Showing papers in "Movement Disorders in 2008"

Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results.

Abstract: We present a clinimetric assessment of the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The MDS-UDPRS Task Force revised and expanded the UPDRS using recommendations from a published critique. The MDS-UPDRS has four parts, namely, I: Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver. Item-specific instructions and an appendix of complementary additional scales are provided. Movement disorder specialists and study coordinators administered the UPDRS (55 items) and MDS-UPDRS (65 items) to 877 English speaking (78% non-Latino Caucasian) patients with Parkinson's disease from 39 sites. We compared the two scales using correlative techniques and factor analysis. The MDS-UPDRS showed high internal consistency (Cronbach's alpha = 0.79-0.93 across parts) and correlated with the original UPDRS (rho = 0.96). MDS-UPDRS across-part correlations ranged from 0.22 to 0.66. Reliable factor structures for each part were obtained (comparative fit index > 0.90 for each part), which support the use of sum scores for each part in preference to a total score of all parts. The combined clinimetric results of this study support the validity of the MDS-UPDRS for rating PD.

Consensus statement of the Movement Disorder Society on tremor

Abstract: This is a proposal of the Movement Disorder Society for a clinical classification of tremors. The classification is based on the distinction between rest, postural, simple kinetic, and intention tremor (tremor during target-directed movements). Additional data from a medical history and the results of a neurologic examination can be combined into one of the following clinical syndromes defined in this statement: enhanced physiologic tremor, classical essential tremor (ET), primary orthostatic tremor, task- and position-specific tremors, dystonic tremor, tremor in Parkinson's disease (PD), cerebellar tremor, Holmes' tremor, palatal tremor, drug-induced and toxic tremor, tremor in peripheral neuropathies, or psychogenic tremor. Conditions such as asterixis, epilepsia partialis continua, clonus, and rhythmic myoclonus can be misinterpreted as tremor. The features distinguishing these conditions from tremor are described. Controversial issues are outlined in a comment section for each item and thus reflect the open questions that at present cannot be answered on a scientific basis. We hope that this statement provides a basis for better communication among clinicians working in the field and stimulates tremor research.

The Sydney Multicenter Study of Parkinson's Disease : The Inevitability of Dementia at 20 years

Abstract: After 20 years follow-up of newly diagnosed patients with Parkinson's disease (PD), 100 of 136 (74%) have died. The mortality rate fell in the first 3 years of treatment, then rose compared to the general population, the standardized mortality ratio from 15 to 20 years reaching 3.1. Drug induced dyskinesia and end of dose failure were experienced by most patients, but the main current problems relate to the non-levodopa responsive features of the disease. Dementia is present in 83% of 20-year survivors. Dementia correlates with increasing age and probably reflects an interplay of multiple pathologies. Seventeen people with dementia had postmortems. Eight had diffuse Lewy bodies as the only cause of dementia, while others had mixed neuropathology. Only one person lives independently and 48% are in nursing homes. Excessive daytime sleepiness is noted in 70%, falls have occurred in 87%, freezing in 81%, fractures in 35%, symptomatic postural hypotension in 48%, urinary incontinence in 71%, moderate dysarthria in 81%, choking in 48%, and hallucinations in 74%. The challenge is to understand the cellular mechanisms underlying the diverse features of advanced PD that go far beyond a lack of dopamine.

The role of executive function and attention in gait

Abstract: Until recently, gait was generally viewed as a largely automated motor task, requiring minimal higher-level cognitive input. Increasing evidence, however, links alterations in executive function and attention to gait disturbances. This review discusses the role of executive function and of attention in healthy walking and gait disorders while summarizing the relevant, recent literature. We describe the variety of gait disorders that may be associated with different aspects of executive function, and discuss the changes occurring in executive function as a result of aging and disease as well the potential impact of these changes on gait. The attentional demands of gait are often tested using dual tasking methodologies. Relevant studies in healthy adults and patients are presented, as are the possible mechanisms responsible for the deterioration of gait during dual tasking. Lastly, we suggest how assessments of executive function and attention could be applied in the clinical setting as part of the process of identifying and understanding gait disorders and fall risk.

A systematic review of prevalence studies of depression in Parkinson's disease: The Prevalence of Depression in PD

Abstract: Prevalence rates of depressive disorders in Parkinson's disease (PD) vary widely across studies, ranging from 2.7% to more than 90%. The aim of this systematic review was to calculate average prevalences of depressive disorders taking into account the different settings and different diagnostic approaches of studies. Using Medline on Pubmed, a systematic literature search was carried out for studies of depression in Parkinson's disease. A total of 104 articles were included and assessed for quality; 51 articles fulfilled the quality criteria. Multiple publications from the same database were not included in the meta‐analysis. In the remaining 36 articles, the weighted prevalence of major depressive disorder was 17% of PD patients, that of minor depression 22% and dysthymia 13%. Clinically significant depressive symptoms, irrespective of the presence of a DSM defined depressive disorder, were present in 35%. In studies using a (semi) structured interview to establish DSM criteria, the reported prevalence of major depressive disorder was 19%, while in studies using DSM criteria without a structured interview, the reported prevalence of major depressive disorder was 7%. Population studies report lower prevalence rates for both major depressive disorder and the clinically significant depressive symptoms than studies in other settings. This systematic review suggests that the average prevalence of major depressive disorder in PD is substantial, but lower than generally assumed. © 2007 Movement Disorder Society

