available recently. Among these, tolcapone and entacapone have been best characterised. Preclinical and clinical studies have shown that COMT inhibitors markedly enhance levodopa availability and prolong its plasma half-life. In recent large clinical trials they proved to be able to ameliorate motor fluctuations, reduce disability, and decrease levodopa requirements in PD patients. The tolerability profiles of entacapone and tolcapone are good. COMT inhibition promises to become an important means of extending the benefits of levodopa therapy in PD.     

Diagnostic and therapeutic value of apomorphine in Parkinsonian patients

Apomorphine is a dopamine agonist administered subcutaneously for the management of motor symptoms of Parkinson's disease (PD). Patients with Parkinsonian syndrome underwent an apomorphine challenge for therapeutic efficacy, a positive response being a reduction of > 15% score on motor unified PD rating scale. Of the 42 patients, aged 37-81, disease duration 12 months to 20 years, 36 had a positive response. Six non-responders were later diagnosed as non-PD as compared with only two of the 36 responders. Tremor-predominant patients obtained higher motor response. Few patients demonstrated a delayed positive response. Seven (three idiopathic PD (iPD), four non-PD) suffered adverse reactions of nausea, vomiting or ill-sustained symptomatic fall in BP. Majority of the patients who continued with apomorphine therapy were able to reduce levodopa and achieved an improvement in dyskinesia and motor symptoms. Thirteen responding patients were managed by increasing dopamine agonists. Five patients, intolerant of oral dopamine agonists, were able to beneficially tolerate apomorphine. Age and disease duration did not influence tolerability or efficacy. The patients treated with apomorphine were able to significantly reduce the dose of levodopa, and there was a reduction in dyskinesia, hallucinations and fluctuations (all p < 0.05). In some patients, apomorphine prevented admission to institutions. We also describe the use of apomorphine in acutely ill patients unable to ingest oral medication. Apomorphine seems to have a diagnostic element for iPD. Its use leads to a reduction in dyskinesia, improvement in motor symptoms and prevention of institutional care. Apomorphine test also identifies patients likely to benefit with an increase in oral medication. Age and disease duration should not prevent the use of this valuable drug. Apomorphine also has a role in acutely ill PD patients.     

Treatment of Parkinson's disease and restless legs syndrome with cabergoline,a long-acting dopamine agonist

Dopamine agonists have diverse chemical and physical properties that can directly stimulate the dopamine receptors, unlike levodopa which undergoes presynaptic breakdown to dopamine before dopaminergic effects in Parkinson's disease (PD). Cabergoline, a dopamine agonist effective given once daily, is being used as treatment for PD. In theory, therapy with cabergoline provides striatal intrasynaptic dopamine replacement of PD in a physiological manner because of its long half-life and the resultant sustained rather than pulsatile dopaminergic stimulation. Several placebo-controlled trials using cabergoline as adjunctive therapy in PD have shown that cabergoline significantly reduces 'off' time, improves motor function and reduces levodopa requirement. Cabergoline has also been used as monotherapy in PD and has been shown to be as effective as other dopamine agonists in improving motor function and to be superior to levodopa in reducing dyskinesias over a five-year period. Work from our group and others have also demonstrated the efficacy of cabergoline in PD patients with nocturnal disabilities and those with restless legs syndrome (RLS). More recently we have reported that cabergoline is a well-tolerated dopamine agonist in both young and elderly patients and has an acceptable side-effect profile.     

多巴胺D1受体激动剂对异动症大鼠电生理活动的影响

目的：探讨多巴胺D1受体在异动症（LID）发生机制中的作用。方法：复制成功的帕金森病（PD）大鼠35只，分为PD组13只，另22只应用复方左旋多巴治疗28d诱发LID大鼠模型，取12只为LID组。第29天取10只在复方左旋多巴治疗前15min腹腔注射MK-801（MK-801组）。采用微电极细胞外记录技术检测LID组大鼠纹状体棘状神经元（SMSNs）电生理活动。尾静脉注射多巴胺D1受体激动剂（SKF-38393）、拮抗剂（SCH-12280）观察神经元电生理活动变化。结果：LID组SMSNs的自发性电活动较对照组（10只正常大组）及MK-801组、PD组明显增多（P〈0．01和0．05），而对照组与MK-800组比较则差异无显著性意义。SKF-38393对LID组大鼠SMSNs自发性电活动的抑制作用呈浓度依赖性，LID组与对照组、MK-801组和PD组比较明显下降（P〈0．01和0．05），PD组与MK801组比较差异无显著性意义。结论：LID大鼠SMSNs的自发性电活动增强，D1受体敏感性增高；通过SKF-38393可以阻抑或减轻LID的发生。     

IL-1 beta, IL-2, IL-6 and TNF-alpha production by peripheral blood mononuclear cells from patients with Parkinson's disease.

The capacity of peripheral blood mononuclear cells (PBMC) from patients with treated Parkinson's disease (PD) to produce interleukin (IL) IL-1 beta IL-2, IL-6, tumor necrosis factor (TNF)-alpha and the proliferative response to mitogens, was compared with that from cells from healthy subjects. The production of IL-2 and the mitogen response were significantly lower in PD patients, whereas the secretion of IL-1 beta, IL-6 and TNF-alpha were significantly enhanced. To evaluate the role of levodopa in creating immunological alterations, PBMC of patients and controls were incubated with concentrations of the drug extrapolated from those used in clinical practice. Levodopa caused an inhibition of mitogen-induced proliferation, stimulation of IL-6 and TNF-alpha production, whereas the secretion of IL-1 beta and IL-2 was not affected. The results of the study provide a further support for the interrelationship between the central nervous and immune system. In addition, the data indicate that the immunological alterations found in PD may be partially attributed to levodopa administration.     

Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients

Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson’s disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using ¹¹C-DASB PET to evaluate serotonin terminal function and ¹¹C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD.     

Self-perception of speech changes in patients with Parkinson's disease following deep brain stimulation of the subthalamic nucleus

Deep brain stimulation of the subthalamic nucleus (STN-DBS) improves the motor difficulties experienced by patients with Parkinson's disease (PD); however, the effects on speech are variable. In this study, patients rated their current post-surgery speech difficulties using the Voice Handicap Index (VHI) and used the same measure to retrospectively rate their pre-surgery speech. Scores pre- and post-surgery were also available on the UPDRS-III, and the patients' intelligibility was assessed by an independent listener. A control group of non-surgical patients with PD (medical group) also completed the VHI for comparison. VHI scores deteriorated equally in the two groups. However, the variability of the change scores in the surgical group was significantly greater than in the medical group. The correlation between the changes in the VHI and UPDRS scores for the surgical group was not significant. Correlations between the VHI scores and intelligibility were significant both before and after surgery, suggesting that patients accurately perceive their difficulties. The findings confirm the variability in the speech difficulties of patients following STN-DBS. The patients' ability to use the VHI offers a means of assessing the effects of their speech on their quality-of-life, and may be clinically useful post-STN-DBS.     

脑卒中后运动功能康复过程中脑皮质功能的改变

目的:观察脑卒中后运动功能恢复过程中脑皮质功能改变的规律,及其与康复效果间的关系。方法:60例累及上肢的脑梗死偏瘫患者,分为康复治疗组35例和单纯药物治疗组25例,并与20例健康者做对照。分别在康复治疗前、康复治疗后2周和1个月时,用经颅多普勒(TCD)测定被动运动肘关节时双侧大脑中动脉(MCA)的血流速度,并用Fugl-Meyer量表评定患侧上肢的运动功能。结果:对照组和2组脑梗死患者正常肢体被动运动时均为对侧MCA的血流速度明显增快,且3次结果类似。患侧肘关节被动运动时,治疗前除对侧MCA血流速度明显增快外,同侧血流速度也明显增快(P<0.05)。但治疗2周和1个月时,单纯药物治疗组同侧血流速度逐渐减慢,而康复治疗组则一直维持在较快的水平。上肢运动功能Fugl-Meyer得分,单纯药物治疗组与同侧血流速度呈负相关(r=-0.89341,P<0.05),康复治疗组则与双侧流速均呈正相关(r=0.99139,0.88812,P<0.05)。结论:正规的康复治疗可以促进卒中运动功能的恢复,机理可能与募集皮质范围加大有关。     

How should we treat a patient with early Parkinson’s disease?

Parkinson’s disease (PD) is characterised by the progressive degeneration of dopaminergic nigro‐striatal neurons and severe striatal dopaminergic deficiency, leading to bradykinesia. Levodopa was the first drug used for PD treatment and is still considered the most useful weapon for the control of PD symptoms. However, levodopa treatment induces motor complications, which is considered as a major problem as the disease progresses. Dopamine agonists, catechol‐O‐methyltransferase inhibitors and monoamine oxidase B inhibitors are some more recently developed drug categories which are expected to have a more favourable effect on motor complications. The choice of the best initial treatment in PD remains a controversial matter. Early therapeutic decisions in PD should balance the need for efficient short‐term symptom control against long‐term complication profile. The individualisation of the treatment seems to be the key for the best approach of early PD patients.     

A review of intermittent subcutaneous apomorphine injections for the rescue management of motor fluctuations associated with advanced Parkinson's disease

BACKGROUND: As Parkinson's disease (PD) progresses,despite optimized pharmacotherapy, patients experience more frequent fluctuations between symptomatic improvement ("on" times) and the return of motor features ("off" times). Apomorphine, the first injectable dopamine agonist available in the United States, is indicated for the acute treatment of "off" episodes (eg, end-of-dose wearing-off episodes, unpredictable "on/off" episodes) in patients with advanced PD who are receiving medically optimal antiparkinsonian therapy. OBJECTIVE: This article reviews the pharmacology,clinical efficacy, and tolerability of intermittent subcutaneous apomorphine injections for the management of "off" episodes in patients with PD. METHODS: MEDLINE (1966-July 2005), the Cochrane Database of Systematic Reviews, and International Pharmaceutical Abstracts (1970-July 2005) were searched for original research and review articles published in English. The search terms were apomorphine and Parkinson's disease. The reference lists of articles were also consulted, as was selected information provided by the manufacturer of apomorphine. All relevant identified studies on intermittent subcutaneous administration of apomorphine were included in the review; trials of continuous subcutaneous infusion and non-subcutaneous administration of apomorphine were excluded. RESULTS: Intermittent subcutaneous administration of apomorphine produced consistent rescue from "of" episodes in patients with advanced PD, with a symptomatic motor improvement between the predose "off" state and postdose "on" state similar to that achieved with levodopa. The onset of effect occurred within 20 minutes, and the duration of effect was approximately 100 minutes. The therapeutic rescue dose ranged from 2 to 6 mg. During the clinical development program for subcutaneously injected apomorphine, patients required a mean of approximately 3 rescue doses per day. Common adverse effects occurring in > or =20% of patients were injection-site reaction, yawning, dyskinesias, drowsiness, nausea and vomiting, dizziness or postural dizziness, and rhinorrhea. CONCLUSIONS: The available clinical studies indicate that apomorphine is effective in providing prompt and consistent rescue from "off" episodes in patients with PD. Antiemetic prophylaxis and close medical supervision are recommended when initiating apomorphine therapy.