[Management of complications related to intraduodenal infusion of levodopa/carbidopa in patients with Parkinson's disease]. / Manejo de las complicaciones relacionadas con la infusion intraduodenal de levodopa/carbidopa en pacientes con enfermedad de Parkinson.

Continuous infusion of intraduodenal levodopa/carbidopa is an effective treatment that improves the motor complications and the quality of life of patients in the advanced stages of Parkinson's disease. However, it is not free of complications. These may present in the post-operative period following surgery (gastrostomy) or in the long-term during the follow-up period and can be related with the medication (levodopa/carbidopa), the stoma, the gastrostomy or the device (pump, enteral tube, parts of the FREKA system). The aim of this review is to report on the management of the complications that can be observed in patients with advanced Parkinson's disease treated with continuous infusion of intraduodenal levodopa/carbidopa.

TITLE: Manejo de las complicaciones relacionadas con la infusion intraduodenal de levodopa/carbidopa en pacientes con enfermedad de Parkinson.La infusion continua de levodopa/carbidopa intraduodenal es un tratamiento eficaz que mejora las complicaciones motoras y la calidad de vida de los pacientes con enfermedad de Parkinson avanzada. Sin embargo, no esta exento de complicaciones. Estas pueden presentarse en el postoperatorio de la cirugia (gastrostomia) o a largo plazo durante el seguimiento, y pueden estar relacionadas con la medicacion (levodopa/carbidopa), el estoma, la gastrostomia o el dispositivo (bomba, sonda enteral, piezas del sistema FREKA). El objetivo de la presente revision es describir el manejo de las complicaciones que pueden presentar los pacientes con enfermedad de Parkinson avanzada tratados con infusion continua de levodopa/carbidopa intraduodenal.

The nature of progression in Parkinson's disease: an application of non-linear, multivariate, longitudinal random effects modelling.

BACKGROUND: To date, statistical methods that take into account fully the non-linear, longitudinal and multivariate aspects of clinical data have not been applied to the study of progression in Parkinson's disease (PD). In this paper, we demonstrate the usefulness of such methodology for studying the temporal and spatial aspects of the progression of PD. Extending this methodology further, we also explore the presymptomatic course of this disease. METHODS: Longitudinal Positron Emission Tomography (PET) measurements were collected on 78 PD patients, from 4 subregions on each side of the brain, using 3 different radiotracers. Non-linear, multivariate, longitudinal random effects modelling was applied to analyze and interpret these data. RESULTS: The data showed a non-linear decline in PET measurements, which we modelled successfully by an exponential function depending on two patient-related covariates duration since symptom onset and age at symptom onset. We found that the degree of damage was significantly greater in the posterior putamen than in the anterior putamen throughout the disease. We also found that over the course of the illness, the difference between the less affected and more affected sides of the brain decreased in the anterior putamen. Younger patients had significantly poorer measurements than older patients at the time of symptom onset suggesting more effective compensatory mechanisms delaying the onset of symptoms. Cautious extrapolation showed that disease onset had occurred some 8 to 17 years prior to symptom onset. CONCLUSIONS: Our model provides important biological insights into the pathogenesis of PD, as well as its preclinical aspects. Our methodology can be applied widely to study many other chronic progressive diseases.

[Hyperdense carotid T in stroke: 'tree sign']. / Bifurcacion carotidea (T) hiperdensa en el ictus: el 'signo del arbol'

TITLE: Bifurcacion carotidea (T) hiperdensa en el ictus: el 'signo del arbol'

Imaging of Dopamine in PD and Implications for Motor and Neuropsychiatric Manifestations of PD.

