Factors predictive of the development of levodopa-induced dyskinesia and wearing-off in Parkinson's disease

Mov Disord. 2013 Apr 29. doi: 10.1002/mds.25364. [Epub ahead of print]

Warren Olanow C, Kieburtz K, Rascol O, Poewe W, Schapira AH, Emre M, Nissinen H, Leinonen M, Stocchi F; Stalevo Reduction in Dyskinesia Evaluation in Parkinson's Disease (STRIDE-PD) Investigators.

Source

Department of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY, USA; Institute for Research, Scientific Institute for Care and Treatment, San Raffaele, Rome, Italy.

Abstract

The Stalevo Reduction in Dyskinesia Evaluation in Parkinson's Disease (STRIDE-PD) study compared the initiation of levodopa (l-dopa) therapy with l-dopa/carbidopa (LC) versus l-dopa/carbidopa/entacapone (LCE) in patients with Parkinson's disease. In the current study, the STRIDE-PD study population was investigated to determine the effect of l-dopa dose and other risk factors on the development of dyskinesia and wearing-off. Patients were randomized to receive LCE (n=373) or LC (n=372). Blinded assessments for dyskinesia and wearing-off were performed at 3-month intervals for the 134- to 208-week duration of the study. The patients were divided into 4 dose groups based on nominal l-dopa dose at the time of onset of dyskinesia (or at study conclusion if there was no dyskinesia): group 1, <400 mg/day (n=157); group 2, 400 mg/day (n=310); group 3, 401 to 600 mg/day (n=201); and group 4, >600 mg/day (n=77). Similar analyses were performed with respect to wearing-off and any motor complication. The times to onset and frequency of dyskinesia, wearing-off, or any motor complication were compared using the log-rank test (overall trend test) and a Cox proportional hazards model (pairwise comparisons). A stepwise Cox proportional hazards model was used to screen predictive factors in a multivariate analysis. The risk of developing dyskinesia and wearing-off increased in an l-dopa dose-dependent manner (P<0.001 for both). Analyses using l-dopa equivalent doses produced comparable results. Factors that were predictive of dyskinesia, in rank order, were: young age at onset, higher l-dopa dose, low body weight, North American geographic region, LCE treatment group, female gender, and more severe Unified Parkinson's Disease Rating Scale (UPDRS) Part II. Multivariate analyses identified similar predictors for wearing-off but included baseline UPDRS Part III and excluded weight and treatment allocation. The risk of developing dyskinesia or wearing-off was closely linked to l-dopa dose. The current results suggest that physicians should use the lowest dose of l-dopa that provides satisfactory clinical control to minimize the risk of both dyskinesia and wearing-off.

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The midbrain to pons ratio: A simple and specific MRI sign of progressive supranuclear palsy

Neurology. 2013 Apr 24. [Epub ahead of print]

Massey LA, Jäger HR, Paviour DC, O'Sullivan SS, Ling H, Williams DR, Kallis C, Holton J, Revesz T, Burn DJ, Yousry T, Lees AJ, Fox NC, Micallef C.

Source

From the Sara Koe PSP Research Centre (L.A.M., D.C.P., S.S.O., H.L., J.H., T.R., A.J.L.), Rita Lila Weston Institute for Neurology Studies and Queen Square Brain Bank, Department of Molecular Neurosciences, UCL Institute of Neurology, London, UK; Department of Brain Repair and Rehabilitation (H.R.J., T.Y., C.M.), UCL Institute of Neurology and Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, Queen Square, London; Dementia Research Centre (N.C.F.), UCL Institute of Neurology, London; Van Cleef Roet Centre for Nervous Diseases (D.R.W.), Monash University, Melbourne, Australia; Forensic Psychiatry Research Unit (C.K.), Queen Mary, University of London; and Institute for Ageing and Health (D.J.B.), Newcastle University, Newcastle upon Tyne, UK.

Abstract

OBJECTIVES:

MRI-based measurements used to diagnose progressive supranuclear palsy (PSP) typically lack pathologic verification and are not easy to use routinely. We aimed to develop in histologically proven disease a simple measure of the midbrain and pons on sagittal MRI to identify PSP.

