Pathological Gambling in Parkinson's disease patients: Dopaminergic medication or personality traits fault?

Impulse control disorders (ICDs) are clinically relevant in Parkinson disease (PD) patients, with an established association with PD medication. Aim of our study was to study whether the increased frequency of pathological gambling (PG), reported in subgroups of PD patients, is related to specific personality tracts additional to dopaminergic medications. Thirty-seven PD patients with a personal history of PG where enrolled. Twenty one PD patients, matched for disease and dopaminergic therapy, never experiencing PG, were enrolled as controls. All subjects were tested with the Minnesota Multiphasic Inventory Personality scales (MMPI-2). Our data showed that PD group with PG exhibited significantly higher mean values of the three validity scales in comparison to the non-PG-PD group, demonstrating an higher tendency to lie. Content scales showed a significant increase of cynicism and bizarre ideation scales score in the PG-PD group, not exhibiting pathological values at the validity scales, (p: 0.02) in comparison to non-PG PD patients. According to our results, PG seems to be associated with precise personality tracts. Personality profiles of cluster A personality disturbances - Axys 2 according with DSM-5 TR (paranoid type) at MMPI-2 might be a warning index helpful in selecting dopaminergic treatment, to avoid subsequent ICDs appearance.

Wearing-off detection in clinical practice: the wearing off real practice key (WORK-PD) study in Parkinson's disease.

OBJECTIVE: Verifying the validity and feasibility of the WOQ-19 as a useful tool in routine clinical practice and in management of patients. METHODS: 532 consecutive Parkinson's disease (PD) patients were recruited from 6 different neurological outpatient units, specialized in movement disorders, of central Italy. Inclusion criteria were diagnosis of PD and any current pharmacological treatment of PD while exclusion criteria were evident cognitive or depressive impairment, infusion with dopamine agonists or Duodopa, or Deep Brain Stimulation therapy. Patients were asked to complete the Italian version of WOQ-19 before the neurological visit. A medical form for the collection of demographic and clinical data of patients and for the evaluation of comprehensibility and usability the WOQ-19 was filled by the neurologist during the visit. RESULTS: Our data confirmed that WOQ-19 was able to identify WO in 69% of patients, a percentage similar to the recently reported in the Italian WOQ-19 validation study. Motor symptoms were more frequent than non-motor symptoms (80% vs. 20%). Patients who experienced WO had a higher age of PD onset, more severe disease, longer disease duration and were more likely to be female. CONCLUSIONS: The WOQ-19 was understandable for the patient, easily administered and suitable for routine outpatient use. It could be also particularly useful in clinical practice in the early identification of non-motor symptoms, often under reported by patients and revealed only with clinical support.

Tetrabenazine improves levodopa-induced peak-dose dyskinesias in patients with Parkinson's disease.

Since levodopa-induced peak dyskinesias (LIDs) may reflect, in part, a disproportionate phasic release of dopamine from synaptic vesicles, we examined the ability of the vesicular depletor tetrabenazine (TBZ) to reduce LIDs in 10 dyskinetic advanced Parkinson's disease (PD) patients. After basal evaluation, the patients received, through a slow titration, oral TBZ twice a day for six weeks (up to 50 mg daily) before being re-assessed after a challenge with levodopa. The primary outcome measure was the change in the Unified Parkinson's Disease Rating Scale (UPDRS) dyskinesia score (items 32 to 34). TBZ was well tolerated. A clear treatment effect on LIDs emerged (up to 45%, p<0.05). In two patients a little worsening of motor performance necessitated an increase of the antiparkinsonian therapy, which did not worsen peak-dose LIDs. The patients experienced a clear benefit in terms of their quality of life. In this open-label pilot study, orally administered TBZ resulted in objective and subjective improvements in LIDs. Larger pharmacological studies are in progress.

Multiple myeloma and paget disease with abnormal skull lesions and intracranial hypertension.

