Jorge Hernández-Vara

Long-term response to continuous duodenal infusion of levodopa/ carbidopa gel in patients with advanced Parkinson disease: The Barcelona registry

INTRODUCTION Continuous infusion of levodopa/carbidopa intestinal gel (LCIG) is an effective treatment for patients with advanced Parkinson Disease (PD) that cannot be further improved by oral therapy. METHODS We conducted an observational, prospective, and multicenter study to collect, in a large sample of PD treated with LCIG, long-term information about the outcome and safety of the treatment. The assessments were performed before LCIG, 1, 3, 6 months after, and ever since, every 6 months. RESULTS We studied 72 patients with a mean observation time of 22 months and a maximum of 48 months. During follow-up 28 patients discontinued the treatment, especially for lack of efficacy or adverse events related to the drug. We obtained a significant improvement of motor and non-motor fluctuations, mean off time and some non-motor symptoms. A significant increase in the percentage of time with dyskinesias was found in patients having less than 50% of the day with dyskinesias before LCIG. However, patients having already many dyskinesias before LCIG experienced a significant decrease of the troublesome dyskinesias, meaning that outcomes might be different depending on specific clinical characteristics. Adverse effects were in general minor but one case of intestinal perforation and one of abdominal cellulite were observed. CONCLUSIONS We confirmed that LCIG is a very effective treatment option for advanced PD; however considering the findings that dyskinesia can increase and the potential for serious side effects, we suggest the necessity for development of guidelines that better define the profile of responders.

Nonmotor Symptoms in LRRK2 G2019S Associated Parkinson’s Disease

Background Idiopathic Parkinson’s disease (IPD) and LRRK2-associated PD (LRRK2-PD) might be expected to differ clinically since the neuropathological substrate of LRRK2-PD is heterogeneous. The range and severity of extra-nigral nonmotor features associated with LRRK2 mutations is also not well-defined. Objective To evaluate the prevalence and time of onset of nonmotor symptoms (NMS) in LRRK2-PD patients. Methods The presence of hyposmia and of neuropsychiatric, dysautonomic and sleep disturbances was assessed in 33 LRRK2-G2019S-PD patients by standardized questionnaires and validated scales. Thirty-three IPD patients, matched for age, gender, duration of parkinsonism and disease severity and 33 healthy subjects were also evaluated. Results University of Pennsylvania Smell Identification Test (UPSIT) scores in LRRK2-G2019S-PD were higher than those in IPD (23.5±6.8 vs 18.4±6.0; p = 0.002), and hyposmia was less frequent in G2019S carriers than in IPD (39.4% vs 75.8%; p = 0.01). UPSIT scores were significantly higher in females than in males in LRRK2-PD patients (26.9±4.7 vs 19.4±6.8; p<0.01). The frequency of sleep and neuropsychiatric disturbances and of dysautonomic symptoms in LRRK2-G2019S-PD was not significantly different from that in IPD. Hyposmia, depression, constipation and excessive daytime sleepiness, were reported to occur before the onset of classical motor symptoms in more than 40% of LRRK2-PD patients in whom these symptoms were present at the time of examination. Conclusion Neuropsychiatric, dysautonomic and sleep disturbances occur as frequently in patients with LRRK2-G2019S-PD as in IPD but smell loss was less frequent in LRRK2-PD. Like in IPD, disturbances such as hyposmia, depression, constipation and excessive daytime sleepiness may antedate the onset of classical motor symptoms in LRRK2-G2019S-PD.

The Association of Apathy With Central Fatigue Perception in Patients With Parkinson's Disease

This study was designed to evaluate the association of different apathy conceptual domains with central fatigue perception in Parkinsons disease (PD), taking into consideration other nonmotor symptoms. To this end, 90 consecutive PD patients (66.7% men, mean age 61.44 ± 13.2 years) underwent a comprehensive neurological and psychiatric examination, including the Structured Clinical Interview for DSM-IV, Parkinson Fatigue Scale, Lille Apathy Rating Scale, Hamilton Depression Scale, and State-Trait Anxiety Inventory. A linear regression model was applied to analyze the relationship between apathy and its different conceptual domains with fatigue severity. Thirty-seven (41.1%) patients presented fatigue. Its presence was associated with higher apathy total scores and with 2 of the 4 apathy conceptual domains (less intellectual curiosity and action initiation) with no associations in the emotion and self-awareness apathy domains. Patients with fatigue scored higher in depression (p < .001), anxiety trait (p < .001), and anxiety state (p = .006). Regression analysis identified that Lille Apathy Rating Scale total score (p = .008), intellectual curiosity and action initiation apathy subscores (p = .001 and p = .003) were associated with fatigue severity in patients with right predominant motor symptoms. Sex, age, disease duration, clinical stage, motor complications, prior psychiatric disorders, and treatment were not significantly associated with presence of fatigue. The findings suggest that some apathy-related domains are more frequent in fatigued PD and may be related with fatigue severity.