METHODS:

Measurements of the midbrain and pontine base on midsagittal T1-weighted MRI were performed in confirmed PSP (n = 12), Parkinson disease (n = 2), and multiple system atrophy (MSA) (n = 7), and in controls (n = 8). Using receiver operating characteristic curve analysis, cutoff values were applied to a clinically diagnosed cohort of 62 subjects that included PSP (n = 21), Parkinson disease (n = 10), MSA (n = 10), and controls (n = 21).

RESULTS:

The mean midbrain measurement of 8.1 mm was reduced in PSP (p < 0.001) with reduction in the midbrain to pons ratio (PSP smaller than MSA; p < 0.001). In controls, the mean midbrain ratio was approximately two-thirds of the pontine base, in PSP it was <52%, and in MSA the ratio was greater than two-thirds. A midbrain measurement of <9.35 mm and ratio of 0.52 had 100% specificity for PSP. In the clinically defined group, 19 of 21 PSP cases (90.5%) had a midbrain measurement of <9.35 mm.

CONCLUSIONS:

We have developed a simple and reliable measurement in pathologically confirmed disease based on the topography of atrophy in PSP with high sensitivity and specificity that may be a useful tool in the clinic.

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"Sleep benefit" in Parkinson's disease: A systematic review

Parkinsonism Relat Disord. 2013 Apr 21. pii: S1353-8020(13)00130-2. doi: 10.1016/j.parkreldis.2013.03.014. [Epub ahead of print]

van Gilst MM, Bloem BR, Overeem S.

Source

Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Nijmegen, The Netherlands.

Abstract

Sleep disorders are common among patients with Parkinson's disease (PD). However, there are also reports of PD patients experiencing a beneficial effect of sleep. Upon awaking in the morning some patients experience good mobility, as if they are in an "on" state induced by medication, contrary to what would be expected after a night without medication. This intriguing phenomenon is known as sleep benefit. Here, we review the available research on sleep benefit in PD, describing its prevalence, clinical effects and determinants. We also discuss the possible mechanisms underlying sleep benefit, and the potential clinical applicability. Finally, we propose a new definition of sleep benefit to allow for improved standardization and homogeneity in future research. Important research targets include the development of objective measures of sleep benefit, as a basis for obtaining a better understanding of sleep benefit, its underlying mechanisms and its potential therapeutic application.

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Diagnostic accuracy of apparent diffusion coefficient and (123)i-metaiodobenzylguanidine for differentiation of multiple system atrophy and Parkinson's disease

PLoS One. 2013 Apr 17;8(4):e61066. doi: 10.1371/journal.pone.0061066. Print 2013.

Umemura A, Oeda T, Hayashi R, Tomita S, Kohsaka M, Yamamoto K, Sawada H.

Source

Clinical Research Center, National Hospital of Utano, Kyoto, Japan ; Department of Neurology, National Hospital of Utano, Kyoto, Japan.

Abstract

BACKGROUND:

It is often hard to differentiate Parkinson's disease (PD) and parkinsonian variant of multiple system atrophy (MSA-P), especially in the early stages. Cardiac sympathetic denervation and putaminal rarefaction are specific findings for PD and MSA-P, respectively.

PURPOSE:

We investigated diagnostic accuracy of putaminal apparent diffusion coefficient (ADC) test for MSA-P and (123)I-metaiodobenzylguanidine (MIBG) scintigram for PD, especially in early-stage patients.

METHODS:

The referral standard diagnosis of PD and MSA-P were the diagnostic criteria of the United Kingdom Parkinson's Disease Society Brain Bank Criteria and the second consensus criteria, respectively. Based on the referral standard criteria, diagnostic accuracy [area under the receiver-operator characteristic curve (AUC), sensitivity and specificity] of the ADC and MIBG tests was estimated retrospectively. Diagnostic accuracy of these tests performed within 3 years of symptom onset was also investigated.

