Sensory abnormalities and pain in Parkinson disease and its modulation by treatment of motor symptoms.

Pain and sensory abnormalities are present in a large proportion of Parkinson disease (PD) patients and have a significant negative impact in quality of life. It remains undetermined whether pain occurs secondary to motor impairment and to which extent it can be relieved by improvement of motor symptoms. The aim of this review was to examine the current knowledge on the mechanisms behind sensory changes and pain in PD and to assess the modulatory effects of motor treatment on these sensory abnormalities. A comprehensive literature search was performed. We selected studies investigating sensory changes and pain in PD and the effects of levodopa administration and deep brain stimulation (DBS) on these symptoms. PD patients have altered sensory and pain thresholds in the off-medication state. Both levodopa and DBS improve motor symptoms (i.e.: bradykinesia, tremor) and change sensory abnormalities towards normal levels. However, there is no direct correlation between sensory/pain changes and motor improvement, suggesting that motor and non-motor symptoms do not necessarily share the same mechanisms. Whether dopamine and DBS have a real antinociceptive effect or simply a modulatory effect in pain perception remain uncertain. These data may provide useful insights into a mechanism-based approach to pain in PD, pointing out the role of the dopaminergic system in pain perception and the importance of the characterization of different pain syndromes related to PD before specific treatment can be instituted.

Bioequivalence of lamotrigine 50-mg tablets in healthy male volunteers: a randomized, single-dose, 2-period, 2-sequence crossover study.

UNLABELLED: OBEJCTIVE: To compare the bioavailability of two 50-mg lamotrigine dispersible tablet formulations (Epilepax®, Ivax-TEVA Argentina Laboratories, Argentina, as a test formulation, and Lamictal®, GlaxoSmithKline, UK, as a reference formulation) in 24 healthy male volunteers. MATERIAL AND METHODS: This study was a randomized, 2-period, 2-sequence crossover design that was open for subjects and investigators, but blind for the bioanalytical lab. Serum samples were obtained over a 120-h interval. A 9-day wash-out period was allowed between treatments. The concentrations of lamotrigine were analyzed by high-performance liquid chromatography followed by ultraviolet-visible detection. Lamotrigine time-concentrations curves were obtained and the following pharmacokinetic parameters were calculated: AUC0-t, AUC0-inf and Cmax. Bioequivalence was declared if the 90% confidence interval (CI) of the mean test/reference ratios for AUC0-t, AUC0-inf and Cmax were within 80.00-125.00%. RESULTS: The geometric mean and respective 90% CI of test/reference percent ratios were 100.83% (92.53-107.88%) for AUC0-t, 99.91% (93.79-108.40%) for AUC0-inf, and 95.62% (90.91-100.57%) for Cmax. No serious adverse events were observed. 1 patient reported a mild rash following the administration of each formulation. CONCLUSION: This single dose study found that the test and reference products met the regulatory criteria for bioequivalence in this sample of fasting healthy volunteers. These results suggest that bioequivalence studies evaluating 50-mg doses of Lamotrigine are feasible and recommended, since such doses may minimize the risk of severe rash or Stevens-Johnson Syndrome. This study was registered at the Argentinean Clinical Trials National Registry (www.anmat.gov.ar), No 1666/2008.

Decision-making in Parkinson's disease patients with and without pathological gambling.

BACKGROUND AND PURPOSE: Pathological gambling (PG) in Parkinson's disease (PD) is a frequent impulse control disorder associated mainly with dopamine replacement therapy. As impairments in decision-making were described independently in PG and PD, the objective of this study was to assess decision-making processes in PD patients with and without PG. METHODS: Seven PD patients with PG and 13 age, sex, education and disease severity matched PD patients without gambling behavior were enrolled in the study. All patients were assessed with a comprehensive neuropsychiatric and cognitive evaluation, including tasks used to assess decision-making abilities under ambiguous or risky situations, like the Iowa Gambling Task (IGT), the Game of Dice Task and the Investment Task. RESULTS: Compared to PD patients without gambling behavior, those with PG obtained poorer scores in the IGT and in a rating scale of social behavior, but not in other decision-making and cognitive tasks. CONCLUSIONS: Low performance in decision-making under ambiguity and abnormal social behavior distinguished PD patients with PG from those without this disorder. Dopamine replacement therapy may induce dysfunction of the ventromedial prefrontal cortex and amygdala-ventral striatum system, thus increasing the risk for developing PG.

Addenbrooke's Cognitive Examination validation in Parkinson's disease.

