Fabienne Ory

Effect of levodopa on pain threshold in Parkinson's disease: A clinical and positron emission tomography study

Patients suffering from Parkinsons disease (PD) frequently experienced painful sensations that could be in part due to central modification of nociception. We compared pain threshold before and after administration of levodopa in PD patients and in controls, and investigated cerebral activity with positron emission tomography (PET) during experimental nociceptive stimulation. Pain threshold was determined using thermal stimulation during two randomized conditions: off and on. We performed H215O PET analysis of regional cerebral blood flow on subjects while they received alternate randomized noxious and innocuous stimuli during off and on conditions. In off condition, pain threshold in nine PD patients was significantly lower than in nine controls. Administration of levodopa significantly raised pain threshold in PD patients but not in controls. During off condition, there was a significant increase in pain‐induced activation in right insula and prefrontal and left anterior cingulate cortices in PD compared to control group. Levodopa significantly reduced pain‐induced activation in these areas in PD. This study shows that pain threshold is lower in PD patients but returns to normal ranges after levodopa administration. Moreover, PD patients have higher pain‐induced activation in nociceptive pathways, which can be reduced by levodopa.

Limitations of current Parkinson's disease therapy.

Levodopa and other dopaminergic medications drastically improve the motor symptoms and quality of life of patients with Parkinsons disease in the early stages of the disease. However, once the “honeymoon” period has waned, usually after a few years of dopaminergic therapy, patients become progressively more disabled despite an ever more complex combination of available antiparkinsonian treatments. Sooner or later, they suffer from “dopa‐resistant” motor symptoms (speech impairment, abnormal posture, gait and balance problems), “dopa‐resistant” nonmotor signs (autonomic dysfunction, mood and cognitive impairment, sleep problems, pain) and/or drug‐related side effects (especially psychosis, motor fluctuations, and dyskinesias). Therefore, the current antiparkinsonian therapy cannot be considered as ideal with regard to both efficacy and safety. Ann Neurol 2003;53 (suppl 3):S3–S15

Progression of multiple system atrophy (MSA): A prospective natural history study by the European MSA study group (EMSA SG)

The disease‐specific Unified Multiple System Atrophy Rating Scale (UMSARS) has been developed recently and validated for assessing disease severity in multiple system atrophy (MSA). Here, we aimed at (1) assessing rates of disease progression in MSA and (2) validating UMSARS for sensitivity to change over time. Impairment was assessed at two time points 12 months apart using UMSARS Part I (historical review), UMSARS Part II (motor examination), as well as measures of global disease severity, including UMSARS Part IV, Hoehn and Yahr (HY) Parkinsons disease staging, Schwab England Activities of Daily Living (SE ADL), and a three‐point global Severity Scale (SS3). Fifty patients (male:female ratio, 1:0.9; possible MSA, 16%; probable MSA, 84%; MSA‐parkinsonian, 58%; MSA‐cerebellar, 42%) were assessed twice with an interval of 12.3 months. UMSARS II scores progressed by 57.3% (P < 0.0001) and UMSARS I scores by 35.6% (P < 0.0001) in relation to the respective baseline scores with no differences between motor subtypes, diagnostic categories and gender. Significant inverse correlations between (1) UMSARS I or UMSARS II progression and (2) baseline disability measures (i.e., the respective UMSARS or SS3 scores) and disease duration were found. Furthermore, the increases in HY staging, SE ADL and SS3 correlated significantly with UMSARS I, UMSARS II, and UMSARS IV progression. This report is the first prospective study showing rapid annual UMSARS rates of decline in MSA. Our data contribute to the ongoing validation process of UMSARS, and they facilitate the planning and implementation of future neuroprotective intervention trials.

The European Multiple System Atrophy-Study Group (EMSA-SG)

