Journal of Parkinson's Disease - Volume 10, issue 3

Authors: Barker, Roger A. | Björklund, Anders | Gash, Don M. | Whone, Alan | Van Laar, Amber | Kordower, Jeffrey H. | Bankiewicz, Krystof | Kieburtz, Karl | Saarma, Mart | Booms, Sigrid | Huttunen, Henri J. | Kells, Adrian P. | Fiandaca, Massimo S. | Stoessl, A. Jon | Eidelberg, David | Federoff, Howard | Voutilainen, Merja H. | Dexter, David T. | Eberling, Jamie | Brundin, Patrik | Isaacs, Lyndsey | Mursaleen, Leah | Bresolin, Eros | Carroll, Camille | Coles, Alasdair | Fiske, Brian | Matthews, Helen | Lungu, Codrin | Wyse, Richard K. | Stott, Simon | Lang, Anthony E.

Article Type: Review Article

Abstract: The concept of repairing the brain with growth factors has been pursued for many years in a variety of neurodegenerative diseases including primarily Parkinson’s disease (PD) using glial cell line-derived neurotrophic factor (GDNF). This neurotrophic factor was discovered in 1993 and shown to have selective effects on promoting survival and regeneration of certain populations of neurons including the dopaminergic nigrostriatal pathway. These observations led to a series of clinical trials in PD patients including using infusions or gene delivery of GDNF or the related growth factor, neurturin (NRTN). Initial studies, some of which were open label, suggested that this approach …could be of value in PD when the agent was injected into the putamen rather than the cerebral ventricles. In subsequent double-blind, placebo-controlled trials, the most recent reporting in 2019, treatment with GDNF did not achieve its primary end point. As a result, there has been uncertainty as to whether GDNF (and by extrapolation, related GDNF family neurotrophic factors) has merit in the future treatment of PD. To critically appraise the existing work and its future, a special workshop was held to discuss and debate this issue. This paper is a summary of that meeting with recommendations on whether there is a future for this therapeutic approach and also what any future PD trial involving GDNF and other GDNF family neurotrophic factors should consider in its design. Show more

Keywords: GDNF, dopaminergic neurons, NRTN, Parkinson’s disease, clinical trials

DOI: 10.3233/JPD-202004

Citation: Journal of Parkinson's Disease, vol. 10, no. 3, pp. 875-891, 2020

Authors: Dorsey, E. Ray | Okun, Michael S. | Bloem, Bastiaan R.

Article Type: Article Commentary

Abstract: The COVID-19 pandemic has driven rapid, widespread adoption of telemedicine. The distribution of clinicians, long travel distances, and disability all limit access to care, especially for persons with Parkinson’s disease. Telemedicine is not a panacea for all of these challenges but does offer advantages. These advantages can be summarized as the 5 C’s: accessible care, increased convenience, enhanced comfort, greater confidentiality to patients and families, and now reduced risk of contagion. Telemedicine also has its limitations, including the inability to perform parts of the physical examination and inequitable access to the Internet and related technologies. Future models will deliver care …to patients from a diverse set of specialties. These will include mental health specialists, physiotherapists, neurosurgeons, speech-language therapists, dieticians, social workers, and exercise coaches. Along with these new care models, digital therapeutics, defined as treatments delivered through software programs, are emerging. Telemedicine is now being introduced as a bridge to restart clinical trials and will increasingly become a normal part of future research studies. From this pandemic will be a wealth of new telemedicine approaches which will fundamentally change and improve care as well as research for individuals with Parkinson’s disease. Show more

Keywords: Parkinson disease, telemedicine, patient comfort, confidentiality, COVID-19, quarantine, health care reform, organizational innovation

DOI: 10.3233/JPD-202109

Citation: Journal of Parkinson's Disease, vol. 10, no. 3, pp. 893-897, 2020

Authors: Victorino, Daniella Balduino | Guimarães-Marques, Marcia | Nejm, Mariana | Scorza, Fulvio Alexandre | Scorza, Carla Alessandra

Article Type: Article Commentary

DOI: 10.3233/JPD-202073

Citation: Journal of Parkinson's Disease, vol. 10, no. 3, pp. 899-902, 2020

Authors: Miocinovic, Svjetlana | Ostrem, Jill L. | Okun, Michael S. | Bullinger, Katie L. | Riva-Posse, Patricio | Gross, Robert E. | Buetefisch, Cathrin M.

