Review of the therapeutic management of Parkinson's disease. Report of a joint task force of the European Federation of Neurological Societies (EFNS) and the Movement Disorder Society-European Section (MDS-ES). Part II: late (complicated) Parkinson's disease

To provide evidence-based recommendations for the management of late (complicated) Parkinson's disease (PD), based on a review of the literature. Complicated PD refers to patients suffering from the classical motor syndrome of PD along with other motor or non-motor complications, either disease-related (e.g. freezing) or treatment-related (e.g. dyskinesias or hallucinations). MEDLINE, Cochrane Library and INAHTA database literature searches were conducted. National guidelines were requested from all EFNS societies. Non-European guidelines were searched for using MEDLINE. Part II of the guidelines deals with treatment of motor and neuropsychiatric complications and autonomic disturbances. For each topic, a list of therapeutic interventions is provided, including classification of evidence. Following this, recommendations for management are given, alongside ratings of efficacy. Classifications of evidence and ratings of efficacy are made according to EFNS guidance. In cases where there is insufficient scientific evidence, a consensus statement ('good practice point') is made.     

Algorithms for the treatment of motor problems in Parkinson's disease

Several different strategies are effective for medical treatment of motor problems in Parkinson's disease (PD). Many guidelines and evidence‐based reviews are available, but there is no documentation or consensus in favor of just one treatment strategy. This review presents two algorithms that may be helpful when deciding how to treat a PD patient at various stages of the disease. The first algorithm suggests one way to treat PD from the first onset of motor symptoms. It is largely based on treatment recommendations from the Scandinavian countries and Germany. The other algorithm is meant as assistance for choosing among the different device‐aided treatments for advanced PD. There is not sufficient comparative data to recommend one particular line of treatment, neither in early PD nor in advanced disease with motor complications. Individualized treatment is needed for each patient. The current algorithms only represent an alternative for aiding treatment decisions.     

European guidelines on management of restless legs syndrome: report of a joint task force by the European Federation of Neurological Societies,the European Neurological Society and the European Sleep Research Society

Background

Since the publication of the first European Federation of Neurological Societies (EFNS) guidelines in 2005 on the management of restless legs syndrome (RLS; also known as Willis‐Ekbom disease), there have been major therapeutic advances in the field. Furthermore, the management of RLS is now a part of routine neurological practice in Europe. New drugs have also become available, and further randomized controlled trials have been undertaken. These guidelines were undertaken by the EFNS in collaboration with the European Neurological Society and the European Sleep Research Society.

Objectives

To provide an evidence‐based update of new treatments published since 2005 for the management of RLS.

Methods

First, we determined what the objectives of management of primary and secondary RLS should be. We developed the search strategy and conducted a review of the scientific literature up to 31 December 2011 (print and electronic publications) for the drug classes and interventions employed in RLS treatment. Previous guidelines were consulted. All trials were analysed according to class of evidence, and recommendations made according to the 2004 EFNS criteria for rating.

Recommendations

Level A recommendations can be made for rotigotine, ropinirole, pramipexole, gabapentin enacarbil, gabapentin and pregabalin, which are all considered effective for the short‐term treatment for RLS. However, for the long‐term treatment for RLS, rotigotine is considered effective, gabapentin enacarbil is probably effective, and ropinirole, pramipexole and gabapentin are considered possibly effective. Cabergoline has according to our criteria a level A recommendation, but the taskforce cannot recommend this drug because of its serious adverse events.     

Evidence-based medical review update: pharmacological and surgical treatments of Parkinson's disease: 2001 to 2004.