BACKGROUND: There is a clear need for brief, sensitive and specific cognitive screening instruments in Parkinson's disease (PD). OBJECTIVES: To study Addenbrooke's Cognitive Examination (ACE) validity for cognitive assessment of PD patient's using the Mattis Dementia Rating Scale (MDRS) as reference method. A specific scale for cognitive evaluation in PD, in this instance the Scales for Outcomes of Parkinson's disease-Cognition (SCOPA-COG), as well as a general use scale the Mini-mental state examination (MMSE) were also studied for further correlation. METHODS: Forty-four PD patients were studied, of these 27 were males (61%), with a mean (SD) age of 69.5 (11.8) years, mean (SD) disease duration of 7.6 (6.4) years (range 1-25), mean (SD) total Unified Parkinson's Disease Rating Scale (UPDRS) score 37 (24) points, UPDRS III 16.5 (11.3) points. MDRS, ACE and SCOPA-COG scales were administered in random order. All patients remained in on-state during the study. RESULTS: Addenbrooke's Cognitive Examination correlated with SCOPA-COG (r = 0.93, P < 0.0001), and MDRS (r = 0.91 P < 0.0001) and also with MMSE (r = 0.84, P < 0.001). Area under the receiver-operating curve, taking MDRS as the reference test, was 0.97 [95% confidence interval (CI): 0.92-1.00] for ACE, 0.92 (95% CI: 0.83-1.00) for SCOPA-COG and 0.91 (95% CI: 0.83-1.00) for MMSE. Best cut-off value for ACE was 83 points [Sensitivity (Se) = 92%; Specificity (Sp) = 91%; Kappa concordance (K) = 0.79], 20 points for the SCOPA-COG (Se = 92%; Sp = 87%; K = 0.74) and 26 points for MMSE (Se = 61%; Sp = 100%; K = 0.69). CONCLUSION: Addenbrooke's Cognitive Examination appears to be a valid tool for dementia evaluation in PD, with a cut-off point which should probably be set at 83 points, displaying good correlation with both the scale specifically designed for cognitive deficits in PD namely SCOPA-COG, as well as with less specific tests such as MMSE.

Prospective randomized 1-year follow-up comparison of bilateral subthalamotomy versus bilateral subthalamic stimulation and the combination of both in Parkinson's disease patients: a pilot study.

It has been suggested that potential risk of hemiballismus after subthalamotomy makes DBS preferable to ablation for IPD treatment; however, cost and the need for regular electrode control have also been observed as disadvantages to stimulation. The objective was to compare efficacy and safety of different surgical approaches to STN, in a prospective randomized pilot study. Sixteen consecutive IPD patients randomized to receive either: bilateral STN-DBS, bilateral subthalamotomy or unilateral subthalamotomy plus contralateral STN-DBS implantation, and followed for 12 months after surgery. One patient died and was excluded from the analysis. Total and motor UPDRS scores, as well as drug-induced dyskinesias improved significantly at 1 year follow-up, regardless of the procedure administered and without statistically significant differences between treatment modalities. Discrete changes were observed on ACE and MMSE scores. Psychiatric examination of patients subjected to bilateral stimulation and lesion, revealed slight increment in apathy and irritability scores, coinciding with significant deterioration of mentation, behaviour and mood as measured using the UPDRS. One patient presented persistent hemiballismus and required ulterior posteroventral pallidotomy. In this small group of patients, overall motor performance significantly improved after all three procedures, without major differences in outcome. Adverse events were, nevertheless, observed after both ablation and stimulation. The role of bilateral subthalamotomy in patients unable to receive a DBS electrode-implant merits further exploration in a larger series of patients with longer follow-up.

Dyskinesias induced by subthalamotomy in Parkinson's disease are unresponsive to amantadine.

BACKGROUND: Dyskinesias are a transient but severe complication of subthalamotomy in some patients. PATIENTS AND METHODS: Three patients with Parkinson's disease undergoing bilateral micro-recording guided surgery of the subthalamic nucleus (STN) are described; deep brain stimulation (DBS) was used in one case, and subthalamotomy in the other two. Prior to surgery, levodopa induced dyskinesia had improved (< or = 50%) under treatment with amantadine (400 mg/day, po) in all three patients. The patient treated with DBS developed severe dyskinesia a few days after discharge and began self medication with amantadine but showed no improvement. This suggested a possible lack of response to amantadine for treatment of dyskinesias induced by surgery of the STN. RESULTS: Both patients treated with bilateral subthalamotomy developed unilateral choreoballistic movements immediately after surgery, despite not taking levodopa (L-dopa). Patients were scored using the dyskinesia scale and started treatment with 400 mg amantadine (po) for 4 days within the first postoperative week with no effect on dyskinesia score or its phenomenology. Amantadine was therefore discontinued. One month after surgery both patients were free of involuntary movements with an improvement of about 60% in the "off" state UPDRS motor score. Six month follow up showed maintained antiparkinsonian benefit, without need for levodopa treatment and complete absence of dyskinesia. CONCLUSION: The present findings suggest that: (i) amantadine probably exerts its anti-dyskinetic effect by acting on the "indirect" pathway; (ii) the pathophysiological mechanisms of subthalamotomy induced dyskinesias may differ from those involved in L-dopa induced dyskinesias; (iii) dyskinesias induced by STN surgery resolve spontaneously as compensatory mechanisms develop.