Management of advanced Parkinson's disease in Israel: Clinicians viewpoint and action items.

Parkinson's disease (PD) is taking a staggering toll on healthcare systems worldwide, with the bulk of the expenditures invested in the late stages of the disease. Considering the rising life expectancy and the increasing prevalence of PD across the globe, a clear understanding of the early signs and treatment options available for advanced PD (APD), will facilitate tailoring management programs and support services. This task is complicated by the lack of both global consensus in defining APD and standardized care guidelines. This perspective prepared by a panel of movement disorder specialists, proposes to extend and optimize currently accepted PD coding to better reflect the diverse disease manifestations, with emphasis on non-motor features. The panel seeks to promote timely diagnosis by adjustment of evaluation tools for use by community neurologists and suggests modification of eligibility criteria for advanced therapy. Moreover, it advocates multidisciplinary assessments of APD patients to drive personalized, patient-centered and holistic management. Overall, earlier and more targeted intervention is expected to markedly improve patient quality of life.

Identification of an early-stage Parkinson's disease neuromarker using event-related potentials, brain network analytics and machine-learning.

OBJECTIVE: The purpose of this study is to explore the possibility of developing a biomarker that can discriminate early-stage Parkinson's disease from healthy brain function using electroencephalography (EEG) event-related potentials (ERPs) in combination with Brain Network Analytics (BNA) technology and machine learning (ML) algorithms. BACKGROUND: Currently, diagnosis of PD depends mainly on motor signs and symptoms. However, there is need for biomarkers that detect PD at an earlier stage to allow intervention and monitoring of potential disease-modifying therapies. Cognitive impairment may appear before motor symptoms, and it tends to worsen with disease progression. While ERPs obtained during cognitive tasks performance represent processing stages of cognitive brain functions, they have not yet been established as sensitive or specific markers for early-stage PD. METHODS: Nineteen PD patients (disease duration of ≤2 years) and 30 healthy controls (HC) underwent EEG recording while performing visual Go/No-Go and auditory Oddball cognitive tasks. ERPs were analyzed by the BNA technology, and a ML algorithm identified a combination of features that distinguish early PD from HC. We used a logistic regression classifier with a 10-fold cross-validation. RESULTS: The ML algorithm identified a neuromarker comprising 15 BNA features that discriminated early PD patients from HC. The area-under-the-curve of the receiver-operating characteristic curve was 0.79. Sensitivity and specificity were 0.74 and 0.73, respectively. The five most important features could be classified into three cognitive functions: early sensory processing (P50 amplitude, N100 latency), filtering of information (P200 amplitude and topographic similarity), and response-locked activity (P-200 topographic similarity preceding the motor response in the visual Go/No-Go task). CONCLUSIONS: This pilot study found that BNA can identify patients with early PD using an advanced analysis of ERPs. These results need to be validated in a larger PD patient sample and assessed for people with premotor phase of PD.

Smartphone Based Timed Up and Go Test Can Identify Postural Instability in Parkinson's Disease.

BACKGROUND: There is a need for standardized and objective methods to measure postural instability (PI) and gait dysfunction in Parkinson's disease (PD) patients. Recent technological advances in wearable devices, including standard smartphones, may provide such measurements. OBJECTIVES: To test the feasibility of smartphones to detect PI during the Timed Up and Go (TUG) test. METHODS: Ambulatory PD patients, divided by item 30 (postural stability) of the motor Unified Parkinson's Disease Rating Scale (UPDRS) to those with a normal (score = 0, PD-NPT) and an abnormal (score ≥ 1, PD-APT) test and a group of healthy controls (HC) performed a 10-meter TUG while motion sensor data was recorded from a smartphone attached to their sternum using the EncephaLog application. RESULTS: In this observational study, 44 PD patients (21 PD-NPT and 23 PD-APT) and 22 HC similar in age and gender distribution were assessed. PD-APT differed significantly in all gait parameters when compared to PD-NPT and HC. Significant difference between PD-NPT and HC included only turning time (P < 0.006) and step-to-step correlation (P < 0.05). CONCLUSIONS: While high correlations were found between EncephaLog gait parameters and axial UPDRS items, the pull test was least correlated with EncephaLog measures. Motion sensor data from a smartphone can detect differences in gait and balance measures between PD with and without PI and HC.

Catastrophizing mediates the relationship between non-motor symptoms and quality of life in Parkinson's disease.

