Parkinson Disease: Schrag A

Schrag A, Barone P, Brown RG, Leentjens AF, McDonald WM, Starkstein S, Weintraub D, Poewe W, Rascol O, Sampaio C, Stebbins GT, Goetz CG. · University Department of Clinical Neurosciences, Royal Free and University College Medical School, London, UK. · Mov Disord. · Pubmed #17394234 links to  free full text

Abstract: Depression is a common comorbid condition in Parkinson's disease (PD) and a major contributor to poor quality of life and disability. However, depression can be difficult to assess in patients with PD due to overlapping symptoms and difficulties in the assessment of depression in cognitively impaired patients. As several rating scales have been used to assess depression in PD (dPD), the Movement Disorder Society commissioned a task force to assess their clinimetric properties and make clinical recommendations regarding their use. A systematic literature review was conducted to explore the use of depression scales in PD and determine which scales should be selected for this review. The scales reviewed were the Beck Depression Inventory (BDI), Hamilton Depression Scale (Ham-D), Hospital Anxiety and Depression Scale (HADS), Zung Self-Rating Depression Scale (SDS), Geriatric Depression Scale (GDS), Montgomery-Asberg Depression Rating Scale (MADRS), Unified Parkinson's Disease Rating Scale (UPDRS) Part I, Cornell Scale for the Assessment of Depression in Dementia (CSDD), and the Center for Epidemiologic Studies Depression Scale (CES-D). Seven clinical researchers with clinical and research experience in the assessment of dPD were assigned to review the scales using a structured format. The most appropriate scale is dependent on the clinical or research goal. However, observer-rated scales are preferred if the study or clinical situation permits. For screening purposes, the HAM-D, BDI, HADS, MADRS, and GDS are valid in dPD. The CES-D and CSDD are alternative instruments that need validation in dPD. For measurement of severity of depressive symptoms, the Ham-D, MADRS, BDI, and SDS scales are recommended. Further studies are needed to validate the CSDD, which could be particularly useful for the assessment of severity of dPD in patients with comorbid dementia. To account for overlapping motor and nonmotor symptoms of depression, adjusted instrument cutoff scores may be needed for dPD, and scales to assess severity of motor symptoms (e.g., UPDRS) should also be included to help adjust for confounding factors. The HADS and the GDS include limited motor symptom assessment and may, therefore, be most useful in rating depression severity across a range of PD severity; however, these scales appear insensitive in severe depression. The complex and time-consuming task of developing a new scale to measure depression specifically for patients with PD is currently not warranted.

Schrag A. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #15654023 links to  free full text

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Gallagher DA, Schrag A. · Department of Clinical Neurosciences, Royal Free and University College Medical School, London, EnglandInstitute of Neurology, University College London, London, England. · CNS Drugs. · Pubmed #18547126 No free full text.

Abstract: Parkinson's disease is a common progressive neurodegenerative condition with multiple motor and nonmotor features contributing to impairment of health-related quality of life (HR-QOL). Pharmacological treatments have been directed primarily at dopamine replacement with levodopa and agents to improve its bioavailability, including DOPA decarboxylase inhibitors, catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase B (MAO-B) inhibitors, as well as synthetic dopamine agonists. These treatments to restore motor function are often very successful in early Parkinson's disease, with objective improvement and concomitant improvement in subjective HR-QOL scores. However, as the disease progresses, motor complications and nonmotor symptoms predominate and are often refractory to therapeutic interventions. Antiparkinsonian medications have been shown to improve motor severity and motor complications of advancing disease, and there is increasing evidence that this can be translated into subjective improvement of HR-QOL from a patient's point of view. However, the degree of improvement is less marked on HR-QOL scores than on motor scores, and some studies do not show improvement of HR-QOL in parallel to motor improvements. A number of explanations are possible, including limitations of the scales used, trial designs and lack of clinical improvement from the patients' point of view. This review concentrates on clinical trials with an index of HR-QOL as an outcome measure, with particular emphasis on well designed, randomized, double-blind, placebo-controlled or active comparator-controlled methodology. Drugs that have been more recently added to the armamentarium of Parkinson's disease, including the oral (pramipexole, ropinirole and piribedil) and transdermal (rotigotine) non-ergotamine-derived dopamine agonists, the novel MAO-B inhibitor rasagiline and the COMT inhibitors tolcapone and entacapone, were included. The effect of each of these agents on overall HR-QOL and depression, a factor that has been shown to significantly contribute to HR-QOL in several multivariate analyses, is discussed.Overall, the literature search revealed 14 double-blind, placebo- or active comparator-controlled trials with an index of HR-QOL as an outcome measure. Entacapone resulted in HR-QOL improvement in nonfluctuating patients (one study) but not clearly in those with motor fluctuations (two studies). Tolcapone was only tested in patients with motor fluctuations and resulted in significant improvement in two of four studies using HR-QOL as an outcome measure. Rasagiline improved HR-QOL as monotherapy in early Parkinson's disease (one study), but not clearly in more advanced disease (one study). Rotigotine improved HR-QOL in both early Parkinson's disease (one study) and more advanced disease with motor fluctuations (one study). The impact of ropinirole and pramipexole on HR-QOL as monotherapy in early Parkinson's disease versus placebo has not been assessed, but both agents have resulted in improved HR-QOL in patients with motor fluctuations (ropinirole one study, pramipexole one study). The evidence for antidepressant efficacy of antiparkinsonian medications is limited.