Parkinson's disease (PD) is characterized by dopamine depletion in the putamen, which leads to motor dysfunction. As the disease progresses, a substantial degree of dopamine depletion also occurs in caudate and nucleus accumbens. This may explain a number of neuropsychiatric manifestations, including depression, apathy, and cognitive decline. Dopamine replacement therapy partially restores motor function but long-term treatment is often associated with motor complications (motor fluctuations and dyskinesias). Positron emission tomography (PET) studies suggest that the dopamine release rate is substantially higher in PD subjects with motor complications compared to stable responders. Notably, this differential pattern of dopamine release is already present in the early stages of the disease, before motor complications become clinically apparent. Converging evidence suggests that striatal dopamine depletion in PD leads to reduced plasticity in the primary motor cortex and, presumably, in non-motor cortical areas as well. Although dopamine replacement therapy tends to restore physiological plasticity, treatment-induced motor, and neuropsychiatric complications could be related to abnormalities in corticostriatal synaptic plasticity.

Impact of non-motor symptoms on health-related and perceived quality of life in Parkinson's disease.

OBJECTIVE: To investigate the impact of non-motor symptoms on health-related and perceived quality of life in Parkinson's disease (PD). METHODS: One hundred and fifty PD patients (57.3% males; 70.9±8.6years old) were included in this cross-sectional, monocenter, evaluation study. Multiple linear regression methods were used to evaluate the direct impact of non-motor symptoms (as assessed by the Non-Motor Symptoms Scale [NMSS]) on 1) the 39-item PD Quality of Life Questionnaire Summary Index score (PDQ-39SI), and 2) a subjective assessment of perceived quality of life (PQ-10), after adjusting for age, sex, mood (Beck Depression Inventory), disability (Schwab&England Activities of Daily Living Scale), and PD-specific motor dysfunction (ON-state Hoehn&Yahr/Unified Parkinson's Disease Rating Scale [UPDRS] part III, and motor complications [UPDRS part IV]). RESULTS: Higher NMSS total scores were systematically associated with worse quality of life (for PDQ-39SI, p=0.013; for PQ-10, p=0.017). PD-specific motor dysfunction had a larger negative impact on health-related quality of life (PDQ-39SI) than non-motor symptoms (2.8% vs 0.7%). In contrast, the negative impact of non-motor symptoms on perceived quality of life (PQ-10) was larger than that found for PD-specific motor dysfunction (2.8% vs 0.9%). While the model for PDQ-39SI provided an adequate fit (adjusted R-squared, 0.83), a substantial proportion of the PQ-10 variance remained unexplained (adjusted R-squared, 0.48). CONCLUSIONS: Non-motor symptoms have a direct negative impact on health-related and perceived quality of life in PD. Perceived quality of life is not adequately explained by motor and non-motor manifestations of the disease.

A predictive model of neurodegeneration in idiopathic REM-sleep behavior disorder.

OBJECTIVE: To investigate whether Parkinson's disease (PD) and dementia are competing risks in subjects with idiopathic rapid-eye-movement sleep behavior disorder (RBD). METHODS: The number of incidental PD cases observed in 11 longitudinal RBD studies was compared with the corresponding expected number as estimated by a simple mathematical model based on population parameters for PD age-of-onset. RESULTS: The expected number of incidental PD cases exceeded observed PD cases (p-value < 0.001) but was in agreement with the sum of observed PD cases and observed mild cognitive impairment/dementia cases (p-value = 0.34). Sensitivity analyses confirmed the results. CONCLUSION: In the RBD population, PD and dementia cases are competing risks, suggesting that alpha-synuclein pathology occurs simultaneously in substantia nigra and neocortex. This observation has implications for the design and analysis of trials of neuroprotection.

Impact of placebo assignment in clinical trials of tic disorders.