The effectiveness of exercise interventions for people with Parkinson's disease: A systematic review and meta‐analysis

Abstract: Parkinson's disease (PD) is a neurodegenerative disorder affecting the physical, psychological, social, and functional status of individuals Exercise programs may be an effective strategy to delay or reverse functional decline for people with PD and a large body of empirical evidence has emerged in recent years The objective is to systematically review randomized controlled trials (RCTs) reporting on the effectiveness of exercise interventions on outcomes (physical, psychological or social functioning, or quality of life) for people with PD RCTs meeting the inclusion criteria were identified by systematic searching of electronic databases Key data were extracted by two independent researchers A mixed methods approach was undertaken using narrative, vote counting, and random effects meta-analysis methods Fourteen RCTs were included and the methodological quality of most studies was moderate Evidence supported exercise as being beneficial with regards to physical functioning, health-related quality of life, strength, balance and gait speed for people with PD There was insufficient evidence support or refute the value of exercise in reducing falls or depression This review found evidence of the potential benefits of exercise for people with PD, although further good quality research is needed Questions remain around the optimal content of exercise interventions (dosing, component exercises) at different stages of the disease

Glial reactions in Parkinson's disease

Abstract: Dopaminergic neurons of the substantia nigra are particularly vulnerable to oxidative and inflammatory attack. Such processes may play a crucial role in the etiology of Parkinson disease (PD). Since glia are the main generators of these processes, the possibility that PD may be caused by glial dysfunction needs to be considered. This review concentrates on glial reactions in PD. Reactive astrocytes and reactive microglia are abundant in the substantia nigra (SN) of PD cases indicating a robust inflammatory state. Glia normally serve neuroprotective roles but, given adverse stimulation, they may contribute to damaging chronic inflammation. Microglia, the phagocytes of brain, may be the main contributors since they can produce large numbers of superoxide anions and other neurotoxins. Their toxicity towards dopaminergic neurons has been demonstrated in tissue culture and various animal models of PD. The MPTP and α-synuclein models are of particular interest. Years after exposure to MPTP, inflammation has been observed in the SN. This has established that an acute insult to the SN can result in a sustained local inflammation. The α-synuclein model indicates that an endogenous protein can induce inflammation, and, when overexpressed, can lead to autosomal dominant PD. Less is known about the role of astrocytes than microglia, but they are known to secrete both inflammatory and anti-inflammatory molecules and may play a role in modulating microglial activity. Oligodendrocytes do not seem to play a role in promoting inflammation although, like neurons, they may be damaged by inflammatory processes. Further research concerning glial reactions in PD may lead to disease-modifying therapeutic approaches. © 2007 Movement Disorder Society

Functional organization of the basal ganglia: therapeutic implications for Parkinson's disease

Abstract: The basal ganglia (BG) are a highly organized network, where different parts are activated for specific functions and circumstances. The BG are involved in movement control, as well as associative learning, planning, working memory, and emotion. We concentrate on the "motor circuit" because it is the best understood anatomically and physiologically, and because Parkinson's disease is mainly thought to be a movement disorder. Normal function of the BG requires fine tuning of neuronal excitability within each nucleus to determine the exact degree of movement facilitation or inhibition at any given moment. This is mediated by the complex organization of the striatum, where the excitability of medium spiny neurons is controlled by several pre- and postsynaptic mechanisms as well as interneuron activity, and secured by several recurrent or internal BG circuits. The motor circuit of the BG has two entry points, the striatum and the subthalamic nucleus (STN), and an output, the globus pallidus pars interna (GPi), which connects to the cortex via the motor thalamus. Neuronal afferents coding for a given movement or task project to the BG by two different systems: (1) Direct disynaptic projections to the GPi via the striatum and STN. (2) Indirect trisynaptic projections to the GPi via the globus pallidus pars externa (GPe). Corticostriatal afferents primarily act to inhibit medium spiny neurons in the "indirect circuit" and facilitate neurons in the "direct circuit." The GPe is in a pivotal position to regulate the motor output of the BG. Dopamine finely tunes striatal input as well as neuronal striatal activity, and modulates GPe, GPi, and STN activity. Dopaminergic depletion in Parkinson's disease disrupts the corticostriatal balance leading to increased activity the indirect circuit and reduced activity in the direct circuit. The precise chain of events leading to increased STN activity is not completely understood, but impaired dopaminergic regulation of the GPe, GPi, and STN may be involved. The parkinsonian state is characterized by disruption of the internal balance of the BG leading to hyperactivity in the two main entry points of the network (striatum and STN) and excessive inhibitory output from the GPi. Replacement therapy with standard levodopa creates a further imbalance, producing an abnormal pattern of neuronal discharge and synchronization of neuronal firing that sustain the "off" and "on with dyskinesia" states. The effect of levodopa is robust but short-lasting and converts the parkinsonian BG into a highly unstable system, where pharmacological and compensatory effects act in opposing directions. This creates a scenario that substantially departs from the normal physiological state of the BG.