Summary.Introduction. The European Multiple System Atrophy-Study Group (EMSA-SG) is an academic network comprising 23 centers across Europe and Israel that has constituted itself already in January 1999. This international forum of established experts under the guidance of the University Hospital of Innsbruck as coordinating center is supported by the 5th framework program of the European Union since March 2001 (QLK6-CT-2000-00661). Objectives. Primary goals of the network include (1) a central Registry for European multiple system atrophy (MSA) patients, (2) a decentralized DNA Bank, (3) the development and validation of the novel Unified MSA Rating Scale (UMSARS), (4) the conduction of a Natural History Study (NHS), and (5) the planning or implementation of interventional therapeutic trials. Methods. The EMSA-SG Registry is a computerized data bank localized at the coordinating centre in Innsbruck collecting diagnostic and therapeutic data of MSA patients. Blood samples of patients and controls are recruited into the DNA Bank. The UMSARS is a novel specific rating instrument that has been developed and validated by the EMSA-SG. The NHS comprises assessments of basic anthropometric data as well as a range of scales including the UMSARS, Unified Parkinson’s Disease Rating Scale (UPDRS), measures of global disability, Red Flag list, MMSE (Mini Mental State Examination), quality of live measures, i.e. EuroQoL 5D (EQ-5D) and Medical Outcome Study Short Form (SF-36) as well as the Beck Depression Inventory (BDI). In a subgroup of patients dysautonomic features are recorded in detail using the Queen Square Cardiovascular Autonomic Function Test Battery, the Composite Autonomic Symptom Scale (COMPASS) and measurements of residual urinary volume. Most of these measures are repeated at 6-monthly follow up visits for a total study period of 24 months. Surrogate markers of the disease progression are identified by the EMSA-SG using magnetic resonance and diffusion weighted imaging (MRI and DWI, respectively). Results. 412 patients have been recruited into the Registry so far. Probable MSA-P was the most common diagnosis (49% of cases). 507 patients donated DNA for research. 131 patients have been recruited into the NHS. There was a rapid deterioration of the motor disorder (in particular akinesia) by 26.1% of the UMSARS II, and – to a lesser degree – of activities of daily living by 16.8% of the UMSARS I in relation to the respective baseline scores. Motor progression was associated with low motor or global disability as well as low akinesia or cerebellar subscores at baseline. Mental function did not deteriorate during this short follow up period. Conclusion. For the first time, prospective data concerning disease progression are available. Such data about the natural history and prognosis of MSA as well as surrogate markers of disease process allow planning and implementation of multi-centre phase II/III neuroprotective intervention trials within the next years more effectively. Indeed, a trial on growth hormone in MSA has just been completed, and another on minocycline will be completed by the end of this year.

Prevalence and pharmacological factors associated with impulse-control disorder symptoms in patients with Parkinson disease.

BackgroundImpulse-control disorders (ICDs) occur in patients with Parkinson disease (PD), especially in younger patients on dopamine therapies. ObjectiveTo assess the prevalence of ICD symptoms and its pharmacological correlations in a sample of French patients with PD and without PD (poststroke). MethodsOutpatients with PD and without PD (poststroke) were screened for compulsive behaviors related to hypersexuality, compulsive shopping, pathological gambling, or compulsive eating by means of the Questionnaire for Impulse-Control Disorders—short version. Full medical history and Unified Parkinson’s Disease Rating Scale scores were also recorded. Dose of dopamine agonists were converted to defined daily doses (DDDs), according to the World Health Organization Anatomical Therapeutic Chemical classification system classification system. ResultsTwo hundred three patients with PD and 52 patients without PD were recruited (mean ± SD age, 67 ± 1 vs 69 ± 2, P= 0.4; males: 62% vs 55% P= 0.2). Symptoms of ICDs were reported by 0% of poststroke patients and 25% of the patients with PD (P < 0.001). Hypersexuality was reported by 10% of the patients with PD, compulsive shopping by 6%, pathological gambling by 3%, and compulsive eating by 14%. A logistic regression analysis found that age younger than 68 years (odds ratio [OR], 3.3; 95% confidence interval, 1.6–6.6) and exposure to dopamine agonists (OR, 20.3; 95% confidence interval, 2.7–65.0) or monoaminooxidase-B inhibitor (OR, 3.7; 95% confidence interval, 1.1–12.6) were significant factors associated with increased ICD frequency. Patients with ICD symptoms were exposed to higher dopamine doses than those without them (1.6 ± 0.1 vs 1.0 ± 0.1 daily-defined doses; P < 0.001). A dose-response pharmacodynamic model disclosed a significant nonlinear dose-response relationship between dopamine agonists and frequency of ICD symptoms (P < 0.01). ConclusionsImpulse-control disorder symptoms were more frequent in the patients with PD than in the poststroke patients with PD. Impulse-control disorder symptoms were related to younger age and exposure to monoaminooxidase-B inhibitors, and showed a nonlinear dose-response relationship with dopamine agonists.

Factors related to orthostatic hypotension in Parkinson's disease.