We report a 73 years old man with a diagnosis of Paget Disease (PD) and symptomatic Multiple Myeloma (MM). Coexistence of MM and PD has rarely been described. PD mimics many of the features of bone destructive process in MM, making differential diagnosis more complicated. In addition, the presence of serious muscolo-skeletal and metabolic complications in both diseases makes management of patients difficult, worsening the prognosis.The comparison of these two diseases has led to the characterization of a common molecular mechanism represented by the receptor activator of nuclear factor-kB ligand (RANKL)/Osteoprotegerin signaling pathway. The improved comprehension of these mechanisms led to the development of new pharmacologic agents (bisphosphonates, cytokines inhibitors) effective for the treatment of these bone diseases.

Low frequency stimulation of the nucleus tegmenti pedunculopontini increases cortical metabolism in parkinsonian patients.

BACKGROUND AND PURPOSE: To evaluate the effects of 25-Hz deep brain stimulation of the nucleus tegmenti pedunculopontini (PPTg) on brain metabolic activity. METHODS: Six patients with Parkinson's disease (PD) who had bilateral stereotactic implantation of PPTg at least 12 months prior to evaluation were included in our study. All underwent, in separate sessions, 18-FDG-PET in core assessment programme for intra-cerebral transplantation as well as motor evaluation [Unified Parkinson's disease rating scale (UPDRS)--Section III] and a battery of cognitive testing. RESULTS: PPTg-ON (low bipolar contacts, 25 Hz) promoted a significant increase of glucose utilization in bilateral prefrontal areas including dorsolateral prefrontal cortex (DLPFC, BA9), orbito-frontal cortex (BA47), anterior cingulate (BA 25-32), superior frontal gyrus (BA 10) and supramarginal gyrus (BA40); a significant increase of uptake and consumption of FDG also occurred in the left ventral striatum, left subgyral (BA 46), right insula (BA 13) and right superior temporal gyrus (BA 22). PPTg-ON was associated with a significant decrease of glucose utilization in the left cerebellar anterior lobe (culmen) and right cerebellar posterior lobe (declive). In the same patients, PPTg-ON improved delayed recall (P < 0.05) and executive functions whilst the UPDRS revealed a modest (-21%) and variable treatment effect. CONCLUSIONS: Low frequency stimulation of PPTg, a sub-region of the pedunculopontine nucleus complex, causes a minor motor benefit but a peculiar profile of cognitive improvement associated with a significant increase in FDG consumption in both prefrontal areas and mono-lateral ventral striatum. These data are consistent with multiple limbic and/or associative domains modulated by PPTg stimulation in our patients with PD.

Deep brain stimulation of pedunculopontine tegmental nucleus (PPTg) promotes cognitive and metabolic changes: a target-specific effect or response to a low-frequency pattern of stimulation?

Deep brain stimulation (DBS) is a reliable treatment for advanced Parkinson's disease (PD) patients, but a possible risk of worsening cognitive functions, although modest, may postpone or halt DBS clinical indication. In a small cohort of PD patients we have pioneered the simultaneous implantation of both the subthalamic nucleus (STN) and the pedunculopontine tegmental nucleus (PPTg). Here we describe the cognitive test performance and the corresponding cortical metabolic activity, as assessed through 18-fluorodeoxyglucose (FDG)-positron emission tomography (PET), of these six PD patients tested in PPTg-ON vs- PPTg-OFF condition. PPTg-ON condition (at low frequency, 25 Hz) induced better performance in tests exploring both executive and attentive domains, which were coupled with an increased glucose utilization in prefrontal and frontal bilateral cortical areas, including both lateral (i.e., BA9) and more antero-medial cortices (BA 25-32). Moreover, during PPTg-ON, a surprising increase of FDG consumption was also observed in the left ventral striatum. These data are consistent with the hypothesis of a positive effect of 25 Hz PPTg-DBS on PD patients' cognitive profile, probably due to a facilitatory effect exerted by PPTg on both associative and limbic pathways.

Pathological gambling from dopamine agonist and deep brain stimulation of the nucleus tegmenti pedunculopontine.