BACKGROUND: The non-motor symptoms of Parkinson's disease (PD), pain, depression, anxiety and sleep disturbances are highly prevalent in persons with PD and have a profound impact on their quality of life (QOL). Catastrophizing is a negative coping style known to influence individuals' ability to cope with their medical symptoms and contributes to negative health-related outcomes, yet, it has not been studied in persons with PD. OBJECTIVE: The objectives of this study were to measure catastrophizing in PD and explore its role as a mediator of the relationship between non-motor symptoms and QOL. METHODS: One-hundred and three individuals diagnosed with PD completed questionnaires regarding pain catastrophizing, QOL and non-motor symptoms: pain, depression, anxiety and sleep disturbances. RESULTS: More than half of the sample exhibited high levels of pain, anxiety and sleep disturbances. Catastrophizing was significantly correlated with QOL and with all of the non-motor symptoms. Catastrophizing mediated the relationship between all of non-motor symptoms and QOL as well as the relationship between age and QOL. CONCLUSIONS: Negative psychologic coping, specifically catastrophizing, has an important role in determining how destructive non-motor symptoms can be on the QOL of persons with PD. This is the first study to measure catastrophizing in this population and demonstrate its negative impact on QOL. Our findings emphasize the need to identify persons at risk for poor QOL and referrer them to appropriate psychological care. Evidence based interventions that target catastrophizing should be tested for their efficacy in persons with PD.

Decreasing battery life in subthalamic deep brain stimulation for Parkinson's disease with repeated replacements: Just a matter of energy delivered?

BACKGROUND: People with Parkinson's disease (PD) treated with deep brain stimulation (DBS) with non-rechargeable implantable pulse generators (IPGs) require elective IPG replacement operations involving surgical and anesthesiologic risk. Life expectancy and the number of replacements per patient with DBS are increasing. OBJECTIVE: To determine whether IPG longevity is influenced by stimulation parameters alone or whether there is an independent effect of the number of battery replacements and IPG model. METHODS: PD patients treated with bilateral subthalamic DBS were included if there was at least one IPG replacement due to battery end of life. Fifty-five patients had one or two IPG replacements and seven had three or four replacements, (80 Kinetra® and 23 Activa-PC®). We calculated longevity corrected for total electrical energy delivered (TEED) and tested for the effect of IPG model and number of previous battery replacements on this measure. RESULTS: TEED-corrected IPG longevity for the 1st implanted IPG was 51.3 months for Kinetra® and 35.6 months for Activa-PC®, which dropped by 5.9 months and 2.8 months, respectively with each subsequent IPG replacement (p < 10-6 for IPG model and p < 10-3 for IPG number). CONCLUSIONS: Activa-PC® has shorter battery longevity than the older Kinetra®, battery longevity reduces with repeated IPG replacements and these findings are independent of TEED. Battery longevity should be considered both in clinical decisions and in the design of new DBS systems. Clinicians need accessible, reliable and user-friendly tools to provide online estimated battery consumption and end of life. Furthermore, this study supports the consideration of using rechargeable IPGs in PD.

Clinical Problem Solving: A Tobacco Merchant Who Can't Spit.

BACKGROUND: A 47 year old man presented with a combination of dry mouth and lightheadedness while standing. His medical background was unremarkable except for cigarette smoking and hyperlipidemia. Sjögren's syndrome was ruled out, and he was referred for evaluation of orthostatic hypotension, which by then included syncopal episodes and injuries. Additional symptoms included dry eyes, constipation, reduced sweating, and erectile dysfunction. After excluding medications and structural cardiac abnormalities as causes of orthostatic hypotension, a clinical autonomic evaluation was performed. The pattern of beat-to-beat blood pressure associated with performance of the Valsalva maneuver, and a low plasma norepinephrine level that did not increase in response to standing, established that the orthostatic hypotension was neurogenic. Treatment with an alpha-adrenoceptor agonist and fludrocortisone yielded partial improvement. After systemic diseases involving autonomic failure were excluded, cardiac sympathetic neuroimaging was performed by 123I-metaliodobenzylguanidine (MIBG) scanning. The normal uptake seen in the heart indicated intact post ganglionic sympathetic innervation. There were no signs of central neurodegeneration or peripheral neuropathy. Because of symptoms and signs of both parasympathetic and sympathetic failure without denervation, an autonomic ganglionopathy was considered. A high titer of antibody to the neuronal nicotinic receptor, which mediates ganglionic neurotransmission, was obtained. The diagnosis of autoimmune autonomic ganglionopathy (AAG) was made, and the management strategy shifted to first lowering the antibody burden by plasma exchanges and then instituting chronic anti-autoimmune treatment with rituximab and a low dose of cortiosteroid. The patient showed remarkable improvement.

The impact of early versus late levodopa administration.