Physiology and Anatomy of Possible Oscillators in the Central Nervous System

Abstract: Pathologic tremors occur when the normal, continuous pattern of muscle activation is replaced by relatively synchronous bursting. This article discusses the possible roles of stretch reflex and central oscillators in producing tremor. The gain and conduction delay in some reflex arcs places the stretch reflex close to oscillation in some muscles during normal operation. Within the brain, cells in the thalamic relay nuclei and inferior olive contain a set of ionic conductancies in the cell membrane that can interact to produce oscillations in membrane potential. This tendency is exaggerated by hyperpolarizing or depolarizing the cell away from the normal resting potential. The activity of neighboring cells can be coupled (by electrotonic gap junctions in the olive and by recurrent axonal projections from the reticular nucleus in the thalamus), thus a large population of cells can oscillate together and exert a powerful rhythmic influence on motor output.

Quality of life in Parkinson's disease: the relative importance of the symptoms.

Abstract: A body of literature now exists, which demonstrates that idiopathic Parkinson's disease (PD) has a major negative impact on quality of life (QoL), and that depression and cognitive impairment are among the main predictors of poor QoL in this disorder. Relatively little work has been done to assess the differential contribution of the specific symptoms of PD to QoL, which was the aim of this study. One hundred thirty patients with PD completed a booklet of questionnaires, which included the PDQ39 as a disease-specific measure of QoL, a symptom checklist, a mobility checklist, as well as patient ratings of disease stage and disability. The results indicated that the contribution of physical, medication-related, and cognitive/psychiatric symptoms to QoL can be significant. Sudden unpredictable on/off states, difficulty in dressing, difficulty in walking, falls, depression, and confusion were PD symptoms, which significantly influenced QoL scores. Among the mobility problems associated with PD, start hesitation, shuffling gait, freezing, festination, propulsion, and difficulty in turning had a significant effect on QoL scores. In addition to depression and anxiety, the major predictors of QoL were shuffling, difficulty turning, falls, difficulty in dressing, fatigue, confusion, autonomic disturbance particularly urinary incontinence, unpredictable on/off fluctuations, and sensory symptoms such as pain. The implications of these results for the medical management of PD are discussed.

Animal Models of Action Tremor

Abstract: This article is devoted to animal models of tremors that emerge from lesions in the Guillain-Mollaret triangle. Cerebellar intention tremor is caused by lesions in the brachium conjunctivum or in the interpositus nucleus, possibly in combination with damage to the dentate nucleus. Impaired feed-forward motor control delays the braking of rapid movements, resulting in target overshoot and subsequent oscillation. Transcortical and transcerebellar sensorimotor loops undergo oscillation at a frequency that depends on the mechanical properties of the limb and the length of the sensorimotor loop (mechanical reflex oscillation). The crescendo quality of intention tremor may be a result of amplification of tremor in reverberating brain stem-cerebellar or thalamocortical loops. So-called rubral or midbrain tremor is caused by a combination of damage to the brachium conjunctivum and nigrostriatal pathways in the vicinity of the red nucleus. Secondary compensatory changes in the motor system are probably involved because midbrain tremor in people usually begins weeks or months after a midbrain stroke or trauma. Harmaline causes enhanced neuronal synchrony and rhythmicity in the inferior olive; this animal model, although as yet unproven, is the most popular one for essential tremor (ET). Additional studies in laboratory animals are needed to define the seemingly universal involvement of the cerebellum and ventrolateral thalamus (ventralis intermedius [Vim]) in virtually all human tremor disorders.