Schrag A. · Royal Free and University College Medical School, University College London NW3 2PF, London, United Kingdom. · J Neurol Sci. · Pubmed #16797028 No free full text.

Abstract: This paper reviews the literature on health-related quality of life (Hr-QoL) and depressive disorders, and the relationship between them, in patients with Parkinson's disease (PD). PD is associated with reduced Hr-QoL, including motor and non-motor physical consequences of the disease, emotional well-being and social functioning. While this effect is greater in advanced disease stages, there is no close relationship between disease duration and impact on quality of life, and the relationship between clinical rating scales and Hr-QoL scores is only moderate. On the other hand, presence and severity of depression in PD strongly correlates with Hr-QoL scores, and a number of studies have reported depression as the main determinant of poor HR-QoL scores. Despite being the main determinant of poor Hr-QoL and being recognized as an important problem by clinicians, until recently depression in PD has received relatively little attention in research studies. It is known that depression and anxiety occur more frequently in PD than in controls. Depression occurs in a bimodal pattern in PD, with increased rates at the onset and a later peak in advanced disease. Both anxiety and depression can also occur before the first motor symptoms of PD and predate the diagnosis of PD, indicating that these co-morbidities are manifestations of the underlying disease process of PD. Imaging studies have demonstrated abnormalities of dopaminergic, noradrenergic and serotonergic functioning with some correlation with severity of depression. The overall relationship between disease severity and rate of depression (except for off-period related depression) is poor, suggesting that nigrostriatal dysfunction alone is not sufficient to explain depressive symptoms in PD. Other factors are likely to contribute to occurrence and severity of depression in PD, either due to extrastriatal pathology or due to psychological and environmental factors leading to reactive depression. Thus, it is likely that depression in PD is multifactorial. The investigation of depression in PD is complicated by diagnostic difficulties in measuring and diagnosing depression in patients with PD due to the considerable overlap between symptoms of PD and depression. While a number of treatment approaches have been suggested, double-blind randomized controlled trials to demonstrate improvement of depression and overall Hr-QoL in PD are warranted.

Schrag A, Schott JM. · Royal Free and University College Medical School, University College London, Department of Clinical Neurosciences, London, UK. · Lancet Neurol. · Pubmed #16545752 No free full text.

Abstract: In this review we discuss the epidemiological, clinical, and genetic characteristics of early-onset parkinsonism, defined as parkinsonism starting before age 40 (sometimes 50) years. Juvenile parkinsonism is very rare and is the result of various secondary or genetic causes. In patients with onset at or above age 21 years, secondary causes require exclusion but are rare; most cases with a fairly pure parkinsonian syndrome (eg, young-onset Parkinson's disease; YOPD) are due to typical Lewy-body Parkinson's disease or, less commonly, genetic causes. In comparison with patients with late-onset disease, most patients with YOPD progress more slowly in terms of motor features and have a longer disease course with preservation of cognitive function, but typically develop motor fluctuations and dyskinesias earlier. Patients with YOPD generally experience a greater effect in their lives than those with late onset, with poorer social adjustment, higher rates of depression, and lower quality of life. Management of YOPD must therefore aim to maintain occupational, social, and daily functioning, while delaying or ameliorating motor complications of treatment, providing psychological support, and, where possible, preventing psychiatric complications including depression.

Schrag A. · University Department of Clinical Neurosciences, Royal Free and University College Medical School, London, UK. <> · Lancet Neurol. · Pubmed #15907741 No free full text.

Abstract: 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.

Schrag A. · University Department of Clinical Neurosciences, Royal Free and University College Medical School, London NW3 2PF, UK. · J Neurol. · Pubmed #15258780 No free full text.