In patients with Parkinson's disease, aberrant or excessive dopaminergic stimulation is commonly indicated as the trigger factor in unmasking impulse control disorders (ICDs) such as pathological gambling. We had the opportunity to follow a patient who experienced Parkinson's disease 7 years ago when he was using pramipexole and again, recently, when he was treated with levodopa (L-dopa) and low frequency stimulation of the nucleus of the pedunculopontine tegmentus (PPTg) but no dopamine agonists. The same patient had shown, when studied with fluorodeoxyglucose-positron emission tomography in the condition PPTg-ON, a peculiar increased activity in the left ventral striatum. This case report confirms that, in a predisposed personality, ICD may arise from the perturbation of endogenous pathways, which connect the brainstem to the basal ganglia.

Cerebellar magnetic stimulation decreases levodopa-induced dyskinesias in Parkinson disease.

BACKGROUND: The neural mechanisms and the circuitry involved in levodopa-induced dyskinesia (LID) are still partially obscure. LID can be considered the consequence of an abnormal pattern or code of activity that originates and is conveyed from the basal ganglia to the thalamus and the cortical motor areas. However, not only striatothalamocortical motor circuits but also other interconnected pathways could be implicated in its pathogenesis. METHODS: In a series of experiments, we applied repetitive transcranial magnetic stimulation (rTMS) over the lateral cerebellum in a group of patients with advanced Parkinson disease, to investigate whether modulation of cerebellothalamocortical circuits by means of rTMS may result in a modification of a dyskinetic state induced by levodopa ingestion. RESULTS: We found that a single session of cerebellar continuous theta burst stimulation (cTBS) was capable of transiently reducing LID. In the same patients, we observed that cerebellar cTBS changed the profile of activation of intracortical circuits in the contralateral primary motor cortex. Cerebellar cTBS reduced short intracortical inhibition and increased long intracortical inhibition, inducing a cortical reorganization that is associated with a reduction of LID. Furthermore, in another experiment, we observed that a 2-week course of bilateral cerebellar cTBS induced persistent clinical beneficial effects, reducing peak-dose LID for up to 4 weeks after the end of the daily stimulation period. CONCLUSIONS: Our study demonstrates that cerebellar continuous theta burst stimulation has an antidyskinetic effect in Parkinson disease patients with levodopa-induced dyskinesia, possibly due to modulation of cerebellothalamocortical pathways.

Acute vs chronic effects of l-dopa on bladder function in patients with mild Parkinson disease.

OBJECTIVE: To compare acute and chronic effects of l-dopa on bladder function in levodopa-naive Parkinson disease (PD) patients who had urinary urgency. METHODS: We evaluated 26 l-dopa-naive PD patients at a university-based PD center with a first urodynamic session with a double examination: in the off treatment condition and 1 hour after acute challenge with carbidopa/l-dopa 50/200 mg; then, a chronic l-dopa monotherapy was administered (mean dose 300 +/- 150 mg). Two months later, patients underwent a second urodynamic session with a single evaluation 1 hour after the acute carbidopa/l-dopa challenge. RESULTS: The first acute l-dopa challenge significantly worsened bladder overactivity (neurogenic overactive detrusor contractions threshold [NDOC-t; 32% of worsening] and bladder capacity [BC; 22% of worsening]); on the contrary, l-dopa challenge during chronic administration ameliorated the first sensation of bladder filling (FS; 120% of improvement), NDOCT-t (93% improvement), and BC (33% of improvement) vs the values obtained with acute administration. An 86% significant improvement of FS in comparison with the basal value was observed. CONCLUSIONS: The acute and chronic l-dopa effects may be due to the different synaptic concentrations or to the activation of postsynaptic mechanisms obtained by chronic administration.

Repetitive transcranial magnetic stimulation of the motor cortex ameliorates spasticity in multiple sclerosis.

