Chronic adaptive versus conventional DBS response patterns in Parkinson’s disease: A pilot randomized crossover trial

ABSTRACTObjectiveThe purpose of this study was to assess the effect of levodopa‐carbidopa intestinal gel (carbidopa‐levodopa enteral suspension) in advanced Parkinson's disease patients with troublesome dyskinesia.MethodsPost hoc analyses of patient data from a 12‐week, randomized, double‐blind study and a 54‐week open‐label study were performed. Efficacy was assessed in the subgroup of patients defined by ≥1 hour of “on” time with troublesome dyskinesia at baseline as recorded in Parkinson's disease symptom diaries (double blind: n = 11 levodopa‐carbidopa intestinal gel, n = 12 oral levodopa‐carbidopa; open label: n = 144 levodopa‐carbidopa intestinal gel). The changes in “off” time, “on” time with and without troublesome dyskinesia, and the overall safety and tolerability of levodopa‐carbidopa intestinal gel were analyzed.ResultsAlthough not significantly different from oral levodopa treatment (P > .05) in the double‐blind study, levodopa‐carbidopa intestinal gel treatment resulted in a reduction from baseline in “on” time with troublesome dyskinesia (mean [standard deviation] hours: baseline = 3.1 [1.7], change from baseline to final = −1.8 [1.8], P = .014), increase in “on” time without troublesome dyskinesia (baseline = 7.4 [2.2], change = 4.4 [3.6], P = .004), and decrease in “off” time (baseline = 5.5 [1.3], change = −2.7 [2.8], P = .015). Similar trends were found in the open‐label study. An increase in levodopa‐carbidopa intestinal gel dose was not significantly correlated with increased “on” time with troublesome dyskinesia in either study (double blind: r = −.073, P = .842; open label: r = −0.001, P = .992). Adverse events were usually mild to moderate in severity and related to the gastrointestinal procedure.ConclusionOur exploratory analyses suggest that optimizing levodopa delivery with levodopa‐carbidopa intestinal gel may reduce troublesome dyskinesia in advanced Parkinson's disease. © 2016 International Parkinson and Movement Disorder Society

Background: At least 14% of Parkinson disease (PD) patients develop impulse control disorders (ICDs). The pathophysiology behind these behaviors and the impact of deep brain stimulation in a real-life setting remain unclear. Objectives: We prospectively examined the impact of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on ICDs in PD patients, as well as the relationship between impaired sensorimotor gaiting and impulsivity. Methods: Patients undergoing bilateral STN-DBS were assessed for ICDs preoperatively and 1-year postoperatively using a validated questionnaire (QUIP-RS). A subset of patients completed the Balloon Analogue Risk Task (BART) and auditory prepulse inhibition (PPI) testing. Results: Analysis revealed 12 patients had an improvement in score assessing ICDs (‘good responders'; p = 0.006) while 4 had a worse or stable score (‘poor responders'; p > 0.05). Good responders further exemplified a significant decrease in hypersexual behavior (p = 0.005) and binge eating (p = 0.01). Impaired PPI responses also significantly correlated with impulsivity in BART (r = -0.72, p = 0.044). Discussion: Following bilateral STN-DBS, 75% of our cohort had a reduction in ICDs, thus suggesting deep brain stimulation effectively manages ICDs in PD. The role of impaired PPI in predisposition to ICDs in PD warrants further investigation.

Levodopa is the most efficacious treatment for Parkinson's disease (PD). Long-term treatment with levodopa is limited due to dyskinesia. Dyskinesia in PD can be socially and functionally disabling. Extended-release amantadine (amantadine ER) is the first approved medication for the treatment of dyskinesia. When it is given at bedtime, it reaches plasma concentration approximately twice the level achieved by amantadine immediate release. Amantadine ER reduces the severity and duration of dyskinesia during the day, reduces OFF time and increases ON time without troublesome dyskinesia. The most common side effects are hallucination, dizziness, orthostatic hypotension and pedal edema. This review discusses the safety and efficacy of amantadine ER in dyskinesia in PD patients.