Age at Onset in LRRK2-Associated PD is Modified by SNCA Variants

Mutations in the leucine-rich repeat kinase 2 (LRRK2) and α-synuclein (SNCA) genes are known genetic causes of Parkinsons disease (PD). Recently, a genetic variant in SNCA has been associated with a lower age at onset in idiopathic PD (IPD). We genotyped the SNCA polymorphism rs356219 in 84 LRRK2-associated PD patients carrying the G2019S mutation. We found that a SNCA genetic variant is associated with an earlier age at onset in LRRK2-associated PD. Our results support the notion that SNCA variants can modify the pathogenic effect of LRRK2 mutations as described previously for IPD.

Quantitative evaluation of striatal I-123-FP-CIT uptake in essential tremor and parkinsonism.

Aim: The aim of this study was to quantitatively evaluate the striatal uptake in 3 groups of patients: essential tremor (ET), drug-induced parkinsonism (DIP), and Parkinson disease (PD), using a voxel-based methodology and volumes of interests (VOIs) analysis. Patients and Method: Sixty patients from the Neurology Department Movement Disorders outpatient clinic in a tertiary hospital with I-123-FP-CIT SPECT were selected. After a clinical follow-up period of 2 years, a final clinical diagnosis of DIP was established for 20 patients (first group); 20 patients were diagnosed with ET (second group), and the third group was made up of 20 patients with a qualitatively pathologic SPECT who were diagnosed with PD. Once processed, DIP studies were spatially normalized to Montreal Neurologic Institute space and an average image was computed to create an I-123-FP-CIT SPECT template using statistical parametric mapping (SPM). Then all the I-123-FP-CIT images from all groups (DIP, ET, and PD) were registered to the new template. VOIs were defined in a digital atlas in Montreal Neurologic Institute space (caudate nucleus, putamen, and occipital cortex). Finally, mean counts were extracted from all VOIs and putamen-occipital and caudate-occipital ratios were computed. Analysis of variance tests were performed with all ratios. A SPM study of patterns evaluated the efficacy of the automated technique to determine whether the significant differences among groups corresponded to the same regions that the method purported to evaluate. Results: The analysis of variance test revealed significant differences between DIP and ET as compared with PD, both in the putamen and in the caudate nucleus. There were significant differences between DIP and ET populations only in the putamen but not in the caudate. The SPM found a lower uptake in the PD group in comparison with the ET and DIP groups. Therefore, in the organic parkinsonism cases, the most significant changes in uptake decrease were found in the putamen nuclei when compared with the DIP and the ET cases. No significant changes were observed between the ET and DIP groups. Conclusions: This study provides a fairly simple, reproducible, and useful methodology to be applied in everyday practice to quantify the studies of dopamine transporters using FP-CIT. We present the different ratios for putamen and caudate nucleus for 3 different groups with FP-CIT images. We obtained an optimal discrimination threshold value between the reference population and the pathologic population for the putamen ratio.

Clinical and imaging markers in premotor LRRK2 G2019S mutation carriers.

BACKGROUND Substantia nigra hyperechogenicity (SN+) has been proposed as a risk marker of Parkinsons disease (PD). Asymptomatic LRRK2 mutation carriers (aLRRK2+), at high risk for developing PD, provide an opportunity for the study of preclinical biomarkers. OBJECTIVE To assess SN echogenicity and other echographic features in LRRK2 G2019S carriers and their clinical and imaging correlates. METHODS Transcranial sonography was performed in 26 LRRK2 G2019S PD patients, 50 first-degree relatives, 31 idiopathic PD (IPD) patients and 26 controls. SN echogenicity and other echographic features were assessed in all study subjects. Dopamine transporter imaging (DAT-SPECT) was performed in 29 first-degree relatives. RESULTS 75% of the LRRK2-PD and 87.5% of the IPD showed SN+ (p = 0.087). aLRRK2+ had a higher frequency of SN+ than non carriers (58.3% vs. 25%, p = 0.039) and controls (58.3% vs. 12.5%; p = 0.002) and had a larger area of SN echogenicity than non carriers (p = 0.030) and controls (p < 0.001). The width of the third ventricle was significantly lower in LRRK2-PD than in IPD (1.9 mm [1.38; 2.75] vs. 3.0 mm [2.3; 5.3]; p = 0.003). Four out of 5 (80%) of the aLRRK2+ with an abnormal DAT-SPECT and four of the 5 (80%) of those with REM sleep behaviour disorder (RBD) had SN+. CONCLUSIONS SN+ is very frequent in LRRK2-PD and aLRRK2+. Most aLRRK2 with possible surrogate markers of PD such as abnormal DAT-SPECT or RBD, also had SN+, which supports that this echofeature might be a marker of PD in these asymptomatic population.

Relationship between poor decision-making process and fatigue perception in Parkinson's disease patients.