Abstract: In patients with Parkinson's disease (PD) disturbances of mental state constitute some of the most difficult treatment challenges of advanced disease, often limiting effective treatment of motor symptoms and leading to increased disability and poor quality of life. This article provides an update on the current knowledge of these complications and the use of old and new drugs in their management. Mental state alterations in PD include depression, anxiety, cognitive impairment, apathy, and treatment-related psychiatric symptoms. The latter range from vivid dreams and hallucinations to delusions, manic symptoms, hypersexuality, dopamine dysregulation syndrome and delirium. While some of these symptoms may be alleviated by anti-parkinsonian medication, especially if they are off-period related, treatment-related phenomena are usually exacerbated by increasing the number or dosage of antiparkinsonian drugs. Elimination of exacerbating factors and simplification of drug regimes are the first and most important steps in improvement of such symptoms. However, the advent of atypical antipsychotics such as clozapine has dramatically helped the management of treatment-related psychiatric complications in PD. In patients with dementia associated with PD cognitive functioning and behavioural problems appear to respond to cholinesterase inhibitors, such as rivastigmine or donepezil. Depression is a common problem in early as well as advanced PD, and selective serotonin reuptake inhibitors, reboxetine, and tricyclic antidepressants have been reported to be effective and well tolerated antidepressants. Randomised, controlled studies are required to assess the differential efficacy and tolerability of antidepressants in patients with PD, including the newer antidepressants with serotonergic and noradrenergic properties.

Schrag A, Quinn N. · Department of Clinical Neurology, Institute of London. · J R Coll Physicians Lond. · Pubmed #10472019 No free full text.

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Schrag A, Keens J, Warner J, Anonymous00236. · Department of Clinical Neurology, Institute of Neurology, London, UK. · Eur J Neurol. · Pubmed #11985633 No free full text.

Abstract: The effect of Ropinirole on tremor in early Parkinson's disease (PD) was assessed. The results of three multicentre, randomized, double-blind trials comparing ropinirole monotherapy with levodopa, bromocriptine and placebo treatment were analysed retrospectively with respect to improvement of resting tremor and postural/action tremor as measured by items 20 and 21 of the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS). Improvements in resting tremor were significantly better with ropinirole than placebo. There were no significant differences between the effect of ropinirole and those of levodopa (L-dopa) or bromocriptine on resting tremor. Postural/action tremor was mild in these early therapy studies, and there were no significant differences between treatment groups. These results suggest that ropinirole monotherapy is effective in treating resting tremor in early PD. On the other hand, response of postural/action tremor to dopaminergic treatment in early PD was not significantly better than to placebo at the dosages used in these trials.

Brundin P, Pogarell O, Hagell P, Piccini P, Widner H, Schrag A, Kupsch A, Crabb L, Odin P, Gustavii B, Björklund A, Brooks DJ, Marsden CD, Oertel WH, Quinn NP, Rehncrona S, Lindvall O. · Section for Neuronal Survival, Division of Neurobiology, Department of Physiological Sciences, Lund University, Sweden. · Brain. · Pubmed #10869050 links to  free full text

Abstract: Five parkinsonian patients were transplanted bilaterally into the putamen and caudate nucleus with human embryonic mesencephalic tissue from between seven and nine donors. To increase graft survival, the lipid peroxidation inhibitor tirilazad mesylate was administered to the tissue before implantation and intravenously to the patients for 3 days thereafter. During the second postoperative year, the mean daily L-dopa dose was reduced by 54% and the UPDRS (Unified Parkinson's Disease Rating Scale) motor score in 'off' phase was reduced by a mean of 40%. At 10-23 months after grafting, PET showed a mean 61% increase of 6-L-[(18)F]fluorodopa uptake in the putamen, and 24% increase in the caudate nucleus, compared with preoperative values. No obvious differences in the pattern of motor recovery were observed between these and other previously studied cases with putamen grafts alone. The amount of mesencephalic tissue implanted in each putamen and caudate nucleus was 42 and 50% lower, respectively, compared with previously transplanted patients from our centre. Despite this reduction in grafted tissue, the magnitudes of symptomatic relief and graft survival were very similar. These findings suggest that tirilazad mesylate may improve survival of grafted dopamine neurons in patients, which is in agreement with observations in experimental animals.

Schrag A, Schelosky L, Scholz U, Poewe W. · Department of Clinical Neurology, Institute of Neurology, London, UK. · Mov Disord. · Pubmed #10091618 No free full text.