While subthalamic nucleus deep brain stimulation (STN-DBS) and levodopa improve motor symptoms in Parkinson disease (PD) to a similar magnitude, their combined effect remains unclear. We sought to evaluate whether STN-DBS and levodopa yield differential effects on motor outcomes, dyskinesia, and activities of daily living (ADL) when combined compared to when administered alone. We conducted a meta-analysis of all studies reporting motor, dyskinesia, and ADL outcomes after bilateral STN-DBS in PD with presurgical Unified Parkinson's Disease Rating Scale (UPDRS-III) in Medication-OFF and Medication-ON states and postsurgical assessments in four conditions: Stimulation-ON/Medication-ON, Stimulation-ON/Medication-OFF, Stimulation-OFF/Medication-ON, and Stimulation-OFF/Medication-OFF. Dyskinesia duration (UPDRS item 32) and ADL (UPDRS-II) were compared between high and low postsurgical levodopa equivalent daily dose (LEDD) reduction. Random-effects meta-analyses using generic-inverse variance were conducted. Confidence in outcomes effect sizes was assessed. Twelve studies were included (n = 401 patients). Stimulation-ON/Medication-ON was associated with an UPDRS-III improvement of - 35.7 points [95% confidence interval, - 40.4, - 31.0] compared with Stimulation-OFF/Medication-OFF, - 11.2 points [- 14.0, - 8.4] compared with Stimulation-OFF/Medication-ON, and - 9.5 points [- 11.0, - 8.0] compared to Stimulation-ON/Medication-OFF within 5years. The difference was maintained beyond 5years by - 28.6 [- 32.8, - 24.4], - 8.1 [- 10.2, - 5.9], and - 8.0 [- 10.3, - 5.6], respectively. No difference was observed between Stimulation-ON/Medication-OFF and Stimulation-OFF/Medication-ON within and beyond 5years. Dyskinesia duration and ADL outcomes were similar in high vs. low postsurgical LEDD reduction. Subthalamic nucleus deep brain stimulation and levodopa independently lessened motor severity in PD to a similar magnitude, but their combined effect was greater than either treatment alone, suggesting therapeutic synergism.

Background:Deep brain stimulation (DBS) is an accepted modality of treatment in patients with Parkinson's disease (PD). Although DBS was approved in advanced PD, it is being done in early PD as well. It was mainly developed to help the patients of PD to overcome the adverse motor effects associated with treatment and treatment failure.Objective:The objective is to study the efficacy of subthalamic nucleus (STN)-DBS procedure in patients with PD.Materials and Methods:This was a prospective, single-center, follow-up observational study using a direct, structured interview of 40 selected PD patients. Preoperative assessment using Unified PD Rating Scale-III (UPDRS-III), Montreal Cognitive Assessment (MOCA), and Parkinson's Disease Questionnaire-39 were done. All the patients underwent DBS. Postoperatively, similar assessment was done during follow-up period of 6 months. The results were analyzed using Student's t-test.Results:The total score of UPDRS-III was reduced by 35% after STN-DBS intervention which was statistically significant (P < 0.05). STN-DBS intervention was successful in significantly reducing all UPDRS-III subscores but failed to reduce the scores in case of postural stability. MOCA scores of the patients were not found to be affected by STN-DBS intervention (P = 0.1466). Similar findings were also observed for MOCA subscores, but there was significant improvement of verbal fluency in all patients. Quality of life(QoL) improved significantly in all patients after STN-DBS intervention in all areas. Lower baseline UPDRS-III scores were found to enhance the QoL both in “off” and “on” state. However, prolonged disease duration and older age at PD onset were found to be hampering factors in the improvement of QoL.Conclusions:STN-DBS is a safe procedure and can be performed in all patients of PD who develop disabling motor fluctuations to improve their QoL irrespective early or advanced disease.

Amantadine improves gait in PD patients with STN stimulation

Inflammation-associated peripheral blood cells and serum lipid levels are associated with Parkinson's disease.