RESULTS:

ADC and MIBG tests were performed on 138 patients (20 MSA and 118 PD). AUC was 0.95 and 0.83 for the ADC and MIBG tests, respectively. Sensitivity and specificity were 85.0% and 89.0% for MSA-P diagnosis by ADC test and 67.0% and 80.0% for PD diagnosis by MIBG test. When these tests were restricted to patients with disease duration ≤3 years, the sensitivity and specificity were 75.0% and 91.4% for the ADC test (MSA-P diagnosis) and 47.7% and 92.3% for the MIBG test (PD diagnosis).

CONCLUSIONS:

Both tests were useful in differentiating between PD and MSA-P, even in the early stages. In early-stage patients, elevated putaminal ADC was a diagnostic marker for MSA-P. Despite high specificity of the MIBG test, careful neurological history and examinations were required for PD diagnosis because of possible false-negative results.

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Dopamine dysregulation syndrome in Parkinson's disease: from clinical and neuropsychological characterisation to management and long-term outcome

J Neurol Neurosurg Psychiatry. 2013 Apr 16. [Epub ahead of print]

Cilia R, Siri C, Canesi M, Zecchinelli AL, De Gaspari D, Natuzzi F, Tesei S, Meucci N, Mariani CB, Sacilotto G, Zini M, Ruffmann C, Pezzoli G.

 

Source

Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy.

 

Abstract

OBJECTIVE:

Dopamine dysregulation syndrome (DDS) refers to a compulsive pattern of dopaminergic drug misuse complicating Parkinson's disease (PD). To date, few data are available on DDS risk factors, cognitive profile and long-term outcome.

METHODS:

In this retrospective case-control study, consecutive PD outpatients fulfilling criteria for DDS were assessed over a 6-year period (2005-2011). They were compared with 70 PD cases matched for age at onset, gender and disease duration, and with 1281 subjects with motor fluctuations and dyskinesias. DDS patients and matched controls underwent extensive neuropsychological assessment. Strategies for DDS patients management and the outcome at the last follow-up visit were recorded.

RESULTS:

Thirty-five patients with DDS were identified, reporting history of depression, family history of PD and drug abuse, greater difference between 'Off' versus 'On' motor symptoms compared to age-matched controls. They had younger age at onset (but not any gender difference) compared to general PD population. Cognitive profile of DDS did not show major abnormalities, including executive functions. DDS patients have been followed up for 3.2±2.1 years and remission was recorded in 40% of cases. Negative DDS outcome was significantly associated with poor caregiver supervision. Sustained remission occurred more commonly on clozapine and on duodenal levodopa infusion and subthalamic nucleus deep brain stimulation (STN-DBS) than on apomorphine pump treatment.

CONCLUSIONS:

Clinicians should be aware of risk factors predisposing to DDS. Duodenal levodopa infusion and, less consistently, STN-DBS were more commonly associated with DDS remission. Effective caregiving plays a key role in long-term behavioural outcome.

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Housing and Health: Very Old People with Self-Reported Parkinson's Disease versus Controls

Parkinsons Dis. 2013;2013:710839. doi: 10.1155/2013/710839. Epub 2013 Mar 26.

Nilsson MH, Haak M, Iwarsson S.

 

Source

Department of Health Sciences, Faculty of Medicine, Lund University, P.O. Box 157, 221 00 Lund, Sweden.

 

Abstract

Objectives. To explore whether aspects of housing and health among very old people with self-reported Parkinson's disease (PD) differ from matched controls. Methods. Data from the ENABLE-AGE Survey Study were used to identify people with self-reported PD (n = 20) and three matched controls/individual (n = 60). The matching criteria were age (mean = 82 years), sex, country, and type of housing. The analyses targeted problems in activities of daily living, objective and perceived aspects of housing, for example, number of environmental barriers, accessibility (i.e., person-environment fit), and usability. Results. The number of physical environmental barriers did not differ (P = 0.727) between the samples. The PD sample had more (P < 0.001) accessibility problems than controls and perceived their homes as less (P = 0.003) usable in relation to activities. They were less independent and had more functional limitations (median 5 versus 2; P < 0.001), and 70% experienced loss of stamina or poor balance. Conclusions. Due to the fact that they have more functional limitations than very old people in general, those with self-reported PD live in housing with more accessibility problems. This explorative study has implications for rehabilitation as well as societal planning, but larger studies including people with a confirmed PD diagnosis are needed.