OBJECTIVE: To investigate whether repetitive transcranial magnetic stimulation (rTMS) can modify spasticity. METHODS: We used high-frequency (5 Hz) and low-frequency (1 Hz) rTMS protocols in 19 remitting patients with relapsing-remitting multiple sclerosis and lower limb spasticity. RESULTS: A single session of 1 Hz rTMS over the leg primary motor cortex increased H/M amplitude ratio of the soleus H reflex, a reliable neurophysiologic measure of stretch reflex. Five hertz rTMS decreased H/M amplitude ratio of the soleus H reflex and increased corticospinal excitability. Single sessions did not induce any effect on spasticity. A significant improvement of lower limb spasticity was observed when rTMS applications were repeated during a 2-week period. Clinical improvement was long-lasting (at least 7 days after the end of treatment) when the patients underwent 5 Hz rTMS treatment during a 2-week protocol. No effect was obtained after a 2-week sham stimulation. CONCLUSIONS: Repetitive transcranial magnetic stimulation may improve spasticity in multiple sclerosis.

Deep brain stimulation in Parkinson's disease patients: biochemical evidence.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) patients augments STN-driven excitation of the internal globus pallidus (GPi). However, other DBS-induced changes are largely unknown. Here we report the biochemical effects of STN-DBS in two basal ganglia stations (putamen--PUT--and GPi) and in a thalamic relay nucleus, the anteroventral thalamus (VA). In six advanced PD patients undergoing surgery, microdialysis samples were collected from GPi, PUT and VA before, during and after one hour of STN-DBS. cGMP was measured in the GPi and PUT as an index of glutamatergic transmission, whereas GABA was measured in the VA. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in the VA (-25%). Simultaneously, cGMP extracellular concentrations were enhanced in the PUT (+200%) and GPi (+481%). DBS differentially affects fibers crossing the STN area: it activates the STN-GPi pathway while inhibiting the GPi-VA one. These findings support a thalamic dis-inhibition, as the main responsible for the clinical effect of STN-DBS. This, in turn, re-establishes a more physiological level of PUT activity.

Effect of cabergoline added to levodopa treatment on sleep-wake cycle in idiopathic Parkinson's disease: an open label 24-hour polysomnographic study.

Few studies focused on the effects of cabergoline on sleep-wake cycle in PD. Twelve patients affected by PD treated with levodopa as monotherapy underwent two 24-hour ambulatory polysomnographic (A-PSG) sessions twice: in baseline condition (levodopa as monotherapy) and after addition of cabergoline. In each condition, a subjective evaluation of sleep quality and daytime sleepiness was obtained by means of Parkinson's disease Sleep Scale (PDSS) and the Epworth Sleepiness Scale. The statistical analysis of sleep parameters revealed a significant increase of sleep efficiency and slow wave sleep under cabergoline. The PDSS total score showed a significant improvement of overall sleep quality after cabergoline. No significant changes in daytime sleepiness were observed. No patient referred and/or showed sleep attacks before and after addition of cabergoline. We hypothesize that the long-lasting effect of cabergoline may improve the objective quality of nocturnal sleep in PD patients complaining nocturnal motor disability without inducing daytime sleepiness.

Helicobacter pylori eradication and l-dopa absorption in patients with PD and motor fluctuations.

OBJECTIVE: To investigate if Helicobacter pylori (HP) eradication could make an effective and long-lasting improvement in the pharmacokinetic and clinical response to l-dopa in patients with Parkinson disease (PD) and motor fluctuations. METHODS: In a group of 34 HP-infected, motor-fluctuating patients with PD, the short-term (1-week) and long-term (3-month) beneficial effect of HP eradication (n = 17) was investigated in a double-blind fashion in comparison with a generic antioxidant treatment (n = 17), by means of pharmacokinetic, clinical, and gastrointestinal assessments. Results were compared with placebo treatment. RESULTS: Differently from the antioxidant-treated patients, the HP-eradicated patients showed a significant increase of l-dopa absorption, which was coupled with a significant improvement of clinical disability and with a prolonged "on-time" duration, whereas gastritis/duodenitis scores significantly decreased in line with a better l-dopa pharmacokinetics. CONCLUSIONS: These data demonstrate a reversible Helicobacter pylori (HP)-induced interference with l-dopa clinical response related to the impaired drug absorption, probably due to active gastroduodenitis. Therefore, the authors suggest that HP eradication may improve the clinical status of infected patients with Parkinson disease and motor fluctuations by modifying l-dopa pharmacokinetics.

Evaluation of basal ganglia haemodynamic changes with perfusion-weighted magnetic resonance imaging in patients with Parkinson's disease.