In his famous monograph “An Essay in Shaking Palsy,” James Parkinson provided astute descriptions of impaired sleep in his case series of patients with Parkinson's disease (PD) two centuries ago. It is only three decades ago that sleep dysfunction started to attract attention of medical and scientific communities involved in the clinical care and research of PD. Tremendous advancements in our understanding of impaired sleep and alertness associated with PD have developed since then. Sleep problems are one of the major, challenging issues in patients with PD, affecting a significant number of patients. The etiology of sleep problems is multifactorial, including disease-related nocturnal symptoms, medication adverse effects, and primary sleep disorders including restless legs syndrome, rapid eye movement sleep behavior disorder, and sleep apnea syndrome. These causes of impaired sleep-wake cycles in the PD population often coexist or even overlap, rendering the management of sleep problems in PD patients difficult. Also, excessive daytime sleepiness is observed in a significant number of patients. In PD patients, therefore, appropriate assessment of disease-related nocturnal disturbances and primary sleep disorders is imperative. This special issue addresses unmet need for understanding PD-related sleep problems. PD sleep scale 2 (PDSS-2) is a recently developed tool for screening and managing sleep disturbance in PD patients, consisting of 15 items which are clinically relevant to nocturnal problems including nonmotor and motor problems in PD [1]. The original PDSS-2 (German and English) has been translated into several languages, including Japanese [2] and Italian [3]. The PDSS-2 has been used to observe treatment response. In a double-blind, placebo-controlled trial, including 287 PD patients, mean PDSS-2 total score decreased by −5.9 points with rotigotine and by −1.9 points with placebo [4]. In this special issue, K. Horvath et al. estimated the threshold representing minimal clinically important difference of the PDSS-2 total score: the study results showed −3.44 points for detecting improvement or the threshold of 2.07 points for observing worsening. This finding is important when planning studies using the PDSS-2 as outcome measures. Full-night polysomnography (PSG) is a gold standard for diagnosing sleep apnea syndrome; however, applying PSG is often difficult in patients with PD, who have severe parkinsonism or psychiatric comorbidity. P. Gros et al. evaluated the usefulness of unattended portable monitoring (PM) for diagnosis of obstructive sleep apnea (OSA) in patients with PD. Although discrepancy between portable monitoring and PSG was greater in PD patients with more motor dysfunction, the authors confirmed the usefulness of portable monitoring in diagnosing moderate to severe OSA in PD patients. These results provide the rationale for the use of portable sleep monitoring in PD and are very relevant for circumstances where a complete PSG in a sleep laboratory is not available and/or feasible. M. Kaminska et al. performed a review on the relationship between OSA and PD. Although the clinical significance of OSA in PD has been controversial [5, 6], the authors suggest the possibility that treatment of OSA could delay cognitive decline or motor dysfunction in patients with PD. This area of research is of high significance as it is important to assess the prevalence of OSA and the impact of its treatment in the PD population. D. Martinez-Ramirez et al. correlated PSG findings and sleep disorders with clinical characteristics in PD patients and found that sleep disorders and sleep architecture were poorly predictable by clinical characteristic of PD patients. This comprehensive study demonstrates the complexity of sleep dysfunction associated with PD and its complex associations with metrics of PD. In a fine and thoughtful study K. Suzuki et al. provided an interesting insight into the complex relationship between PD and restless legs syndrome (RLS) and leg motor restlessness (LMR). A significant relationship between RLS and PD is suggested by observing a favorable response to dopaminergic treatment in both disorders. However, RLS prevalence in PD patients varies according to different studies. Recently, LMR, characterized by an urge to move the legs that does not fulfill the diagnostic criteria for RLS, has been reported more frequently in patients untreated with PD than healthy controls. This review article may provide a new insight into the relationship between RLS, LMR, and PD. Finally, the complex and still only partially understood interaction of impulse control disorders in PD and sleep is discussed in a review from the clinic of one of the guest editors. In summary, sleep problems are common but underreported by PD patients and underdiagnosed by health professionals. Further understanding of mechanisms that underlie impaired sleep and alertness in PD will allow for development of much needed treatment approaches for this nonmotor manifestation of PD. Koichi Hirata Birgit Hogl Eng King Tan Aleksandar Videnovic

Parkinson's disease, ischemic stroke, dementia, and cranial computed tomography: Preliminary study