The objective of this study is to update a previous evidence-based medicine (EBM) review on Parkinson's disease (PD) treatments, adding January 2001 to January 2004 information. The Movement Disorder Society (MDS) Task Force prepared an EBM review of PD treatments covering data up to January 2001. The authors reviewed Level I (randomized clinical trials) reports of pharmacological and surgical interventions for PD, published as full articles in English (January 2001-January 2004). Inclusion criteria and ranking followed the original program and adhered to EBM methodology. For Efficacy Conclusions, treatments were designated Efficacious, Likely Efficacious, Non-Efficacious, or Insufficient Data. Four clinical indications were considered for each intervention: prevention of disease progression; treatment of Parkinsonism, as monotherapy and as adjuncts to levodopa where indicated; prevention of motor complications; treatment of motor complications. Twenty-seven new studies qualified for efficacy review, and others covered new safety issues. Apomorphine, piribedil, unilateral pallidotomy, and subthalamic nucleus stimulation moved upward in efficacy ratings. Rasagiline, was newly rated as Efficacious monotherapy for control of Parkinsonism. New Level I data moved human fetal nigral transplants, as performed to date, from Insufficient Data to Non- efficacious for the treatment of Parkinsonism, motor fluctuations, and dyskinesias. Selegiline was reassigned as Non-efficacious for the prevention of dyskinesias. Other designations did not change. In a field as active in clinical trials as PD, frequent updating of therapy-based reviews is essential. We consider a 3-year period a reasonable time frame for published updates and are working to establish a Web-based mechanism to update the report in an ongoing manner.     

Relationships between deep brain stimulation and impulse control disorders in Parkinson's disease, with a literature review

Impulse control disorders (ICDs) are behavioural/neuropsychiatric complications of the pharmacological treatment of Parkinson's disease. Long term motor complications of PD can be effectively treated using deep brain stimulation (DBS) of subcortical nuclei. The relationships between ICDs and DBS treatment of the motor complications of Parkinson's disease remain unclear. We describe 50 consecutive patients in whom detailed neuropsychiatric assessments were performed as part of our routine pre-operative assessment. Eight had current or past ICDs during pre-operative assessment. These patients were more likely to be male and were younger than those without ICDs. Other psychosocial variables did not predict the presence of ICDs. Detailed neuropsychological examination failed to show any between-group differences. Our prevalence rate of 16% helps raise awareness of ICDs in this specialised clinic population and may reflect common denominators between significant motor fluctuations and dopaminergic drug - related behavioural disturbances. Four patients were deemed suitable for surgery after multi-disciplinary assessment. One had re-emergence of his ICD 18 months post-operatively, the ICD having resolved in the first 18 months. We also review published literature and the evidence regarding post-operative outcomes. We recommend the routine pre-operative examination of patients for psychopathology and emphasize the importance of post-operative psychiatric surveillance.     

Prognostic factors for the progression of Parkinson's disease: a systematic review.

The purpose of this systematic review is to summarize studies that describe the course of Parkinson's disease (PD) and to identify factors that predict change in motor impairment, disability, and quality of life. A literature search was conducted in MEDLINE, EMBASE, CINAHL, and Web of Science limited to the English, French, German, Spanish, and Dutch language. Reports were selected if the study involved subjects with PD, the outcome measures described impairment, disability, or quality of life and follow-up was at least 6 months. All included studies were scored for methodological quality. Data were extracted and summarized in a best evidence synthesis. We screened 1,535 titles and abstracts, of which 27 fulfilled our inclusion criteria. A meta-analysis to quantitatively aggregate progression scores of motor impairment and disability was not possible because of the wide variety of outcome measures used and the heterogeneous study populations. Limited evidence is found for lower UPDRS-ME at baseline, dementia and SE < 70% as prognostic factors for future motor impairment. There is strong evidence for higher age at onset and higher PIGD-score; and limited evidence for higher bradykinesia-score, non-tremor dominant subtype, symmetrical disease at baseline, and depression as prognostic factors for progression of disability. Prognostic factors were identified for impairment and disability. The literature on prognosis in PD is not fulfilling the high methodological standards applied nowadays. There is a need for prospective cohorts of PD patients assembled at a common early point in the disease with long time follow-up.     