PURPOSE: The aim of our study was to assess the regional cerebral blood flow (rCBF) of basal ganglia and thalami in patients with Parkinson's disease (PD) using perfusion-weighted magnetic resonance imaging (PW-MRI). MATERIAL AND METHODS: Twenty subjects affected by idiopathic PD according to the United Kingdom Brain Bank criteria were enrolled in the study. Twenty normal subjects matched for age and gender were included as controls. After 20-day therapy withdrawal, the PD patients underwent PW-MRI. The rCBF was calculated both in patients and in controls. The regions of interest were manually positioned on rCBF maps over the caudate nucleus, the putamen, the external and internal globus pallidus, and over the ventrolateral nucleus of the thalamus. Data were normalised with those obtained from parieto-occipital white matter (POWM). Statistical analysis was performed using a parametric ANOVA test. RESULTS: Patients showed a significant (p<0.01) interhemispheric asymmetry; rCBF values were higher on the more severely affected side. Controls showed no interhemispheric asymmetry. CONCLUSION: Our study suggests that PW-MRI is a valuable tool for assessing haemodynamic changes in PD patients. Haemodynamic change pattern may be useful in the early diagnosis of PD.

rTMS of supplementary motor area modulates therapy-induced dyskinesias in Parkinson disease.

The neural mechanisms and circuitry involved in levodopa-induced dyskinesia are unclear. Using repetitive transcranial magnetic stimulation (rTMS) over the supplementary motor area (SMA) in a group of patients with advanced Parkinson disease, the authors investigated whether modulation of SMA excitability may result in a modification of a dyskinetic state induced by continuous apomorphine infusion. rTMS at 1 Hz was observed to markedly reduce drug-induced dyskinesias, whereas 5-Hz rTMS induced a slight but not significant increase.

Pergolide effect on cognitive functions in early-mild Parkinson's disease.

In the present study, we evaluated the effect of pergolide, a mixed D1/D2 agonist, on cognitive function in mild Parkinson's disease (PD). After a two-week wash-out phase, twenty patients with a Hoehn and Yahr score

Sleep episodes and daytime somnolence as result of individual susceptibility to different dopaminergic drugs in a PD patient: a polysomnographic study.

The association between excessive daytime somnolence (EDS) and idiopathic Parkinson's disease (PD) is often reported but still debated. The possible role of antiparkinsonian therapy or primarily of PD on excessive diurnal sleepiness is controversial. We describe the case of a 61-year-old patient affected by PD who experienced sleep episodes (SE) occurring during pramipexole plus L-Dopa therapy. Polysomnographic sleep studies and subjective evaluations of daytime sleepiness (Epworth Sleepiness Scale) were carried out under administration of pramipexole plus L-Dopa, L-Dopa monotherapy and cabergoline plus L-Dopa. The polysomnography revealed two sleep events during pramipexole plus L-Dopa. Moreover, the polysomnographic data showed an increase of both diurnal and nocturnal sleep under pramipexole plus L-Dopa compared with cabergoline plus L-Dopa and L-Dopa as monotherapy. In addition, while Epworth Sleepiness Scale (ESS) Score showed a mild sleepiness under pramipexole (ESS score=11), ESS scores were normal under both L-Dopa and cabergoline plus L-Dopa. Sleep episodes also disappeared under both L-Dopa and cabergoline plus L-Dopa (2- and 12-month follow-up). We hypothesize that an individual susceptibility to specific antiparkinsonian drug may play a significant role in the genesis of sleepiness in our PD patient.

High-frequency rTMS improves time perception in Parkinson disease.

Patients with Parkinson disease (PD) are impaired in time processing. The authors investigated the effects of high-frequency (5 Hz) repetitive transcranial magnetic stimulation (rTMS) in patients with PD performing a time reproduction task. The authors found significant improvement in time processing induced by rTMS when trains were applied over the right dorsolateral prefrontal cortex (DLPFC) but not over the supplementary motor area, suggesting that the circuit involving the basal ganglia and the DLPFC might constitute the neural network subserving time perception.