Long-Term Electrical Inhibition of Deep Brain Targets in Movement Disorders

Abstract: Stimulation of the thalamic nucleus ventralis intermedius (Vim) at high (130-Hz) frequency has been used over the last 8 years as a treatment in 134 patients with movement disorders (91 Parkinson's disease [PD], 23 essential tremor [ET], 21 various dyskinesias and dystonias, including four multiple sclerosis [MS]), implanted with long-term electrodes connected to a programmable stimulator. In PD patients, tremor was selectively suppressed for < or = 11 years. In ET patients, results were satisfactory, but in 35% of the cases deteriorated with time, when tremor had an action component. Other types of dyskinesias were much less influenced. Sixty-eight patients were bilaterally implanted, and 14 were implanted contralateral to a previous thalamotomy. Side effects were often minor, well tolerated, and immediately reversible. Three secondary scalp infections led to temporary removal of implanted material. There was no permanent morbidity. Long-term Vim stimulation, which is reversible, adaptable, and well tolerated, even by bilaterally operated-on (68 of 134) and by elderly patients, should replace thalamotomy in the regular surgical treatment of parkinsonian and essential tremors. More recently, we stimulated the subthalamic nucleus (STN) in 51 patients (44 bilateral) and the globus pallidus internus (GPi) in 12 patients (seven bilateral). STN stimulation has a spectacular effect on akinesia and rigidity and may improve the patients so as to maintain them all day at a level similar to their best "on" periods. A 30-50% reduction in drug dosage was possible in most of the patients. GPi stimulation has indications and effects similar to those of pallidectomy: abnormal involuntary movements are totally suppressed, whereas effects on akinesia and rigidity are not so important as they are with STN stimulation. For all three targets, morbidity is low and reversible, even when bilateral implantations are performed. The deep-brain stimulation method has now proved its safety as compared with ablative surgery and is able to provide a significant improvement to these severely disabled patients. Long-term follow up is establishing the security of the method, which should be considered in earlier stages of the disease actively to participate to rehabilitation.

Understanding and treating freezing of gait in parkinsonism, proposed working definition, and setting the stage.

Abstract: Although the term “freezing of gait” (FOG) was not used by early authors and notably not by Parkinson himself,1 the typical propulsive high frequency stepping associated with this gait disturbance was described by him as a feature of Parkinson’s disease (PD). Martin2 also reported examples of an inability to initiate locomotion accompanied by disturbed stepping patterns in postencephalitic parkinsonism with a dramatic response to visual cues. It was not until the early 1970s that FOG started to get increased attention, based on the realization that its response to levodopa was more complex than that of bradykinesia and rigidity. During those early days, it was first suggested that levodopa can sometimes induce or even worsen FOG.3 Based on those reports and the occurrence of FOG in atypical parkinsonism, it has long been considered a levodopa-resistant symptom. It took 30 years of experience with levodopa treatment to understand that this is a misconception. Schaafsma et al. demonstrated that “off”-related FOG episodes were significantly shorter in duration and markedly fewer in frequency when turning from “off” to “on.”4 However, the concept of a complex relationship with levodopa treatment still holds, as is evidenced by the continued manifestation of FOG in the “on” period, and its relationship with other levodopa-resistant symptoms such as postural instability.5,6 Despite its fascinating and unique nature, its common appearance among people with advanced PD, and its significant contribution to the development of major disability and frequent falls,7 research about the pathophysiology and treatment of FOG moved slowly forward. One possible reason for that delay is the unpredictable and episodic nature of freezing, which makes it very difficult to capture true spontaneous episodes. In addition, FOG appears most frequently at home during unobserved behavior and in response to specific environmental triggers8 and rarely in the gait lab.9 Another difficulty that might have slowed down FOG research is its lack of definition. This is of special importance, considering the fact that FOG is very heterogeneous in nature and can frequently be confused with bradykinesia or akinesia. Taking all those difficulties together, we thought it is time to join forces and move research about FOG forward to a better understanding of its mechanisms and hopefully with time leading to more effective treatment. This supplement is the result of a satellite symposium which was held just prior to the Kyoto International Movement Disorders Congress in late October 2006. In this meeting, a number of state-of-the-art presentations were put forward, summarizing the most recent clinical and research findings. All speakers and two additional leading figures in the field of FOG research were subsequently invited to contribute to this first ever supplement devoted to FOG in parkinsonism. As part of the introduction to this supplement, we propose a working definition of FOG. We are aware of the difficulties inherent to this task but believe that this first step has to be taken to improve communication and upgrade the quality of scientific terminology among researchers. The most common feature associated with FOG is the unique subjective feeling of patients describing that “their feet get glued to the ground.” As suggested in one of the supplement papers on the clinimetrics of FOG,10 this characteristic feeling may aid in accurate history *Correspondence to: Alice Nieuwboer, Departement Revalidatiewetenschappen, Faculteit Bewegingsen Revalidatiewetenschappen, Katholieke Universiteit Leuven, Tervuursevest 101, 3001-B Leuven (Heverlee), Belgium. E-mail: alice.nieuwboer@faber.kuleuven.be Received 26 November 2007; Accepted 29 November 2007 Published online 25 July 2008 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.21927 Movement Disorders Vol. 23, Suppl. 2, 2008, pp. S423–S425 © 2008 Movement Disorder Society

The Montreal cognitive assessment as a screening tool for cognitive impairment in Parkinson's disease.

Abstract: Cognitive impairment is common in Parkinson's disease (PD) and can occur early in the disease course. No effective screening test exists for detection of early or mild cognitive impairment in PD. We examined the Montreal Cognitive Assessment (MoCA) as a screening tool for cognitive dysfunction in PD. The test-retest intraclass correlation coefficient was 0.79 and the interrater intraclass correlation coefficient was 0.81. The correlation coefficient between the MoCA and a neuropsychologic battery was 0.72. The MoCA is reliable and valid in the PD population and warrants further study as a screening tool for cognitive dysfunction.