左旋多巴在帕金森病治疗中的地位及进展

数十年来,左旋多巴曾为帕金森病(PD)治疗带来革命性的改变,并始终作为PD治疗的金标准享有及其重要的地位。然而,伴随其治疗产生的运动并发症却成为困扰医患的一大难题。近年来,随着对运动并发症机制的研究,越来越多的证据表明持续性多巴胺能刺激(CDS)可在产生良好疗效的同时降低运动并发症的风险,故其被作为PD治疗的新理念备受关注。为此,大量研究致力于开发能形成CDS状态的左旋多巴新制剂,从而探寻出提高疗效与降低运动并发症之间的平衡点。文中就左旋多巴治疗PD的回顾及进展予以介绍。     

EFNS guidelines on the molecular diagnosis of mitochondrial disorders

Objectives: These European Federation of Neurological Sciences (EFNS) guidelines are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics for diagnosing mitochondrial disorders (MIDs), which gain increasing attention and are more frequently diagnosed due to improved diagnostic tools. Background: Since the publication of the first EFNS guidelines on the molecular diagnosis of inherited neurological diseases in 2001, rapid progress has been made in this field, necessitating the creation of an updated version. Search strategy: To collect data about the molecular diagnosis of MIDs search for literature in various electronic databases, such as Cochrane library, MEDLINE, OMIM, GENETEST or Embase, were carried out and original papers, meta‐analyses, review papers, and guideline recommendations were reviewed. Results: The guidelines summarise the possibilities and limitations of molecular genetic diagnosis of MIDs and provide practical recommendations and diagnostic criteria in accordance with the EFNS Scientific Committee to guide the molecular diagnostic work‐up of MIDs. Recommendations: The proposed guidelines suggest an approach to the molecular diagnosis of MIDs in a manner accessible to general neurologists.     

Deep brain stimulation for the treatment of Parkinson's disease.

Deep brain stimulation (DBS) is increasingly accepted as an adjunct therapy for Parkinson's disease (PD). It is considered a surgical treatment alternative for patients with intractable tremor or for those patients who are affected by long-term complications of levodopa therapy such as motor fluctuations and severe dyskinesias. Thalamic stimulation in the ventral intermediate nucleus (Vim) leads to a marked reduction of contralateral tremor but has no beneficial effect on other symptoms of Parkinson's disease. The subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) are targeted for the treatment of advanced Parkinson's disease. Several studies have proven the efficacy of STN-DBS and GPi-DBS in alleviating off motor symptoms and dyskinesias. Sub-thalamic nucleus deep brain stimulation is currently considered superior to GPi-DBS because the antiakinetic effect seems to be more pronounced, allows a more marked reduction of antiparkinsonian medication, and requires less stimulation energy. More recently, however, a number of reports on possible psychiatric and behavioral side effects of STN-DBS have been a matter of concern. Given the chronic nature of PD and the noncurative approach of DBS, both targets will need to be reevaluated on the basis of their long-term efficacy and their impact on quality of life. Despite the rapidly increasing numbers of DBS procedures, surprisingly few controlled clinical trials are available that address important clinical issues such as: When should DBS be applied during the course of disease? Which patients should be selected? Which target should be considered? Which guidelines should be followed during postoperative care? Here is summarized the available evidence on DBS as a therapeutic tool for the treatment of Parkinson's disease and the current state of debate on open issues.     

European Stroke Initiative (EUSI) Recommendations for Stroke ManagementThe European Stroke Initiative Writing Committee

The European Stroke Initiative (EUSI) is the common body of stroke-related activities within the European Federation of Neurological Societies (EFNS), the European Neurological Society (ENS) and the European Stroke Council (ESC). The Executive committee of the EUSI has authorized the writing committee of the EUSI to create recommendations for stroke management covering all areas of stroke treatment. The recommendations are listed according to levels of evidence pre-specified and modified according to several proposals in the literature. The recommendations have been approved by the executive committees of the EUSI, the ESC, the EFNS and the ENS. They are called recommendations rather than guidelines in order to underline the large amount of individual decision making due to the fact that for many important questions, no data of high evidence level is available. The EUSI plans to review and update the recommendations on a regular basis.     