Abstract: We investigated the effect of an anticholinergic (biperiden) and a dopamine agonist (apomorphine) on tremor, rigidity, and akinesia in patients with idiopathic Parkinson's disease. In a standardized, crossover study design 17 patients received single-dose challenges of 5 mg biperiden intravenously and a previously determined dose of apomorphine subcutaneously on 2 consecutive days. Resting (RT), postural (PT), and action tremor (AT) were assessed using spectral analysis of accelerometer data, and Unified Parkinson's Disease Rating Scale (UPDRS) scores for rigidity and akinesia were determined before and after administration of the study drug. Both single-dose challenges significantly reduced the amplitude of RT, PT, and AT, but only apomorphine significantly reduced UPDRS scores for rigidity and akinesia. In only one patient was tremor reduced by the dopamine agonist but not by the anticholinergic. We found that anticholinergic and dopaminergic agents are both effective in reducing tremor in IPD, and there was no evidence for a selective anticholinergic responsiveness of parkinsonian tremor. Akinesia and rigidity, on the other hand, were not improved by biperiden. We therefore conclude that dopaminergic substances are as effective as anticholinergics in patients with parkinsonian tremor and additionally improve other parkinsonian signs.

Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stern MB, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, van Hilten JJ, LaPelle N, Anonymous00025. · Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, USA. · Mov Disord. · Pubmed #19025984 links to  free full text

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.

Katzenschlager R, Head J, Schrag A, Ben-Shlomo Y, Evans A, Lees AJ, Anonymous00008. · National Hospital for Neurology and Neurosurgery, Queen Square, London, UK. · Neurology. · Pubmed #18579806 No free full text.

Abstract: BACKGROUND: Ten-year follow-up results from the Parkinson's Disease Research Group of the United Kingdom trial demonstrated that there were no long-term advantages to initiating treatment with bromocriptine compared with l-dopa in early Parkinson disease (PD). Increased mortality in patients on selegiline combined with l-dopa led to premature termination of this arm after 6 years. METHODS: Between 1985 and 1990, 782 patients were recruited into an open pragmatic multicenter trial and were randomized to l-dopa/decarboxylase inhibitor (DDCI), l-dopa/DDCI plus selegiline, or bromocriptine. The main endpoints were mortality, disability, and motor complications. For final follow-up, health-related quality of life and mental function were also assessed. RESULTS: Median duration of follow-up at final assessment was 14 years in the 166 (21%) surviving participants who could be contacted. After adjustment for baseline characteristics, disability scores were better in the l-dopa than in the bromocriptine arm (Webster: 16.6 vs 19.8; p = 0.03; Northwestern University Disability: 34.3 vs 30.0, p = 0.05). Physical functioning (difference 20.8; 95% CI 10.0, 31.6; p < 0.001) and physical summary scores (difference 5.2; 95% CI 0.7, 9.7; p = 0.03) on the 36-item short-form health survey were also superior on l-dopa. Differences in mortality rates and prevalence of dyskinesias, motor fluctuations, and dementia were not significantly different. CONCLUSION: Initial treatment with the dopamine agonist bromocriptine did not reduce mortality or motor disability and the initially reduced frequency in motor complications was not sustained. We found no evidence of a long-term benefit or clinically relevant disease-modifying effect with initial dopamine agonist treatment.

Papapetropoulos S, Katzen H, Schrag A, Singer C, Scanlon BK, Nation D, Guevara A, Levin B. · Divisions of Movement Disorders Department of Neurology, University of Miami, Miller School of Medicine Miami, FL, USA. · BMC Neurol. · Pubmed #18570642 links to  free full text

Abstract: BACKGROUND: Hallucinations occur in 20-40% of PD patients and have been associated with unfavorable clinical outcomes (i.e., nursing home placement, increased mortality). Hallucinations, like other non-motor features of PD, are not well recognized in routine primary/secondary clinical practice. So far, there has been no instrument for uniform characterization of hallucinations in PD. To this end, we developed the University of Miami Parkinson's disease Hallucinations Questionnaire (UM-PDHQ) that allows comprehensive assessment of hallucinations in clinical or research settings. METHODS: The UM-PDHQ is composed of 6 quantitative and 14 qualitative items. For our study PD patients of all ages and in all stages of the disease were recruited over an 18-month period. The UPDRS, MMSE, and Beck Depression and Anxiety Inventories were used for comparisons. RESULTS AND DISCUSSION: Seventy consecutive PD patients were included in the analyses. Thirty-one (44.3%) were classified as hallucinators and 39 as non-hallucinators. No significant group differences were observed in terms of demographics, disease characteristics, stage, education, depressive/anxiety scores or cognitive functioning (MMSE) between hallucinators and non-hallucinators. Single mode hallucinations were reported in 20/31 (visual/14, auditory/4, olfactory/2) whereas multiple modalities were reported in 11/31 patients. The most common hallucinatory experience was a whole person followed by small animals, insects and reptiles. CONCLUSION: Using the UM-PDHQ, we were able to define the key characteristics of hallucinations in PD in our cohort. Future directions include the validation of the quantitative part of the questionnaire than will serve as a rating scale for severity of hallucinations.