INTRODUCTION Orthostatic hypotension (OH), a frequent feature of Parkinsons disease (PD) can contribute to falls and is usually related to the disease itself and/or to drugs. OBJECTIVES To explore factors related to OH and to assess the concordance between abnormal blood pressure (BP) fall after standing and the presence of orthostatic symptoms. METHODS Non-demented, non-operated idiopathic PD out-patients were questioned about the presence of orthostatic symptoms. Afterward, BP was measured 5-min after lying down and for 3-min after standing up. OH was defined as systolic and/or diastolic BP fall ≥ 20 and/or 10 mmHg after standing. Patients were further evaluated by the Unified PD Rating Scale (UPDRS) and their medications were recorded. RESULTS 103 patients were included in this study (mean age = 66 ± 1 years, mean disease duration = 9 ± 1 years; mean UPDRS II+III in ON-state = 37 ± 2 points). Forty-one subjects (40%) reported the presence of orthostatic symptoms during the previous week and 38 (37%) had OH according to manometric definition. Independent factors related to OH, as assessed by logistic regression were age >68 years (OR, 95% CI=3.61, 1.31-9.95), polypharmacy (defined as intake of >5 medications, OR = 3.59, 1.33-9.69), amantadine (7.45, 1.91-29.07) or diuretics (5.48, 1.10-54.76), whereas the consumption of entacapone was protective (0.20, 0.05-0.76). The agreement between abnormal BP fall and presence of orthostatic symptoms was poor (kappa = 0.12 ± 0.1, p = 0.23). CONCLUSION OH was significantly related to older age, polypharmacy and amantadine or diuretics intake, while entacapone exposure appeared to reduce the risk of OH. Low concordance between OH and orthostatic symptoms was observed.

Deep Brain Stimulation for Parkinson’s Disease: Correlation between Intraoperative Subthalamic Nucleus Neurophysiology and Most Effective Contacts

Though intraoperative neurophysiology is essential to precisely define the definitive target, little is known regarding its predictive value in defining the most effective contact for chronic deep brain stimulation. In this retrospective study, we reviewed the correlation between intraoperative neurophysiology and contacts selected for chronic stimulation. Twenty consecutive patients implanted for subthalamic nucleus (STN) stimulation were reviewed. There was no significant correlation between the electrophysiologically defined STN and the most effective contact for chronic stimulation at 3 months or at 6 months. Furthermore, there was a discrepancy between the most effective contact for rigidity versus akinesia or tremor at 3 months. Interestingly, at 3 months, the same electrode contact was maximally efficient for rigidity, akinesia and tremor in only 13 of the 39 cases. This lack of correlation did not affect the global improvement.

Do Parkinson’s disease patients disclose their adverse events spontaneously?

BackgroundUnderreporting of adverse drug reactions is common but has been rarely studied in Parkinson’s disease (PD).ObjectiveTo compare the prevalence of adverse events (AEs) in relation to antiparkinsonian drugs in PD patients using two different data collection methods: patient’s spontaneous reporting versus a predefined investigator-driven structured interview. Secondary objectives were to assess factors related to spontaneous reporting and to compare the rate of AE reporting in PD patients with that of a group of non-parkinsonian post-stroke patients.Study designCross-sectional study.PatientsAmbulatory, cognitively intact PD or post-stroke outpatients.InterventionsNone.Outcome measuresPatients were first asked by means of an an open question to disclose any unpleasant effects in connection with their current medications that had occurred during the previous week. Afterwards, a predefined questionnaire listing the most common AEs known to be related to antiparkinsonian drugs was used to question the same patients in a systematic manner about the presence of any AE during the same week. Chronological and semiological criteria were used to classify the reported AEs as “unrelated” or “possibly/plausibly related” to the antiparkinsonian treatment.ResultsA total of 203 PD and 52 post-stroke patients of comparable age and sex were recruited. Eighty-five PD and five post-stroke patients reported spontaneously at least one AE (42 vs. 10%, p < 0.01), while 203 PD and 47 post-stroke patients reported at least one AE following the structured questionnaire (100 vs. 90%, p < 0.001). In PD patients, there were a total of 112 spontaneously reported AEs as compared with 1,574 according to the structured questionnaire (7%). Spontaneous disclosure of AEs was associated with experiencing >2 AEs [OR = 1.2 (1.1–3.2)], logistic regression). Seventy-four percent of PD patients had ≥1 AE possibly/plausibly related to antiparkinsonian drugs.ConclusionsResults showed that only 7% of AEs were reported spontaneously by patients, thus underscoring the importance of systematically asking about AEs in PD patients.