BACKGROUND: Understanding the impact of placebo treatment is pivotal to the correct interpretation of clinical trials. The aim of present study was to examine the placebo effect in tic disorders. METHODS: Raw data were obtained for 6 placebo-controlled parallel and cross-over trials that involved medical interventions for tic disorders. Tic severity was measured using the Yale Global Tic Severity Scale. Placebo effect was defined as an improvement of at least 30% over baseline scores in the total tic score and was considered clinically relevant when at least 10% of patients in the placebo-arm met that benchmark. RESULTS: In total, 91 placebo-treated patients (80% males; mean age, 16.5 years; standard deviation, 10.5 years) were included. Although there was a trend toward improvement in the total tic scores after placebo administration (P=0.057), the magnitude of the placebo effect was small (Cohen's d=0.16) but relevant (19% of the sample). Females were more likely than males to have a placebo effect. CONCLUSIONS: The magnitude of the placebo effect in tic disorders appeared to be small. Further longitudinal studies using objective assessments for tic disorders are warranted to confirm the current results. © 2013 Movement Disorder Society.

Levodopa dosage determines adherence to long-acting dopamine agonists in Parkinson's disease.

OBJECTIVE: To test whether adherence to non-ergot, once-daily dopamine agonist (ODDA) therapy depends upon concomitant levodopa daily dose in Parkinson's disease (PD). METHODS: Consecutive levodopa-treated PD patients on ODDA therapy were invited to participate in the study. ODDA adherence was measured using subjective (Morisky-Green test, MGT) and objective (electronic monitoring of refill compliance, IANUS) methods. A combination of MGT and IANUS was used to define full (100%) adherence to ODDA therapy. Logistic regression methods were used to investigate the impact of levodopa daily dose on ODDA adherence after adjusting for relevant covariates. RESULTS: Thirty-nine patients (19 men, 20 women; age, 70.2±8.9 years) were enrolled in the study. Twelve (31%) participants admitted to suboptimal ODDA compliance. Only 18 (46%) were estimated to be fully compliant. As expected, adherence was inversely related to levodopa daily dose. For every 100mg increase in levodopa dose, the risk to failure to adhere increased 1.86 times (95% CI, 1.21-3.74; p=0.0020). The covariate "total daily number of drugs" (not total daily number of pills) was also associated with worse adherence (p=0.0061). In contrast, patients who were initially treated with a dopamine agonist showed better ODDA adherence than those who were initially treated with levodopa (p=0.012). Levodopa doses greater than 600 mg/day were associated with suboptimal compliance. CONCLUSIONS: In levodopa-treated PD patients, adherence to ODDA therapy is suboptimal and strongly associated with the levodopa daily dose and the total number of drugs used to treat patients' medical conditions.

Role of DaTSCAN and clinical diagnosis in Parkinson disease.

OBJECTIVE: To assess the role of DaTSCAN in the diagnosis of Parkinson disease (PD). METHODS: Using the sensitivity and specificity values obtained in the 2 studies that recently led the US Food and Drug Administration to approve the use of DaTSCAN for the diagnosis of PD, calculations were carried out to estimate the accuracy of the clinical diagnosis taking DaTSCAN findings as the standard of truth. RESULTS: In early PD, a clinical diagnosis of "possible" or "probable" PD has a sensitivity of 98% and a specificity of 67%. The specificity increases to 94% once the clinical diagnosis becomes established. The overall accuracy of the clinical diagnosis is 84% in early PD and 98% at later stages. The clinical diagnostic accuracy is mathematically identical to the diagnostic accuracy of DaTSCAN imaging. CONCLUSIONS: In the absence of neuropathologic validation, the overall accuracy of a clinical diagnosis of PD is very high and mathematically identical to the accuracy of DaTSCAN imaging, which calls into question the use of radiotracer neuroimaging as a diagnostic tool in clinical practice.

Polyneuropathy while on duodenal levodopa infusion in Parkinson's disease patients: we must be alert.