Objective: To determine if the non-motor sections of the Movement Disorder Society's (MDS) version of the Unified Parkinson's Disease Rating Scale (UPDRS) could supplement the original UPDRS as a patient completed assessment of changes in non-motor symptoms in Parkinson's disease (PD) patients after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS). Methods: Thirty PD patients who underwent bilateral STN DBS were assessed using the total UPDRS and the non-motor sections of the MDS-UPDRS prior to surgery and one year following surgery. This study focuses on non-motor symptoms as assessed by Part I of the UPDRS and Part 1A and 1B of the MDS-UPDRS. Results: One year following surgery, no individual non-motor symptoms or the total mentation score of the UPDRS were significantly changed. In comparison, the MDS-UPDRS showed significant improvements in sleep and urinary problems and a trend towards improvement in anxiety, constipation, daytime sleepiness, fatigue and pain. Conclusions: This study provides evidence that the MDS-UPDRS non-motor sections, when completed by the patients, can supplement the original version of the UPDRS as an effective method of measuring changes in non-motor symptoms after DBS. It also reinforces the benefits of bilateral STN DBS on non-motor symptoms of PD.

Effect of STN/GPi DBS on swallowing function in Parkinson's disease as assessed by Video fluoroscopy: A retrospective study

Parkinson's disease (PD) is a neurodegenerative pathology characterized by the degeneration of midbrain dopamine neurons, whose development and maintenance in brain is related to the transcription factor NR4A2 (also called Nurr1). Notably, NR4A2 is a neuroprotective agent with anti-inflammatory role in microglia and astrocytes. Furthermore, mutations in NR4A2 gene are associated to the familial form of PD, and its gene expression level is down-regulated in blood obtained from PD patients. NR4A2 belongs to the NR4A subfamily consisting of three members: NR4A1, NR4A2, and NR4A3. The NR4A subfamily shares high degree of homology in their molecular structure and cooperates in a spectrum of functions ranging from central nervous system to immune control during physiological and pathological conditions. Considering the close functional link between the member of NR4A subfamily, we performed a gene expression analysis of NR4A1, NR4A2, and NR4A3 in peripheral blood obtained from PD patients and healthy controls (HC). Then, in order to evaluate possible involvement of the NR4A subfamily in other neurodegenerative processes, we carried out the same analysis on blood obtained from Alzheimer's disease (AD) patients. A correlation between clinical features and gene expression was also evaluated. We found a marked down-regulated gene expression of the NR4A subfamily obtained from PD patients, but only a NR4A1 decrease in AD patients compared to HC. This study reports that the entire NR4A subfamily and not only NR4A2 could be systemically involved in PD suggesting that the study of these factors could be a promising approach to develop PD therapy.

Changes in Speech Characters of Patients With Parkinson’s Disease After Bilateral Subthalamic Nucleus Stimulation