A comparison of the mini mental state exam to the montreal cognitive assessment in identifying cognitive deficits in Parkinson's disease

Abstract: Dementia is an important and increasingly recognized problem in Parkinson's disease (PD). The mini-mental state examination (MMSE) often fails to detect early cognitive decline. The Montreal cognitive assessment (MoCA) is a brief tool developed to detect mild cognitive impairment that assesses a broader range of domains frequently affected in PD. The scores on the MMSE and the MoCA were compared in 88 patients with PD. A pronounced ceiling effect was observed with the MMSE but not with the MoCA. The range and standard deviation of scores was larger with the MoCA(7-30, 4.26) than with the MMSE(16-30, 2.55). The percentage of subjects scoring below a cutoff of 26/30 (used by others to detect mild cognitive impairment) was higher on the MoCA (32%) than on the MMSE (11%) (P < 0.000002). Compared to the MMSE, the MoCA may be a more sensitive tool to identify early cognitive impairment in PD.

Freezing of gait and executive functions in patients with Parkinson's disease.

Abstract: Freezing of gait (FOG) is a frequent, disabling symptom of Parkinson's disease (PD). FOG usually lasts a few seconds. It refers to brief paroxysmal events during which a subject is unable to start or continue locomotion. Despite its frequency, FOG pathophysiology is unclear. Because a frontal lobe dysfunction or a disconnection between the frontal lobe and basal ganglia has been implicated in FOG, we explored frontal functions in PD patients using neuropsychological tests. Thirteen early-stage PD patients [Hoehn & Yahr score (HY phonemic verbal fluency: P = 0.011; TPCT: P = 0.024). FOG correlated with lower scores at frontal tests in patients with early-stage PD.

Apathy and anhedonia rating scales in Parkinson's disease: Critique and recommendations

Abstract: Apathy is a common condition in Parkinson's disease (PD) and is generally defined as a lack of motivation. It is associated with more severe cognitive dysfunction and a decrease in activities of daily living (ADL) performance. Anhedonia, the inability to experience pleasure, can be a symptom of both depressive and apathetic syndromes. The Movement Disorder Society (MDS) commissioned a task force to assess the clinimetric properties of apathy and anhedonia scales in PD patients. A systematic literature review was conducted to identify scales that have either been validated or used in PD patients. Apathy scales identified for review include the Apathy Evaluation Scale (AES), the Apathy Scale (AS), the Apathy Inventory (AI), and the Lille Apathy Rating Scale (LARS). In addition, item 4 (motivation/initiative) of the Unified Parkinson's Disease Rating Scale (UPDRS) and item 7 (apathy) of the Neuropsychiatric Inventory (NPI) were included. Anhedonia scales identified for review were the Snaith-Hamilton Pleasure Scale (SHAPS) and the Chapman scales for physical and social anhedonia. Only the AS is classified as "recommended" to assess apathy in PD. Although item 4 of the UPDRS also meets the criteria to be classified as recommended, it should be considered for screening only because of the obvious limitations of a single item construct. For the assessment of anhedonia, only the SHAPS meets the criteria of "Suggested." Information on the validity of apathy and anhedonia scales is limited because of the lack of consensus on diagnostic criteria for these conditions.

Parkinson's disease-cognitive rating scale: a new cognitive scale specific for Parkinson's disease.

Abstract: Cognitive defects associated with cortical pathology may be a marker of dementia in Parkinson's disease (PD). There is a need to improve the diagnostic criteria of PD dementia (PDD) and to clarify the cognitive impairment patterns associated with PD. Current neuropsychological batteries designed for PD are focused on fronto-subcortical deficits but are not sensitive for cortical dysfunction. We developed a new scale, the Parkinson's Disease-Cognitive Rating Scale (PD-CRS), that was designed to cover the full spectrum of cognitive defects associated with PD. We prospectively studied 92 PD patients [30 cognitively intact (CogInt), 30 mild cognitive impairment (MCI), 32 PDD] and 61 matched controls who completed the PD-CRS and neuropsychological tests assessing the cognitive domains included in the PD-CRS. Acceptability, construct validity, reliability, and the discriminative properties of the PD-CRS were examined. The PD-CRS included items assessing fronto-subcortical defects and items assessing cortical dysfunction. Construct validity, test-retest and inter-rater reliability of PD-CRS total scores showed an intraclass correlation coefficient >0.70. The PD-CRS showed an excellent test accuracy to diagnose PDD (sensitivity 94%, specificity 94%). The PD-CRS total scores and confrontation naming item scores-assessing "cortical" dysfunction-independently differentiated PDD from non-demented PD. Alternating verbal fluency and delayed verbal memory independently differentiated the MCI group from both controls and CogInt. The PD-CRS appeared to be a reliable and valid PD-specific battery that accurately diagnosed PDD and detected subtle fronto-subcortical deficits. Performance on the PD-CRS showed that PDD is characterized by the addition of cortical dysfunction upon a predominant and progressive fronto-subcortical impairment.