Some reports have emerged describing the occurrence of Guillain-Barré syndrome and polyneuropathy related to vitamin B(12) deficiency in some patients with Parkinson's disease (PD) treated with continuous duodenal levodopa infusion. We describe five PD patients who developed axonal polyneuropathy and vitamin B(12) deficiency while on treatment with duodenal levodopa infusion, review other cases reported in the literature, discuss potential etiologic factors, and suggest a possible algorithm for the management and prevention of this complication. One case of Guillain-Barré syndrome and at least 12 cases of polyneuropathy related to vitamin B(12) deficiency have been reported in PD patients treated with duodenal levodopa infusion. Levodopa gel infusion may induce a decrease in vitamin B(12) levels, leading to peripheral neuropathy. Additional pathogenetic mechanisms include alterations related to the metabolism of L: -dopa, abnormal L: -dopa absorption, and direct neurotoxicity of L: -dopa at high doses. Vitamin B(12) supplementation may need to be considered in PD patients on duodenal levodopa infusion therapy. Vitamin B(12) deficiency in patients on duodenal levodopa infusion therapy may be more frequent than the published data suggest. We must be alert.

Frontostriatal cognitive staging in Parkinson's disease.

Cognitive impairment and behavioural disorders are often encountered in subjects with Parkinson's disease (PD). A simple PD-related frontostriatal cognitive dysfunction (PDFCD) staging is proposed. Executive dysfunction and mental fatigue (stage I), depression/anxiety (stage IIa), apathy/pain (stage IIb), and dementia (stage III) reflect a sequential process of dopamine depletion occurring in different regions of the striatum (stages I and II) and the frontal cortex (stage III). In addition to these nonmotor manifestations present in the unmedicated (OFF) state, the PDFCD model also predicts a number of complications related to dopaminergic treatment (ON state), from impulse control disorders (stages I and IIa) to hallucinations (stage IIb) and psychosis (stage III). Although the model admittedly needs further refinements, it provides a framework for hypothesis testing and may help clinicians optimize therapeutic strategies.

Longitudinal evolution of compensatory changes in striatal dopamine processing in Parkinson's disease.

Parkinson's disease is a relentlessly progressive neurodegenerative disease. Breakdown of compensatory mechanisms influencing putaminal dopamine processing could contribute to the progressive motor symptoms. We studied a cohort of 78 subjects (at baseline) with sporadic Parkinson's disease and 35 healthy controls with multi-tracer positron emission tomography scans to investigate the evolution of adaptive mechanisms influencing striatal dopamine processing in Parkinson's disease progression. Presynaptic dopaminergic integrity was assessed with three radioligands: (i) [(11)C](±)dihydrotetrabenazine, to estimate the density of vesicular monoamine transporter type 2; (ii) [(11)C]d-threo-methylphenidate, to label the dopamine transporter; and (iii) 6-[(18)F]fluoro-L-DOPA, to assess the activity of aromatic amino acid decarboxylase and storage of 6-[(18)F]-fluorodopamine in synaptic vesicles. The subjects with Parkinson's disease and the healthy controls underwent positron emission tomography scans at the initial visit and after 4 and 8 years of follow-up. Non-linear multivariate regression analyses with random effects were utilized to model the longitudinal changes in tracer values in the putamen standardized relative to normal controls. We found evidence for possible upregulation of dopamine synthesis and downregulation of dopamine transporter in the more severely affected putamen in the early stage of Parkinson's disease. The standardized 6-[(18)F]fluoro-L-DOPA and [(11)C]d-threo-methylphenidate values tended to approach [(11)C](±)dihydrotetrabenazine values in the putamen in later stages of disease (i.e. for [(11)C](±)dihydrotetrabenazine values <25% of normal), when the rates of decline in the positron emission tomography measurements were similar for all the markers. Our data suggest that compensatory mechanisms decline as Parkinson's disease progresses. This breakdown of compensatory strategies in the putamen could contribute to the progression of motor symptoms in advanced disease.

Age-specific progression of nigrostriatal dysfunction in Parkinson's disease.