Long-term levodopa therapy in patients with Parkinson's disease (PD) is associated with motor complications including motor fluctuations (MF) and levodopa-induced dyskinesias (LID). The time to appearance of MF and LID is apparently related to both the timing and the duration of levodopa therapy, but is highly variable. We performed a retrospective analysis of all levodopa-treated PD patients to explore the effect of time from PD onset to levodopa initiation on time to MF or LID. We used a Cox multivariate regression model after stratifying patients into four quartiles, according to the time to levodopa initiation. Data from 170 PD patients (117 males, age at onset: 65.1 ± 11.6 years, time to levodopa treatment: 23.8 ± 28.4 months) was included in the analysis. Early levodopa administration was associated with a shorter time from diagnosis to both MF (p < 0.001) and LID (p = 0.001). The hazard ratio to develop MF and LID from the time of PD diagnosis was 2.48 (p < 0.001) and 2.71 (p = 0.002), respectively. In our population, we found that delaying levodopa administration was associated with a longer time to the appearance of motor complications after diagnosis. While disease duration is the most important determinant of the onset of motor complications, delaying levodopa could prolong the 'complication-free' period.

Clinical Experience With Deferiprone Treatment for Friedreich Ataxia.

Friedreich ataxia is an inherited disorder characterized by degeneration of the peripheral and central nervous system and hypertrophic cardiomyopathy. Homozygous mutations in the frataxine (FXN) gene reduce expression of frataxin and cause accumulation of iron in the mitochondria. Deferiprone, an oral iron chelator, has been shown effective in cell and animal models of Friedreich ataxia. The results of a 6-month randomized, double blind placebo-controlled study suggested that deferiprone 20 mg/kg/day may reduce disease progression. The authors present their experience of 5 Friedreich ataxia patients treated with deferiprone (20 mg/kg/day), in addition to idebenone treatment, followed over a period of 10-24 months, under off-label authorization. The patients were monitored for laboratory parameters, cardiac assessment, neurological evaluations, and quality of life. The authors conclude that combined therapy of a low dose of deferiprone with idebenone is relatively safe, might improve neurological function, and seems to improve heart hypertrophy, warranting further studies.

The melanocortin 1 receptor (Mc1r) variants do not account for the co-occurrence of Parkinson's disease and malignant melanoma.

Parkinson's disease (PD) is characterized by loss of melanin-positive dopaminergic neurons in the substantia nigra. Malignant melanoma (MM), a melanocyte-derived neoplasm, occurs with higher than expected frequency among PD patients. Red-haired individuals exhibit a threefold risk for developing MM than dark-haired people; PD risk also increases with lighter hair color. One plausible explanation for the associations between MM, hair color, and PD is the melanocortin-1 receptor (MC1R) gene that plays a key role in hair and skin pigmentation as well as in MM predisposition. We hypothesized that specific MC1R variants may predispose to both MM and PD. Genotyping of the MC1R gene was performed for 16 PD patients with MM (PD+ MM+) and for three sets of age, sex, and ethnically matched controls, including 36 patients with PD (PD+ MM-), 37 with MM (PD- MM+) and 37 with neither diagnosis (PD- MM-). No association was found between MC1R variants and the co-occurrence of PD and MM. The risk for MM was higher in carriers of two MC1R variants versus with no MC1R variant (odds ratio (OR)=5.0, 95% confidence interval (CI) 1.7-14.4, p=0.003). The risk for PD in carriers of two MC1R variants was markedly lower (OR=0.213, 95% CI 0.063-0.725) compared with individuals with no MC1R variant (p=0.013). In this study, MC1R variants were not associated with both MM and PD. Further studies in larger cohorts are necessary to confirm these preliminary results.

The LRRK2 G2019S mutation status does not affect the outcome of subthalamic stimulation in patients with Parkinson's disease.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established therapy for advanced Parkinson's disease (PD). The most common genetic mutation associated with PD identified to date is the G2019S mutation of the LRRK2 gene, which is highly prevalent in the Ashkenazi Jewish population. The effect of STN-DBS surgery in patients carrying this mutation has not been systematically studied. We therefore performed a case-control study to evaluate the impact of the G2019S mutation status on the outcomes of bilateral STN-DBS. METHODS: The study sample included 39 Jewish PD patients with bilateral STN-DBS. Thirteen patients (5 females) were G2019S mutation heterozygous. The control group consisted of 26 PD patients with bilateral STN-DBS, negative for the mutation, matched (2:1) for gender, age at PD onset, and disease duration at surgery. Clinical data including the Unified PD Rating Scale scores (UPDRS), levodopa equivalent daily dose (LEDD), and clinical global impression of change (CGIC) concerning both motor and neuropsychiatric outcome- were available at 3 time points (preoperative baseline, 6-12 months and 3 years postoperatively). RESULTS: Implementing a linear mixed model, a significant improvement (p < 0.05) was found for the whole group concerning reduction in motor UPRDS (off state) and LEDD pre- vs. postoperatively, as expected. No difference in clinical outcome was found between carriers and matched non-carriers at baseline or at postoperative follow-up (up to 3 years). CONCLUSIONS: In our study, STN-DBS outcomes were not influenced by the LRRK2 G2019S mutation, and thus knowledge of carrier status may not be relevant to the considerations of patient selection for surgery.