Köllensperger M, Geser F, Seppi K, Stampfer-Kountchev M, Sawires M, Scherfler C, Boesch S, Mueller J, Koukouni V, Quinn N, Pellecchia MT, Barone P, Schimke N, Dodel R, Oertel W, Dupont E, Østergaard K, Daniels C, Deuschl G, Gurevich T, Giladi N, Coelho M, Sampaio C, Nilsson C, Widner H, Sorbo FD, Albanese A, Cardozo A, Tolosa E, Abele M, Klockgether T, Kamm C, Gasser T, Djaldetti R, Colosimo C, Meco G, Schrag A, Poewe W, Wenning GK, Anonymous00007. · Section for Clinical Neurobiology, Department of Neurology, Innsbruck Medical University, Austria. · Mov Disord. · Pubmed #18442131 No free full text.

Abstract: The clinical diagnosis of multiple system atrophy (MSA) is fraught with difficulty and there are no pathognomonic features to discriminate the parkinsonian variant (MSA-P) from Parkinson's disease (PD). Besides the poor response to levodopa, and the additional presence of pyramidal or cerebellar signs (ataxia) or autonomic failure as major diagnostic criteria, certain other clinical features known as "red flags" or warning signs may raise the clinical suspicion of MSA. To study the diagnostic role of these features in MSA-P versus PD patients, a standardized red flag check list (RFCL) developed by the European MSA Study Group (EMSA-SG) was administered to 57 patients with probable MSA-P and 116 patients with probable PD diagnosed according to established criteria. Those red flags with a specifity over 95% were selected for further analysis. Factor analysis was applied to reduce the number of red flags. The resulting set was then applied to 17 patients with possible MSA-P who on follow-up fulfilled criteria of probable MSA-P. Red flags were grouped into related categories. With two or more of six red flag categories present specificity was 98.3% and sensitivity was 84.2% in our cohort. When applying these criteria to patients with possible MSA-P, 76.5% of them would have been correctly diagnosed as probable MSA-P 15.9 (+/-7.0) months earlier than with the Consensus criteria alone. We propose a combination of two out of six red flag categories as additional diagnostic criteria for probable MSA-P.

Katzenschlager R, Schrag A, Evans A, Manson A, Carroll CB, Ottaviani D, Lees AJ, Hobart J. · National Hospital for Neurology and Neurosurgery, University College, London, UK. · Neurology. · Pubmed #17679674 No free full text.

Abstract: BACKGROUND: Drug-induced dyskinesias are a common and disabling clinical problem in the long-term management of Parkinson disease (PD). Their management and the development of new treatments rely on rigorous and meaningful dyskinesia measurement. Although clinician-based approaches exist, patient-based measures are limited. METHOD: Potential rating scale items concerning daily activities affected by dyskinesias were generated from patients, literature review, and expert opinion. The resulting 42-item questionnaire was administered to 98 patients known to have problematic dyskinesias; 72 patients were invited to complete it twice for test-retest reliability (trt). Rasch analysis guided scale development. Results were cross-validated using traditional psychometric methods by examining scaling assumptions (item means and variances, item-total correlations), reliability (Cronbach alpha, trt), and validity (factor analysis). External validation was performed against standard dyskinesia measures: blinded video rating using modified Goetz and Abnormal Involuntary Movements Scales (AIMS), and Unified PD Rating Scale (UPDRS) questions 32-34. RESULTS: Response rates were high. Fourteen items were removed because of high missing data. The remaining items were Rasch analyzed. Two items were removed because of misfit. The resulting 26 items formed a clinically and statistically conformable set. Traditional psychometric criteria were satisfied and external validation showed good correlation with the UPDRS items and moderate to good correlation with objective dyskinesia measures. CONCLUSION: The 26-item Parkinson Disease Dyskinesia Scale (PDYS-26) satisfied multiple criteria for reliable and valid measurement. Correlations with objective measures suggest that it captures related but not identical constructs. As a patient-derived scale that generates linear measurements, it could complement existing clinician-based dyskinesia measures.

Gallagher DA, O'Sullivan SS, Evans AH, Lees AJ, Schrag A. · Department of Clinical Neurosciences, Royal Free & University College Medical School, London, United Kingdom. · Mov Disord. · Pubmed #17580327 No free full text.