OBJECTIVE: To investigate in vivo the impact of age on nigrostriatal dopamine dysfunction in Parkinson's disease (PD). METHODS: PD patients (n = 78) and healthy control subjects (n = 35) underwent longitudinal positron emission tomography assessments using 3 presynaptic dopamine markers: (1) [¹¹C](±)dihydrotetrabenazine (DTBZ), to estimate the density of the vesicular monoamine transporter type 2; (2) [¹¹C]d-threo-methylphenidate, to estimate the density of the plasma membrane dopamine transporter; and (3) 6-[¹8F]-fluoro-L-dopa, to estimate the activity of the enzyme dopa-decarboxylase. RESULTS: The study comprised 438 PD scans and 241 control scans (679 scans in total). At symptom onset, the loss of putamen DTBZ binding was substantially greater in younger compared to older PD patients (p = 0.015). Remarkably, however, the rate of progression of DTBZ binding loss was significantly slower in younger patients (p < 0.05). The estimated presymptomatic phase of the disease spanned more than 2 decades in younger patients, compared to 1 decade in older patients. INTERPRETATION: Our results suggest that, compared to older patients, younger PD patients progress more slowly and are able to endure more damage to the dopaminergic system before the first motor symptoms appear. These observations suggest that younger PD patients have more efficient compensatory mechanisms.

Functional neuroimaging in Parkinson's disease.

INTRODUCTION: Functional neuroimaging techniques have greatly contributed to improving our understanding of Parkinson's disease (PD) neurodegeneration and related compensatory mechanisms. AREAS COVERED: In this paper, the authors analyze the role of functional neuroimaging as a diagnostic tool in PD and review functional neuroimaging studies on PD progression and compensatory adaptations. Through this, the article provides the reader with sensible approaches for the use of functional neuroimaging in the diagnosis of PD. The reader is also provided with knowledge on the time course of nigrostriatal dopamine dysfunction in PD as well as an overview of the potential beneficial and deleterious effects of increased dopamine turnover. Finally, the reader is provided with a critical discussion of the differential effects of levodopa and dopamine agonists on presynaptic dopamine markers and the implications for the interpretation of clinical trials. EXPERT OPINION: Functional neuroimaging probably plays a limited role in the diagnosis of PD. Parkinson's disease pathology leads to an exponential decline in nigrostriatal dopamine function and a compensatory increase in dopamine turnover, which may help delay symptom onset. On the negative side, increased dopamine turnover contributes to the development of treatment-related motor complications. Presynaptic markers of dopamine function are subject to regulatory changes, compromising the direct interpretation of neuroimaging results in trials of neuroprotective therapies for PD.

Dopamine turnover increases in asymptomatic LRRK2 mutations carriers.

Increase in dopamine (DA) turnover was found to occur early in symptomatic Parkinson's disease (PD) and to be functionally related to the dopamine transporter (DAT). The objectives of this study were to examine changes in DA turnover in the asymptomatic PD phase; to compare them with changes in other dopaminergic markers, and to investigate a possible relationship between DAT and DA turnover. Eight subjects from families at increased risk of PD due to LRRK2 mutation were investigated. Positron emission tomography imaging was performed with: ¹8F-fluorodopa to determine the effective DA distribution volume (EDV), the inverse of DA turnover, and the DA uptake rate K(occ), a marker of DA synthesis and storage; ¹¹C-methylphenidate (MP, a DAT marker) and ¹¹C-dihydrotetrabenazine (DTBZ, a VMAT2 marker) to estimate the binding potentials BP(ND_MP) and BP(ND_DTBZ). On average, EDV showed the largest reduction from age-matched control values (42%) followed by BP(ND_MP) (23%) and BP(ND_DTBZ) (17%), whereas K(occ) remained in the normal range for all subjects. No correlation was found between EDV and any other marker. DA turnover was found to be elevated in asymptomatic mutation carriers at increased risk of PD. Such change was determined to be larger than and statistically independent from changes observed with the other markers. These results support a compensatory role of increased DA turnover in presymptomatic disease and indicate that at this stage, in contrast to the symptomatic PD phase, increased turnover is not related to DAT.