Growing and clinical evidence supports the conclusion that Parkinson’s Disease (PD) is a complex multisystem disorder not exclusively affecting the dopaminergic circuits. In fact, the dopaminergic neuronal loss does not cover all the clinical aspects of PD. Therefore, different non-dopaminergic neurotransmitter systems have been invoked as playing a role in the PD clinical picture. Principally, the inefficiency of serotonergic circuitry has been demonstrated in PD animal models, as well as in post-mortem and in vivo human studies. In the recent article published in Brain, Zahi Qamhawi and colleagues interrogated 123I-FP-CIT single-photon emission computed tomography documenting raphe serotonergic dysfunction in a large group of early PD patients compared to a subset of possible PD patients without evidence of dopaminergic deficit (SWEDD) and a population of healthy controls (1). This paper combined an accurate clinical evaluation with a sophisticated neuroimaging protocol and documented in PD patients a mean raphe serotonin (5-HT) transporter availability significantly lower than both SWEDD patients and controls. These findings, achieved in a large cohort of PD patients, enforced previous autoptic examinations documenting serotonergic neurons loss due to Lewy body pathology in the raphe nuclei of PD patients (2). Accordingly, neuroimaging studies have shown the progressive 5-HT transporter availability reduction in the raphe nuclei as PD pathology progresses (3–5). It is well accepted that concentration of 5-HT and its metabolite 5-hydroxyindolacetic acid (5-HIAA) in CSF reflects the serotonergic metabolism and turnover in the CNS (6, 7). We performed a case-control study investigating CSF levels of 5-HT and 5-HIAA in a cohort of PD patients, after a 3-day dopaminergic therapy withdrawal and in absence of serotonergic agents (8). We demonstrated the significant reduction of CSF 5-HT and 5-HIAA concentrations in PD patients compared to controls. We also found the significant reduction of CSF 5-HT and 5-HIAA in the PD population with respect to Alzheimer’s Disease patients (8), thus highlighting that the impairment of serotonergic system could represent a specific effect of synuclein-mediated neurodegeneration (8). As a matter of fact, novel experimental studies in alpha-synuclein (α-syn) mouse model of PD showed the impairment of serotonergic system owing to the intracellular accumulation of α-syn in serotonergic neurons coupled with the reduction of 5-HT levels in lower brainstem (9). Based on the clinical presentation, Qamhawi and collegues divided PD patients into two subgroups corresponding to patients with and without resting tremor. Remarkably, patients with tremor had lower mean raphe 5-HT transporter availability than patients unaffected by tremor. Since tremor amplitude, constancy, and severity negatively correlated with raphe 5-HT transporter availability in the whole PD cohort, authors suggested that the serotonergic system inefficiency could be responsible for parkinsonian tremor. This finding was consistent with previous studies detecting an association between 5-HT receptor availability in the raphe nuclei and severity of parkinsonian tremor (10). However, in our CSF study, we found no differences in CSF 5-HT and 5-HIAA levels between tremor dominant and non-tremor dominant patients. This discrepancy could be ascribed to the fact that Qamhawi and collegues studied de novo early PD patients, whereas we investigated patients with higher Hoehn and Yahr stage and greater motor disability at the Unified PD Rating Scale-motor section. It could be of interest to evaluate in follow-up studies how the serotonergic transmission damage may influence PD motor symptoms along with the progression of the disease. Concurrently, the reliability of the proposed difference in raphe 5-HT transporter availability found by Qamhawi and coworkers in early PD patients should be also analyzed in more advanced PD patients. Remarkably, Qamhawi and coauthors documented that raphe 5-HT transporter availability did not correlate with PD non-motor symptoms, such as fatigue, depression, and sleep-wake cycle disturbances. In agreement with this finding, we did not identify mutual interplays linking CSF 5-HT and 5-HIAA concentrations to depression, apathy, and sleep disturbances. Although our report sustained Qamhawi and coworkers results, literature proposes controversial data regarding the involvement of serotonergic pathways breakage in the pathophysiology of PD non-motor symptoms (11), thus requiring further investigations. All considering, we suppose that the reduced 5-HT transporter availability, as shown by Qamhawi and collegues, and the 5-HT synthesis, metabolism, and turnover impairment, resulting in reduced CSF levels of 5-HT and 5-HIAA (8) may both contribute to the serotonergic transmission dysfunction evident in PD. Hence, serotonin circuitry inefficiency could represent the fitting partner of the dopaminergic deficit in PD.

Benefits of intensive speech treatment have been documented for a range of speech signs in English speakers with Parkinson's Disease (PD). However, the answer to a critical question that whether the same treatment benefits speech variables including intelligibility in Mandarin speakers is still unclear. In order to develop a targeted speech treatment for Mandarin speakers with PD, we reviewed the efficacy of intensive speech treatment to improve vocal loudness and functional communication and discuss possible explanations for efficacy on Mandarin speakers with PD. Literatures about intensive speech treatment for Mandarin speakers with PD were retrieved from PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), Wanfang and Weipu Database for Chinese Technical Periodicals (VIP) Database. Search strategy was (voice therapy OR speech therapy OR voice treatment OR speech treatment OR voice training OR speech training OR voice rehabilitation OR speech rehabilitation OR Lee Silverman voice treatment OR intensive speech treatment) and (Parkinson's disease) and (Mandarin speakers OR Chinese OR Chinese people). Five randomized controlled trials were selected and possible explanations for efficacy on individuals with PD are discussed. Further research directions are suggested. The existing evidence from treatment efficacy studies of intensive speech treatment provides support for improving vocal loudness, speech intelligibility, pitch and rate in Mandarin speakers with PD. Our future research will continue to work to conduct a large sample multicenter randomized controlled trial to provide high quality evidence and understand the basic mechanisms accompanying treatment-related change.