Abstract: Pathological gambling (PG) has been reported as a complication of the treatment of Parkinson's disease (PD). We examined all published cases of PG for prevalence and risk factors of this complication, the relationship of PG and use of dopamine agonists (DA), and the relationship of PG to the dopamine dysregulation syndrome (DDS). The prevalence of PG in prospective studies of PD patients using DA has been reported between 2.3 and 8%, compared to approximately 1% in the general population. As in the general population, PD patients with this complication are often young, male and have psychiatric co-morbidity. The vast majority are on DA, often at maximum dose or above. Differences between oral DA failed to reach significance. PG associated with levodopa monotherapy is uncommon, but in the majority of cases levodopa is co-prescribed, suggesting possible cross-sensitization of brain systems mediating reward. PG can occur with DDS but often occurs in isolation. In contrast to DDS, escalation and self regulation of anti-parkinsonian medication are not usually seen. PG in patients with PD using DA is higher than PG reported in the general population, but shares similar characteristics and risk factors. PG is predominantly associated with oral DA. It often occurs in isolation and may not be associated with DDS, which typically occurs on treatment with levodopa or subcutaneous apomorphine.

Schrag A, Dodel R, Spottke A, Bornschein B, Siebert U, Quinn NP. · Department of Clinical Neurosciences, Royal Free Hospital, University College London, London, United Kingdom. · Mov Disord. · Pubmed #17415791 No free full text.

Abstract: Few prospective data on the clinical progression of Parkinson's disease (PD) in patient groups outside treatment trials in selected patients are available, and controversy exists on the rate of clinical disease progression with advancing disease. In this study, we investigated the rate of clinical progression of PD in a clinic-based sample of 145 patients over 1 year and in a community-based sample of 124 patients over 4 years. Depending on the sample and clinical scale used, mean deterioration of motor and disability scores ranged from 2.4 to 7.4% of the maximum possible score per year, and standard deviations indicated that there was considerable variability of progression rates between individuals. The progression of motor scores decreased with follow-up over 4 years and significantly decreased in more advanced disease stages. Deterioration of disability scores did not differ between disease stages; this may reflect the increasing rate of disease complications, which contribute to increasing disability in addition to motor impairment alone, in more advanced disease. Thus, motor fluctuations, hallucinations, depression, memory problems, and bladder symptoms were all reported more often at follow-up in the community-based sample (all P < 0.01), and dyskinesias, motor fluctuations, falls, and hallucinations were more common and cognitive and depression scores worse in higher disease stages in the clinic-based sample (all P < 0.001). We conclude that progression of motor scores in PD decreases with advancing disease in PD. However, disability continues to deteriorate with advancing disease and with the development of disease complications that are likely to be related to additional extrastriatal pathology.

Ishihara LS, Cheesbrough A, Brayne C, Schrag A. · Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #17400591 No free full text.

Abstract: OBJECTIVE: To calculate the best possible estimates for age specific life expectancy (LE) and anticipated age at the time of death (AAD) in patients with Parkinson's disease (PD) compared with the general population in the UK. These may be of greater value to patients than standardised mortality ratios (SMRs), which are usually reported in studies on mortality in PD. METHODS: A literature review identified articles with data on age stratified life expectancy or SMRs to calculate estimations of LE using the Gompertz function and data on mortality and LE in the UK from the Office of National Statistics and Actuarial Department for the year 2003. RESULTS: Two UK studies and four from Western Europe were used to estimate LE and AAD for patients with PD from SMRs. The mean LEs of patients with PD compared with the general population were: 38 (SD 5) years for onset between 25 and 39 years compared with 49 (SD 5) years; 21 (SD 5) years for onset between 40 and 64 years compared with 31 (SD 7) years; and 5 (SD 4) years for onset age > or = 65 years compared with 9 (SD 5) years. The average AAD of patients with PD with onset between 25 and 39 years was 71 (SD 3) years and considerably lower than that of the general population (82 (SD 2) years). The difference between average AAD for older individuals with PD (onset > or = 65 years) and the general population was smaller, with an AAD of approximately 88 (SD 7) years compared with 91 (SD 5) years. CONCLUSIONS: The calculations showed that LE and AAD in PD are reduced for all onset ages but this reduction is greatest in individuals with a young onset. While the results are average estimates, these can provide useful indications of LE and AAD.