BACKGROUND Fatigue is a common non-motor symptom in Parkinsons disease patients. The reasons for its perception are not completely understood. One suggested possibility might be that perceived fatigue is related with abnormal interpretation of somatic symptoms. It has been described that somatic markers misinterpretation leads to poor decision-making. We hypothesized that fatigued Parkinsons disease patients would show poorer performance than non-fatigued in a decision-making task. METHODS To test our hypothesis, 89 Parkinsons disease patients were assessed for the presence of fatigue using the Parkinson Fatigue Scale. All patients were also administered scales evaluating psychopathology and neuropsychological tests, including the Iowa Gambling Task. RESULTS 33 (37.1%) patients fulfilled the established criteria for fatigue. In the univariate analysis, fatigued patients showed higher levels of anxiety (state: p = 0.001, trait: p < 0.001), impulsivity (p = 0.051), and depression (p < 0.001) than non-fatigued patients. No statistically significant differences in other neuropsychological test results (Stroop, Trail Making Test, Tower of London) were found between fatigued and non-fatigued patients except for the Iowa Gambling Task, in which fatigued patients showed poorer performance (p = 0.001) after controlling for confounding factors. CONCLUSIONS These results suggest that fatigued Parkinsons disease patients may present abnormal decision-making process, which may reflect abnormal processing of somatic markers when faced with an activity that requires effort.

Reversible hemichorea associated with extracranial carotid artery stenosis

Hemichorea associated with carotid artery occlusive disease is extremely rare. It has been recently suggested that carotid artery stenosis should be considered in the differential diagnosis of chorea, even in the absence of a preceding stroke or transient ischemic attack. Although the pathophysiology of this condition is still under discussion, some reports suggest that impaired cerebral blood flow in the basal ganglia is a key contributing factor. We herein report a case of hemichorea related to severe stenosis of the left internal carotid artery with no basal ganglia lesions on brain MRI. After carotid revascularization, hemichorea gradually subsided and reversible left thalamic and putaminal hypoperfusion were demonstrated by functional neuroimaging. This case report supports the hypothesis about the central role of hemodynamic ischemia in the pathophysiology of hemichorea associated with carotid artery stenosis, and highlights the importance of vascular imaging studies for the early identification of carotid disease in patients with chorea, even in the absence of other clinical signs.

Factores clínicos y psicopatológicos asociados a los trastornos del control de impulsos en la enfermedad de Parkinson

INTRODUCTION Impulse control disorders (ICD) constitute a complication that may arise during the course of Parkinsons disease (PD). Several factors have been linked to the development of these disorders, and their associated severe functional impairment requires specific and multidisciplinary management. The objective of this study was to evaluate the frequency of ICDs and the clinical and psychopathological factors associated with the appearance of these disorders. METHODS Cross-sectional, descriptive, and analytical study of a sample of 115 PD patients evaluated to determine the presence of an ICD. Clinical scales were administered to assess disease severity, personality traits, and presence of psychiatric symptoms at the time of evaluation. RESULTS Of the 115 patients with PD, 27 (23.48%) displayed some form of ICD; hypersexuality, exhibited by 14 (12.2%), and binge eating, present in 12 (10.1%), were the most common types. Clinical factors associated with ICD were treatment with dopamine agonists (OR: 13.39), earlier age at disease onset (OR: 0.92), and higher score on the UPDRS-I subscale; psychopathological factors with a significant association were trait anxiety (OR: 1.05) and impulsivity (OR: 1.13). CONCLUSIONS ICDs are frequent in PD, and treatment with dopamine agonists is the most important risk factor for these disorders. High impulsivity and anxiety levels at time of evaluation, and younger age at disease onset, were also linked to increased risk. However, presence of these personality traits prior to evaluation did not increase risk of ICD.

Does reduced [123I]-FP-CIT binding in Huntington's disease suggest pre-synaptic dopaminergic involvement?

OBJECTIVE To evaluate the usefulness of SPECT in assessing damage to the pre-synaptic dopaminergic system in Huntingtons disease (HD) using [(123)I]-FP-CIT (DaTSCAN), a selective radioligand with regulatory approval as the diagnostic test for investigating functional dopaminergic neuron loss in the striatum in Parkinsons disease. METHODS We studied twelve symptomatic HD patients using DaTSCAN/SPECT imaging. [(123)I]-FP-CIT caudate and putamen uptake levels were qualitatively and semi-quantitatively analyzed to assess pre-synaptic damage in the striatal dopamine system. Possible correlations were analyzed between HD severity on the Unified Huntingtons Disease Rating Scale (UHDRS), duration of clinical symptoms, and [(123)I]-FP-CIT/SPECT striatal uptake. RESULTS DaTSCAN/SPECT qualitative analysis showed reduced striatal uptake in eight patients. Semi-quantitative analysis revealed a significant reduction in four. Of these four, uptake reduction was at putamen level in all, and also at caudate level in one. Although we observed no linear correlation between HD severity and reduced striatal [(123)I]-FP-CIT uptake, the patients with the worst UHDRS scores had more severe reductions in radioligand uptake. CONCLUSION This is the first study to use in vivo [(123)I]-FP-CIT/SPECT imaging to confirm prior descriptions using PET of a pre-synaptic dopaminergic system defect in HD.