The history of dopamine and levodopa in the treatment of Parkinson's disease.

Abstract: The discoveries of dopamine as a neurotransmitter in the brain, its depletion in patients with Parkinson disease, and its replacement with levodopa therapy were major revolutionary events in the rise to effective therapy for patients with this disorder. This review describes these events and the persons who carried out these accomplishments. Their impact went beyond a single clinical entity of parkinsonism, for it opened up the beginning of a much better understanding of the role of dopamine in other neurologic movement disorders and also in many psychiatric diseases.

Transplanted dopaminergic neurons develop PD pathologic changes: A second case report

Abstract: This report describes pathological changes within the grafted neurons of another patient with Parkinson's disease (PD) who died 14 years posttransplantation. Although numerous healthy appearing grafted neurons were present at this long-term time point, some displayed Lewy bodies as evidenced by alpha-synuclein, ubiquitin, and thioflavin-S staining. Additionally, there was a general loss of dopamine transporter-immunoreactivity in grafted neurons. Some grafted cell displayed a loss of tyrosine hydroxylase. These data support the emerging concept that PD-like pathology is seen in young grafted neurons when they survive long term.

Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice.

Abstract: Only in the last three decades, the restless legs syndrome (RLS) has been examined in randomized controlled trials. The Movement Disorder Society (MDS) commissioned a task force to perform an evidence-based review of the med- ical literature on treatment modalities used to manage patients with RLS. The task force performed a search of the published literature using electronic databases. The therapeu- tic efficacy of each drug was classified as being either effica- cious, likely efficacious, investigational, nonefficacious, or lacking sufficient evidence to classify. Implications for clini- cal practice were generated based on the levels of evidence and particular features of each modality, such as adverse

Chronic pain in Parkinson's disease: The cross-sectional French DoPaMiP survey

Abstract: Pain is a frequent, but poorly studied symptom of Parkinson's disease (PD). DoPaMiP survey aimed to assess the prevalence of chronic pain in PD, to describe PD patients with chronic pain, and to record analgesic consumption. About 450 parkinsonian patients underwent structured standardized clinical examination and completed self-reported questionnaires in a cross sectional survey. Pains related or unrelated to PD were identified according to predefined criteria. About 98 patients with other chronic disorders than PD were examined to assess if pain was more frequent in PD than in this population. Two thirds parkinsonian patients (278 of 450) had chronic pain. Twenty-five patients with non-chronic pain (<3-month duration) were excluded from subsequent analysis. Twenty six percent (111 of 425) parkinsonian patients had pain unrelated to PD ("non-PD-pain", caused mainly by osteoarthritis), while 39.3% (167 of 425) had chronic pain related to PD ("PD-pain"). In this last group, PD was the sole cause of pain in 103 and indirectly aggravated pain of another origin (mainly osteoarthritis) in 64. Parkinsonian patients with "PD-pain" were younger at PD onset, had more motor complications, more severe depressive symptoms than those without pain or with "non-PD pain." "PD-pain" was more intense (P = 0.03), but was less frequently reported to doctors (P = 0.02), and was associated with less frequent analgesic consumption than "non-PD-pain." Pain was twice more frequent in PD patients than in patients without PD after adjustment for osteo-articular comorbidities (OR = 1.9; 95% CI 1.2-3.2). Chronic pain is frequent but underreported in PD. Awareness of this problem should be increased and the assessment of analgesic strategies improved.

The evolution of disability in Parkinson disease.

Abstract: The objectives of this study are to assess the level of disease severity associated with disability in Parkinson disease (PD) and the sequence of loss of independence in basic and instrumental activities of daily living (ADLs and IADLs). Six hundred eighteen patients with PD were evaluated for disease severity with the Unified PD Rating Scale (UPDRS) and for disability with the Older Americans Resource and Services Disability Subscale (OARS). The association between patient-reported disability on ADLs and IADLs and level of disease severity on the total UPDRS was examined cross-sectionally. Disability, with loss of independent function is reported between total UPDRS scores 30 to 40, and HY stages II to III. Difficulty with daily activities, without loss of independent function is reported earlier, at UPDRS <20 and HY I to II. Difficulty with walking is initially reported, followed by problems with a number of gait-dependent activities including housework, dressing, transferring in and out of bed, and traveling in the community. The transition from HY stage II to III marks a pivotal milestone in PD, when gait and balance impairment results in disability in many gait-dependent activities. The onset of disability in PD can be identified by asking patients about their walking, housework, dressing, and traveling. While individual patients vary in progression, the benchmarks of disability in this study provide guidance when counseling patients about prognosis. Better understanding of the stages of disability may facilitate the development of novel outcome measures in clinical trials in PD.