Goetz CG, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stebbins GT, Stern MB, Tilley BC, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, Van Hilten JJ, LaPelle N. · Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, USA. · Mov Disord. · Pubmed #17115387 links to  free full text

Abstract: This article presents the revision process, major innovations, and clinimetric testing program for the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (UPDRS), known as the MDS-UPDRS. The UPDRS is the most widely used scale for the clinical study of Parkinson's disease (PD). The MDS previously organized a critique of the UPDRS, which cited many strengths, but recommended revision of the scale to accommodate new advances and to resolve problematic areas. An MDS-UPDRS committee prepared the revision using the recommendations of the published critique of the scale. Subcommittees developed new material that was reviewed by the entire committee. A 1-day face-to-face committee meeting was organized to resolve areas of debate and to arrive at a working draft ready for clinimetric testing. The MDS-UPDRS retains the UPDRS structure of four parts with a total summed score, but the parts have been modified to provide a section that integrates nonmotor elements of PD: I, Nonmotor Experiences of Daily Living; II, Motor Experiences of Daily Living; III, Motor Examination; and IV, Motor Complications. All items have five response options with uniform anchors of 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Several questions in Part I and all of Part II are written as a patient/caregiver questionnaire, so that the total rater time should remain approximately 30 minutes. Detailed instructions for testing and data acquisition accompany the MDS-UPDRS in order to increase uniform usage. Multiple language editions are planned. A three-part clinimetric program will provide testing of reliability, validity, and responsiveness to interventions. Although the MDS-UPDRS will not be published until it has successfully passed clinimetric testing, explanation of the process, key changes, and clinimetric programs allow clinicians and researchers to understand and participate in the revision process.

Schrag A, Banks P. · Royal Free and University College Medical School, University College London, London, United Kingdom. · Mov Disord. · Pubmed #16941456 No free full text.

Abstract: We examined time to loss of employment in two U.K.-based studies of 151 and 308 patients with Parkinson's disease (PD) with onset age before 65 years. Fifty-two percent and 57% of patients had retired early due to PD, 18% and 5% of patients were unemployed, and 8% and 11% were part-time-employed. Mean age of retirement was 55.8 years compared to an average retirement age of 62 years in the U.K. population. Mean time to loss of employment was 4.9 years, ranging from a mean of 6.7 years in those with onset before age 45 to 1.7 years in those with onset after age 56, but the range was large (0-17 years). After censoring for those still working and those retiring at a normal retirement age, survival analysis revealed that 46% had stopped working after a disease duration of 5 years and 82% after 10 years with a median survival to loss of employment of 6.0 (95% CI: 5.4-6.6) years. Age of onset correlated negatively with time to loss of employment (r = -0.6; P < 0.001). There were no differences between sexes, rural vs. urban living, types of work, those living alone or with a partner, and those with and without children in their household. We conclude that Parkinson's disease leads to loss of employment on average within less than 10 years of disease onset. However, the variability of time to loss of employment is large, indicating that other factors than onset age and disease duration influence loss of patients' employment.

Schrag A, Sampaio C, Counsell N, Poewe W. · Royal Free and University College Medical School, University College London, London, United Kingdom. · Mov Disord. · Pubmed #16673410 No free full text.

Abstract: The Unified Parkinson's Disease Rating Scale (UPDRS) is the main outcome measure in clinical trials of Parkinson's disease (PD). The minimal change that represents a clinically meaningful improvement is unknown. The objective of this study was to determine the minimal change on the UPDRS that represents a clinically meaningful improvement in early PD after 6 months of treatment. Data from two independent randomized treatment trials over 6 months involving 603 patients with de novo PD were analyzed to determine the minimal clinically important change (MCIC), referred to the status before treatment, for the UPDRS motor, activities of daily living (ADL), and total scores. An anchor-based method using ratings on a seven-point global clinical improvement was used. A change of five points on the UPDRS motor part was found to be the most appropriate cutoff score for all Hoehn and Yahr stages I to III, and a change of eight points for the UDPRS total score. For the UDPRS ADL score, an MCIC of two points for Hoehn and Yahr stages I/I.5 and II and of three points for Hoehn and Yahr stage II.5/III was the most appropriate cutoff score. These data give the first estimate for cutoffs defining clinically important changes in UPDRS ADL and motor scores. Further studies using larger databases from more diverse study populations are encouraged to better define and solidify the MCIC for the UPDRS.

Schrag A, Geser F, Stampfer-Kountchev M, Seppi K, Sawires M, Köllensperger M, Scherfler C, Quinn N, Pellecchia MT, Barone P, Del Sorbo F, Albanese A, Ostergaard K, Dupont E, Cardozo A, Tolosa E, Nilsson CF, Widner H, Lindvall O, Giladi N, Gurevich T, Daniels C, Deuschl G, Coelho M, Sampaio C, Abele M, Klockgether T, Schimke N, Eggert KM, Oertel W, Djaldetti R, Colosimo C, Meco G, Poewe W, Wenning GK, Anonymous00441. · Department of Clinical Neurosciences, Royal Free & University College Medical School, London, United Kingdom. · Mov Disord. · Pubmed #16502399 No free full text.