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Frequency of non-motor symptoms in Peruvian patients with Parkinson's disease

Arq Neuropsiquiatr. 2013 Apr;71(4):216-9.

Cosentino C, Nuñez Y, Torres L.

Abstract

Introduction: Non-motor symptoms in Parkinson's disease are often not well recognized in clinical practice. Non-motor symptoms questionnaire (NMSQuest) is a simple instrument that allows patients or caregivers to report non-motor symptoms in a practical manner. Objective: We attempted to determine the prevalence of non-motor symptoms in three hundred Parkinson's disease outpatients. Results: The mean total non-motor symptoms was 12.41, ranging from 0 to 27 of a maximum of 30. At least one was present in 99.3% of patients. A progressive increase in mean total score was observed across each 5-year interval. Depression domain scored the most "positive" answers while urinary and anxiety /memory were secondly and thirdly most prevalent respectively. Conclusion: The large number of patients included in this study allowed evaluation of the occurrence of non-motor symptoms in early and advanced disease in addition to the relationship of these kinds of symptoms with progression of disease.

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A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies

JAMA Neurol. 2013 Apr 15:1-9. doi: 10.1001/jamaneurol.2013.1925. [Epub ahead of print]

 

Nalls MA, Duran R, Lopez G, Kurzawa-Akanbi M, McKeith IG, Chinnery PF, Morris CM, Theuns J, Crosiers D, Cras P, Engelborghs S, De Deyn PP, Van Broeckhoven C, Mann DM, Snowden J, Pickering-Brown S, Halliwell N, Davidson Y, Gibbons L, Harris J, Sheerin UM, Bras J, Hardy J, Clark L, Marder K, Honig LS, Berg D, Maetzler W, Brockmann K, Gasser T, Novellino F, Quattrone A, Annesi G, De Marco EV, Rogaeva E, Masellis M, Black SE, Bilbao JM, Foroud T, Ghetti B, Nichols WC, Pankratz N, Halliday G, Lesage S, Klebe S, Durr A, Duyckaerts C, Brice A, Giasson BI, Trojanowski JQ, Hurtig HI, Tayebi N, Landazabal C, Knight MA, Keller M, Singleton AB, Wolfsberg TG, Sidransky E.

Abstract

IMPORTANCE While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders. OBJECTIVE To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB). DESIGN We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity. SETTING Eleven centers from sites around the world performing genotyping. PARTICIPANTS Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity. MAIN OUTCOME MEASURES Frequency of GBA1 mutations in cases and controls. RESULTS We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78-14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53-15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P < .001), with higher disease severity scores. CONCLUSIONS AND RELEVANCE Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.

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Serial sevens - can practise make perfect?

The 'serial sevens' task, in which subjects are asked to count backwards from 100 by repeatedly subtracting 7 (e.g. 100-93-86-79-72-etc), is a commonly used test in the assessment of cognition. It is part of the standard set of tasks used to assess people for cognitive decline - the mini mental state examination (or MMSE) and is worth 5 out of the 30 available marks. Attention and memory are required to perform the task.

Dementia is common and rates will increase dramatically in the coming years. There is a strong drive towards earlier detection with a view to earlier treatment - identification of mild cognitive impairment. In parallel, public awareness of dementia or cognitive impairment has increased significantly also. Many people know or have known someone with dementia and many will have attended hospital or general practice appointments with this person. Dementia now receives greater mention in the media, both factual and fictional, than ever before. For these reasons, subjects are increasingly likely to be aware of the mental tests that will be performed if their cognition comes under assessment. The 'serial sevens' test has gained particular notoriety!

In the PREDICT-PD study we use a standard battery of cognitive tests called the Montreal Cognitive Assessment or MoCA, which like the MMSE, includes the 'serial sevens' task. It is not uncommon for our research subjects to say that they were expecting the 'serial sevens' as part of the assessment and consequently have been practising. A practised test uses different memory retrieval processes and significantly less attention; I am certain that practise improves the likelihood of scoring full marks.