Nonmotor symptoms as presenting complaints in Parkinson's disease: a clinicopathological study.

Abstract: Nonmotor symptoms (NMS) are increasingly recognized as a significant cause of morbidity in later stages of Parkinson's disease (PD). Prodromal NMS are also a well recognized component of the clinical picture in some patients but the prevalence of NMS as presenting complaints, and their impact on clinical management, in pathologically-proven cases of PD is unknown. The presenting complaints of 433 cases of pathologically-proven PD archived at the Queen Square Brain Bank for Neurological Diseases were identified from the clinical case notes. 91/433 (21%) of patients with PD presented with NMS of which the most frequent were pain (15%), urinary dysfunction (3.9%), anxiety, or depression (2.5%). Presenting with NMS is associated with a delayed diagnosis of PD (Mann-Whitney U, P = 0.001). These patients were more likely to be misdiagnosed initially and were more likely to have been referred to orthopedic surgeons or rheumatologists than neurologists (nonmotor group 5.5% vs. motor group 44.2%, chi(2) P < 0.0001). NMS are commonly seen as presenting complaints in pathologically confirmed PD, and initial misdiagnosis may be associated with potentially inappropriate medical interventions. Presenting with NMS does not affect the motor response to medication, but is associated with shorter disease duration (chi(2) P = 0.016).

Comparison of desipramine and citalopram treatments for depression in Parkinson's disease: A double-blind, randomized, placebo-controlled study

Abstract: Depression is one of the most common psychiatric disturbances in Parkinson's disease (PD). Recent reviews have highlighted the lack of controlled trials and the ensuing difficulty in formulating recommendations for antidepressant use in PD. We sought to establish whether antidepressants provide real benefits and whether tricyclic and selective serotonin reuptake inhibitor (SSRI) antidepressants differ in their short-term efficacy, because the time to onset of therapeutic benefit remains an important criterion in depression. The short-term efficacy (after 14 and 30 days) of two antidepressants (desipramine, a predominantly noradrenergic reuptake inhibitor tricyclic and citalopram, a SSRI) was assessed in a double-blind, randomized, placebo- controlled study of 48 nondemented PD patients suffering from major depression. After 14 days, desipramine prompted an improvement in the Montgomery Asberg Depression Rating Scale (MADRS) score, compared with citalopram and placebo. Both antidepressants produced significant improvements in the MADRS score after 30 days. Mild adverse events were twice as frequent in the desipramine group as in the other groups. A predominantly noradrenergic tricyclic antidepressant induced a more intense short-term effect on parkinsonian depression than did an SSRI. However, desipramine's lower tolerability may outweigh its slight short-term clinical advantage.

Long-term follow-up of impulse control disorders in Parkinson's disease.

Abstract: Recent studies have linked dopamine agonist (DA) usage with the development of impulse control disorders (ICDs) in Parkinson's disease (PD). Little is known about optimal management strategies or the long-term outcomes of affected patients. To report on the clinical interventions and long-term outcomes of PD patients who developed an ICD after DA initiation. Subjects contacted by telephone for a follow-up interview after a mean time period of 29.2 months. They were administered a modified Minnesota Impulse Disorder Interview for compulsive buying, gambling, and sexuality, and also self-rated changes in their ICD symptomatology. Baseline and follow-up dopamine replacement therapy use was recorded and verified by chart review. Of 18 subjects, 15 (83.3%) participated in the follow-up interview. At follow-up, patients were receiving a significantly lower DA levodopa equivalent daily dosage (LEDD) (Z = -3.1, P = 0.002) and a higher daily levodopa dosage (Z = -1.9, P = 0.05), but a similar total LEDD dosage (Z = -0.47, P = 0.64) with no changes in Unified Parkinson's Disease Rating Scale motor score (Z = -1.3, P = 0.19). As part of ICD management, 12 (80.0%) patients discontinued or significantly decreased DA treatment, all of whom experienced full or partial remission of ICD symptoms by self-report, and 10 (83.3%) of whom no longer met diagnostic criteria for an ICD. For PD patients who develop an ICD in the context of DA treatment, discontinuing or significantly decreasing DA exposure, even when offset by an increase in levodopa treatment, is associated with remission of or significant reduction in ICD behaviors without worsening in motor symptoms.