Factors associated with hospitalisation among people with Parkinson's disease – A systematic review and meta-analysis

IntroductionParkinson's disease (PD) is associated with an increased risk of admission to hospital; however data on the main reasons for admission are lacking. Our objective was to determine the pooled prevalence of the most common factors leading to admission among people with Parkinson's disease.MethodologyA systematic literature search was conducted in 11 electronic databases. We included all studies providing reasons for admissions among PD patients without restrictions to diagnostic criteria of PD, language or year of study. In the included studies, methodological quality, publication bias and heterogeneity were assessed. Meta-analysis was performed using random-effects models to calculate the pooled estimates of the identified top factors that lead to admission among people with PD.ResultsA total of 7283 studies were identified of which nine studies including 7162 people with PD were included in this review. There was a high degree of heterogeneity between studies regarding reasons for hospitalisation. The pooled prevalence of the topmost reasons for hospitalisation among people with PD was 22% (95%CI 16.0%–30.0%) for infections (mainly urinary tract infections and pneumonia); 19% (95%CI 13.0%–27.0%) for worsening motor manifestations of PD; 18% (95%CI 14.0%–21.0%) for falls/fractures; 13% (95%CI 9.0%–18%) for cardiovascular co-morbidities; 8% (95%CI 4.0%–13.0%) for neuropsychiatric and 7% (95%CI 4.0%–11.0%) for gastrointestinal complications.ConclusionThe main reasons for hospitalisation among people with PD are infections, worsening motor features, falls/fractures, cardiovascular co-morbidities, neuropsychiatric and gastrointestinal complications. Further research is needed on targeting and implementing preventative strategies.     

Treatment of advanced stage patients with Parkinson's disease

Most patients with Parkinson's disease (PD) receiving chronic levodopa therapy eventually manifest one or more motor response complications, including 'wearing-off' phenomena and on-off phenomena. Additionally, as the disease progresses, motor, neurologic, and neuropsychiatric complications increase and may include freezing spells, falls, dementia, depression and psychosis. The management of patients with advanced PD presents a special clinical challenge because patients may experience an enhanced sensitivity to small changes in plasma levodopa levels and because they may suffer adverse reactions to antiparkinsonian drugs. Management of advanced PD is directed toward decreasing the dose of the offending drug while raising the dose of alternative drug with the goal of maintaining symptom control. In this article, the spectrum of late complications experienced by patients with advanced PD and their management are discussed.     

A review of studies describing the use of acetyl cholinesterase inhibitors in Parkinson's disease dementia

OBJECTIVE: To review the literature relating to the use of acetyl cholinesterase inhibitors in Parkinson's disease dementia (PDD). METHOD: MEDLINE (1966--December 2004), PsychINFO (1972--December 2004), EMBASE (1980--December 2004), CINHAL (1982--December 2004), and the Cochrane Collaboration were searched in December 2004. RESULTS: Three controlled trials and seven open studies were identified. Efficacy was assessed in three key domains: cognitive, neuropsychiatric and parkinsonian symptoms. CONCLUSION: Cholinesterase inhibitors have a moderate effect against cognitive symptoms. There is no clear evidence of a noticeable clinical effect against neuropsychiatric symptoms. Tolerability including exacerbation of motor symptoms--in particular tremor--may limit the utility of cholinesterase inhibitors.     

Physical therapy in Parkinson's disease: Evolution and future challenges

Even with optimal medical management using drugs or neurosurgery, patients with Parkinson's disease (PD) are faced with progressively increasing mobility problems. For this reason, many patients require additional physical therapy. Here, we review the professional evolution and scientific validation of physical therapy in PD, and highlight several future challenges. To gain insight in ongoing, recently completed or published trials and systematic reviews, we performed a structured literature review and contacted experts in the field of physical therapy in PD. Following publication of the first controlled clinical trial in 1981, the quantity and quality of clinical trials evaluating the efficacy of physical therapy in PD has evolved rapidly. In 2004 the first guideline on physical therapy in PD was published, providing recommendations for evidence‐based interventions. Current research is aiming to gather additional evidence to support specific intervention strategies such as the prevention of falls, and to evaluate the implementation of evidence into clinical practice. Although research focused on physical therapy for PD is a relatively young field, high‐quality supportive evidence is emerging for specific therapeutic strategies. We provide some recommendations for future research, and discuss innovative strategies to improve the organization of allied health care in PD, making evidence‐based care available to all PD patients. © 2008 Movement Disorder Society     

Levodopa in the treatment of Parkinson's disease: current controversies.