Alternatives to 'serial sevens' exist and include: using a number other than seven, naming months of the year in reverse order and spelling WORLD backwards. Each of these are slightly different in terms of difficulty and it is tricky to pool data in a research setting if different tests have been used. On an individual basis, substitution of the 'serial sevens' test for an alternative is often appropriate and may yield findings that were not apparent when a practised 'serial sevens' test was performed. Nonetheless clinicians should be aware that prior knowledge of such tests, particularly ones that can be practised, may mask a subtle decline in cognition when using standardised assessments.

- Alastair Noyce

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A systematic review of biomarkers for disease progression in Parkinson's disease

BMC Neurol. 2013 Apr 12;13(1):35. [Epub ahead of print]

McGhee DJ, Royle PL, Thompson PA, Wright DE, Zajicek JP, Counsell CE.

 

Abstract

BACKGROUND:

Using surrogate biomarkers for disease progression as endpoints in neuroprotective clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from true disease-modifying effects. A systematic review was undertaken to determine what biomarkers for disease progression in Parkinson's disease (PD) exist.

METHODS:

MEDLINE and EMBASE (1950--2010) were searched using five search strategies. Abstracts were assessed to identify papers meriting review in full. Studies of participants with idiopathic PD diagnosed by formal criteria or clearly described clinical means were included. We made no restriction on age, disease duration, drug treatment, or study design. We included studies which attempted to draw associations between any tests used to investigate disease progression and any clinical measures of disease progression. The electronic search was validated by hand-searching the two journals from which most included articles came.

RESULTS:

183 studies were included: 163 (89%) cross-sectional, 20 (11%) longitudinal. The electronic search strategy had a sensitivity of 71.4% (95% CI 51.1-86.0) and a specificity of 97.1% (95% CI 96.5-97.7). In longitudinal studies median follow-up was 2.0 years (IQR 1.1-3.5). Included studies were generally poor quality - cross-sectional with small numbers of participants, applying excessive inclusion/exclusion criteria, with flawed methodologies and simplistic statistical analyses.

CONCLUSION:

We found insufficient evidence to recommend the use of any biomarker for disease progression in PD clinical trials, which may simply reflect the poor quality of research in this area. We therefore present a provisional 'roadmap' for conducting future disease progression biomarker studies, and recommend new quality criteria by which future studies may be judged.

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Pharmacologic Treatment of Anxiety Disorders in Parkinson Disease

Am J Geriatr Psychiatry. 2013 Mar 29. pii: S1064-7481(12)00053-X. doi: 10.1016/j.jagp.2012.10.023. [Epub ahead of print]

Pontone GM, Williams JR, Anderson KE, Chase G, Goldstein SR, Grill S, Hirsch ES, Lehmann S, Little JT, Margolis RL, Palanci J, Rabins PV, Weiss HD, Marsh L.

Source

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD. Electronic address: gponton1@jhmi.edu.

Abstract

OBJECTIVE:

Neither best practices nor an evidence base for the pharmacologic treatment of anxiety in Parkinson disease (PD) has been established. This study investigated pharmacologic treatment of anxiety disorders in idiopathic PD and the associated clinical features.

DESIGN:

Cross-sectional.

SETTING:

Three community-based movement disorder neurology practices.

PARTICIPANTS:

250 subjects with PD.

MEASUREMENTS:

Anxiety disorder diagnoses were established by consensus using a panel of six psychiatrists with expertise in geriatric psychiatry and movement disorders. Current medications were provided by the treating neurologists at the time of interview.

RESULTS:

Among subjects with anxiety disorders only, 53% were untreated with medications. When anxious subjects with comorbid depressive disorders were included, 70.8% were on medications effective for treatment of anxiety. Subjects with anxiety and comorbid depressive disorders were more likely to be treated for their psychiatric disturbances than subjects with anxiety disorders alone (odds ratio: 8.33), as were subjects with comorbid motor fluctuations (odds ratio: 3.65). There were no differences in the types of anti-anxiety medications used in regard to the presence of depression or motor fluctuations.

CONCLUSIONS:

These findings suggest that over half of nondepressed PD patients with clinically significant anxiety are untreated with medication. A better understanding of the role of clinical features associated with anxiety in PD, such as depression and motor fluctuations, may improve the recognition and treatment of anxiety disorders in this population.