Abstract: Although multiple system atrophy (MSA) is a neurodegenerative disorder leading to progressive disability and decreased life expectancy, little is known about patients' own evaluation of their illness and factors associated with poor health-related quality of life (Hr-QoL). We, therefore, assessed Hr-QoL and its determinants in MSA. The following scales were applied to 115 patients in the European MSA-Study Group (EMSA-SG) Natural History Study: Medical Outcome Study Short Form (SF-36), EQ-5D, Beck Depression Inventory (BDI), Mini-Mental state examination (MMSE), Unified MSA Rating Scale (UMSARS), Hoehn & Yahr (H&Y) Parkinson's disease staging scale, Composite Autonomic Symptom Scale (COMPASS), and Parkinson's Disease Sleep Scale (PDSS). Forty-six percent of patients had moderate to severe depression (BDI > or = 17); Hr-QoL scores on the SF-36 and EQ-5D were significantly impaired. Pain, the only domain with similar scores in MSA and published PD patients, was reported more frequently in patients with MSA-P (predominantly parkinsonian motor subtype) than MSA-C (predominantly cerebellar motor subtype; 76% vs. 50%; P = 0.005). Hr-QoL scores correlated most strongly with UMSARS motor, COMPASS, and BDI scores but not with MMSE scores, age at onset, or disease duration. The COMPASS and UMSARS activities of daily living scores were moderate-to-strong predictors for the SF-36 physical summary score and the BDI and UMSARS motor scores for the SF-36 mental summary score. This report is the first study to show that Hr-QoL is significantly impaired in MSA. Although not all possible factors related to impaired Hr-QoL in MSA could be assessed, autonomic dysfunction, motor impairment, and depression were most closely associated with poor Hr-QoL, and therapeutic management, therefore, should concentrate upon these aspects of the disease.

Schrag A, Hovris A, Morley D, Quinn N, Jahanshahi M. · Royal Free and University College Medical School, University College London NW3 2PF, London, UK. · Parkinsonism Relat Disord. · Pubmed #16271496 No free full text.

Abstract: The majority of care of patients with Parkinson's disease (PD) is provided by informal caregivers; their caregiving not only offers physical and emotional support for patients but also plays a large economic role and prevents early nursing home placement. In order to support caregivers in this role, it is necessary to understand the extent of caregiver-burden and factors associated with increased caregiver-burden and distress. We therefore conducted a postal survey in 123 caregivers of patients with PD to assess caregiver-burden and factors associated with it. The majority of caregivers were female (66%). Over 40% of caregivers indicated that their health had suffered as a result of caregiving, almost half had increased depression scores, and two-thirds reported that their social life had suffered. After adjustment of disease duration, there was no difference in caregiver-burden between younger and older caregivers, or between male and female caregivers. Caregiver-burden increased with increasing disability and symptoms of PD, particularly with mental health problems such as depression, hallucinations, or confusion, and with falls. Caregiver-burden scores also correlated significantly with the patients' depression and quality of life scores, and with caregivers' own satisfaction with their marital and sexual relationship. We conclude that more attention should be paid to caregivers' emotional and physical health, particularly in advancing PD with psychiatric complications and falls. These findings also demonstrate that caregiver and patient quality of life are closely linked and emphasize the importance of including caregiver-burden among the problems associated with PD in order to improve patient and caregiver lives.

Schrag A, Morley D, Quinn N, Jahanshahi M. · Royal Free & University College Medical School, University College London, London NW3 2PF, UK. · Parkinsonism Relat Disord. · Pubmed #15465395 No free full text.

Abstract: Although chronic illness is likely to affect the well-being of patients' children, no assessment tools are currently available to measure this impact of parental illness. We therefore developed such an instrument based on interviews with children of patients with Parkinson's disease (PD). This questionnaire and other measures of psychological well-being were completed by 89 children, aged 12-48, years of patients with PD. Factor analysis revealed six domains with 38 questions. These six domains of the 'Parental Illness Impact Scale (Parkinson's disease)' or PIIS (PD) had satisfactory internal consistency and validity. Its six sub-scales correlated significantly and differentially with corresponding measures, including the Quality of Life in Epilepsy Inventory for Adolescents (QOLIE-AD-48; r = -0.2 to 0.85), the Beck Depression Inventory (r = -0.07 to -0.40) or Birleson Depression Self-Rating Scale (r = 0.04 to -0.62), and the Rosenberg Self-Esteem Scale (r = -0.01 to 0.33) as well as age (r = -0.37 to 0.28) and parent's disease duration (r = -0.31 to 0.34). The PIIS is the first instrument to assess the impact of parental illness on children. Its psychometric properties should be tested further in larger samples, including children of patients with other chronic disorders such as multiple sclerosis or chronic heart disease.