Levodopa is the most effective symptomatic agent in the treatment of Parkinson's disease (PD) and the "gold standard" against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy.     

A profile of neuropsychiatric problems and their relationship to quality of life for Parkinson's disease patients without dementia

Neuropsychiatric problems are common in Parkinson's disease (PD) but there is little information regarding how they impact on quality of life. PD patients without dementia (49) were assessed for low mood/depression, fatigue, apathy, sleep problems and hallucinations. Measures of quality of life and motor function were also obtained. Over 77% of the patients reported symptoms consistent with one or more neuropsychiatric problems. Low mood/depression, anxiety and the presence of hallucinations predicted poorer quality of life after controlling for motor symptoms. Additional to the motor symptoms, we found that specific neuropsychiatric problems may impact on quality of life for PD patients.     

Pergolide versus levodopa monotherapy in early Parkinson's disease patients: The PELMOPET study.

Dopamine agonists are used as initial treatment in patients with Parkinson's disease (PD) to reduce incidence and severity of motor complications. This paradigm is based on long-term studies, allowing "rescue" therapy with levodopa. The present strict monotherapy study (PELMOPET, the acronym for the pergolide-versus-L-dopa-monotherapy-and-positron-emission-tomography trial) evaluated the efficacy and safety of pergolide versus levodopa without levodopa "rescue" medication. This multicenter, double-blind, randomized, 3-year trial compared pergolide monotherapy (n=148) with levodopa monotherapy (n=146) in dopamine-naive patients with early PD (Hoehn and Yahr stage 1-2.5). Primary efficacy measures were clinical efficacy, severity and time to onset of motor complications, and disease progression. During the 3 years, severity of motor complications was significantly lower and time to onset of dyskinesia was significantly delayed in the group receiving pergolide (3.23 mg/day) compared with those receiving levodopa (504 mg/day). However, time to onset of motor complications was not longer in patients receiving pergolide after 3 years. Symptomatic relief (assessed by Unified Parkinson's Disease Rating Scale [UPDRS], UPDRS II, and III, Clinical Global Impressions [CGI] severity, and CGI and Patient Global Impressions [PGI] improvement) was significantly greater in patients receiving levodopa. Adverse events led to discontinuation of therapy in 17.6% of pergolide patients and 9.6% of levodopa patients. This is the first study comparing strict monotherapy with a dopamine agonist versus levodopa in previously untreated early PD. In principle, both levodopa and a dopamine agonist such as pergolide seem to be suitable options as initial PD therapy. The choice remains with the treating physician based on the different efficacy and adverse event profiles.     

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.     

Non-dopaminergic treatment of cognitive impairment and dementia in Parkinson's disease: a review

OBJECTIVE: To review the clinical management of cognitive impairment and dementia related to Parkinson's disease (PD), with emphasis on pharmacologic intervention strategies such as cholinesterase inhibitors. DATA SOURCES: A MEDLINE, EMBASE, PsychINFO, and Cochrane Collaboration search of English language literature from 1970 to 2004 was performed to identify reviews, studies, case reports, and letters pertaining to the treatment of cognitive impairment in PD. The bibliographies of selected articles were reviewed for additional references. STUDY SELECTION: Human studies or case reports in adults with PD describing the use of drug and other therapies for the treatment of cognitive impairment in PD. DATA EXTRACTION: Studies were reviewed for study design, number of subjects, outcome measures, dosage, side-effects, particularly, worsening of PD motor symptoms. CONCLUSION: The strongest evidence for the pharmacological treatment of cognitive impairment and dementia in PD supports the use of cholinesterase inhibitors. Evidence for the efficacy and safety of other agents in PD dementia is either insufficient or inconclusive, but offers intriguing clues for potential future treatments. No reports from the Cochrane Collaboration were found.