Placebo response in Parkinson's disease: Comparisons among 11 trials covering medical and surgical interventions

Abstract: Placebo-associated improvements have been previously documented in small series of Parkinson's disease (PD) patients. Using a strict definition of placebo-associated improvement, we examined rates and timing of placebo responses to identify patient- and study-based characteristics, predicting positive placebo response in several PD clinical trials. We collected individual patient data from the placebo groups of 11 medical and surgical treatment trials involving PD patients with differing PD severities and placebo-assignment likelihoods. We defined a positive placebo response as > or = 50% improvement in total Unified Parkinson's Disease Rating Scale motor (UPDRSm) score or a decrease by > or = 2 points on at least two UPDRSm items compared to baseline. We calculated positive placebo response rates at early (3-7 weeks), mid (8-18 weeks), and late (23-35 weeks) stages of follow-up. Odds ratios for patient- and study-based characteristics were obtained from a model fitted using generalized estimating equations. There were 858 patients on placebo who met inclusion criteria for analysis. Three studies involved patients without need of symptomatic treatment, two involved patients without motor fluctuations needing symptomatic treatment, and six (three medical and three surgical) involved patients with motor fluctuations. The overall placebo response rate was 16% (range: 0-55%). Patients with higher baseline UPDRSm scores and studies that focused on PD with motor fluctuations, surgical interventions, or those with a higher probability of placebo assignment showed increased odds of positive placebo response. Placebo responses were temporally distributed similarly during early, mid, and late phases of follow-up. Placebo-related improvements occur in most PD clinical trials and are similarly distributed across all 6 months of follow-up. Recognition of factors that impact placebo response rates should be incorporated into individual study designs for PD clinical trials.

Speech rate and rhythm in Parkinson's disease.

Abstract: Articulatory rate and pause time in a standardized reading task in Parkinson's disease (PD) patients in correlation to disease duration and severity as compared to healthy controls were analyzed. In 121 PD patients and 70 healthy controls, an acoustical analysis was performed on the first and last sentence of a standardized 170-syllabic text, using a commercial audio software. Articulatory rate and speech to pause ratios were calculated by measuring the length of each syllable and each pause both at the end of words and within polysyllabic words. No significant difference in overall articulatory rate was found between PD patients and controls. Both groups showed an accelerated speech rate in the last sentence compared to the first; however, PD patients had a higher speech acceleration than did controls. PD patients exhibited a significantly reduced percental pause duration in relation to total speech time in the first sentence and a reduced percental pause time within polysyllabic words. PD patients made significantly less but longer pauses at the end of words and less pauses within polysyllabic words. UPDRS III showed an inverse relation to number and rate of intraword pauses, and disease duration was negatively correlated with articulatory rate. The characteristics of parkinsonian speech feature was not only a stronger acceleration of articulation rate in the course of speaking but also a significant reduction of the total numbers of pauses, indicating an impaired speech rhythm and timing organization.

Apathy following subthalamic stimulation in Parkinson disease: a dopamine responsive symptom.

Abstract: To evaluate the effects of the dopamine D2-D3 agonist ropinirole in patients who developed apathy after complete withdrawal from dopaminergic medication following successful subthalamic nucleus (STN) stimulation for advanced Parkinson disease (PD). We assessed apathy (Apathy Scale, Apathy Inventory), mood (Montgomery-Asberg Depression Rating Scale), cognitive functions (Mattis Dementia rating scale, frontal score, executive tests) and motor state (UPDRS-III) in 8 PD patients treated with STN stimulation without dopaminergic treatment and who became apathetic. Assessments were made at baseline and after 6 weeks of ropinirole treatment (7.2 +/- 5.9 mg/d; range 1-18 mg/d). Apathy improved with ropinirole in all but 1 patient (54 +/- 24%; range 0-78%). Mood also improved (75 +/- 31%; range 0-100%), but not in correlation with the change in apathy. Cognitive performance was not modified. Stimulation contacts were located within the STN in all patients except the one who remained apathetic in spite of ropinirole treatment (zona incerta). We suggest that apathy, which was compensated for by an enhancement of D2-D3 receptor stimulation in PD patients with STN stimulation: (1) depends on a dopaminergic deficit in associativo-limbic areas of the brain and (2) can be avoided if a dopaminergic agonist is administered postoperatively.

Anxiety rating scales in Parkinson's disease: critique and recommendations.

Abstract: Anxiety syndromes are common in patients with Parkinson's disease (PD) with up to 30% suffering from panic disorder, and up to 11% from generalized anxiety disorder (GAD). Anxiety is associated with increased subjective motor symptoms, more severe gait problems, dyskinesias, freezing, and on/off fluctuations. Anxiety has a negative impact on health related quality of life and is strongly associated with depressive syndromes. Since a variety of anxiety scales have been used in PD patients, the Movement Disorder Society commissioned a task force to assess the clinimetric properties of these scales in PD. A systematic review was conducted to identify anxiety scales that have either been validated or used in patients with PD. Six anxiety rating scales were identified. These were the Beck anxiety inventory, the hospital anxiety and depression scale, the Zung self-rating anxiety scale and anxiety status inventory, the Spielberger state trait anxiety inventory, and the Hamilton anxiety rating scale. In addition, Item 5 (anxiety) of the neuropsychiatric inventory was included in the review. No scales met the criteria to be "recommended," and all scales were classified as "suggested." Essential clinimetric information is missing for all scales. Because several scales exist and have been used in PD, the task force recommends further studies of these instruments. If these studies show that the clinimetric properties of existing scales are inadequate, development of a new scale to assess anxiety in PD should be considered.