Article Type: Article Commentary

Abstract: Most medical centers are postponing elective procedures and deferring non-urgent clinic visits to conserve hospital resources and prevent spread of COVID-19. The pandemic crisis presents some unique challenges for patients currently being treated with deep brain stimulation (DBS). Movement disorder (Parkinson’s disease, essential tremor, dystonia), neuropsychiatric disorder (obsessive compulsive disorder, Tourette syndrome, depression), and epilepsy patients can develop varying degrees of symptom worsening from interruption of therapy due to neurostimulator battery reaching end of life, device malfunction or infection. Urgent intervention to maintain or restore stimulation may be required for patients with Parkinson’s disease who can develop a rare but …potentially life-threatening complication known as DBS-withdrawal syndrome. Similarly, patients with generalized dystonia can develop status dystonicus, patients with obsessive compulsive disorder can become suicidal, and epilepsy patients can experience potentially life-threatening worsening of seizures as a result of therapy cessation. DBS system infection can require urgent, and rarely emergent surgery. Elective interventions including new implantations and initial programming should be postponed. For patients with existing DBS systems, the battery status and electrical integrity interrogation can now be performed using patient programmers, and employed through telemedicine visits or by phone consultations. The decision for replacement of the implantable pulse generator to prevent interruption of DBS therapy should be made on a case-by-case basis taking into consideration battery status and a patient’s tolerance to potential therapy disruption. Scheduling of the procedures, however, depends heavily on the hospital system regulations and on triage procedures with respect to safety and resource utilization during the health crisis. Show more

Keywords: COVID-19, coronavirus, battery depletion, telemedicine, DBS withdrawal

DOI: 10.3233/JPD-202072

Citation: Journal of Parkinson's Disease, vol. 10, no. 3, pp. 903-910, 2020

Authors: Cubo, Esther | Hassan, Anhar | Bloem, Bas R. | Mari, Zoltan | on behalf of the MDS-Telemedicine Study Group

Article Type: Editorial

DOI: 10.3233/JPD-202108

Citation: Journal of Parkinson's Disease, vol. 10, no. 3, pp. 911-913, 2020

Authors: Hauser, Robert A. | Zeitlin, Leonid | Fisher, Stanley | D’Souza, Richard

Article Type: Research Article

Abstract: Background: Carbidopa (CD) and levodopa (LD) extended release (CD-LD ER) capsules are designed to combine both immediate and extended release pharmacokinetics. In the phase 3, randomized, double-blind, ADVANCE-PD trial, patients randomized to CD-LD ER experienced a 1.17-hour greater reduction in OFF time compared to patients randomized to CD-LD IR (p  < 0.0001). Objective: To compare CD-LD IR optimization to CD-LD ER conversion based on patient dyskinesia status at baseline using data from the ADVANCE-PD trial. Methods: This was a retrospective analysis of the ADVANCE-PD study. Patients were categorized by dyskinesia status at baseline into 1) those who …had No Dyskinesia (ND), 2) those who had Non-Troublesome Dyskinesia Only (NTDO), and 3) those who had Troublesome Dyskinesia (TD). Results: Comparative reductions in OFF time favoring CD-LD ER over CD-LD IR were similar for the ND (–1.08 h, p  = 0.0071, n  = 183) and NTDO (–1.12 h, p  = 0.0104, n  = 131) groups, and smaller for the TD group (–0.82 h, p  = 0.2382, n  = 79). Reductions in OFF time for both CD-LD ER conversion and CD-LD IR adjustment were largest within the ND group and smallest within the TD group (CD-LD ER: ND –2.86 h, NTDO –2.11 h, TD –1.36 h; CD-LD IR: ND –1.78 h, NTDO –0.99 h, TD –0.55 h). Conclusion: Responses to both CD-LD IR adjustment and CD-LD ER conversion depended on baseline dyskinesia status. Significant reductions in OFF time with CD-LD ER compared to CD-LD IR were observed in the ND and NTDO groups. In the TD group, comparing CD-LD ER conversion to CD-LD IR optimization, benefits were still observed, but there was less reduction in OFF time, less reduction in troublesome dyskinesia, and fewer patients self-rated themselves much or very much improved than in the ND and NTDO groups. These data suggest that in clinical practice, the best chances for success with conversion from CD-LD IR to CD-LD ER are in patients without TD. Show more

Keywords: Levodopa, extended release, Parkinson’s disease, treatment, dyskinesia, OFF

DOI: 10.3233/JPD-202010

Citation: Journal of Parkinson's Disease, vol. 10, no. 3, pp. 915-925, 2020

Authors: Simoni, Simone | Paoletti, Federico Paolini | Eusebi, Paolo | Cappelletti, Giulia | Filidei, Marta | Brahimi, Elona | Nigro, Pasquale | Santangelo, Valerio | Parnetti, Lucilla | Calabresi, Paolo | Tambasco, Nicola

Article Type: Research Article

Abstract: Background: Dopaminergic medications in Parkinson’s disease (PD) are usually associated with the development of both levodopa-induced dyskinesias (LID) and impulse control and repetitive behavior disorders (ICRB). Objective: To assess the prevalence and the severity of ICRB in a cohort of moderate and advanced PD patients and to investigate the potential interplay between ICRB, LID and dopaminergic therapies. Methods: 117 PD patients were consecutively recruited. LID were assessed by using the Rush Dyskinesia Rating Scale (RDRS). ICRB were tested by means of Questionnaire for Impulsive Compulsive Disorders in Parkinson’s Disease Rating Scale (QUIP-RS). Results: 55 …patients were affected by LID. Among them, 37 were treated only by oral therapy, OT (LID/OT), while 18 were on treatment with jejunal levodopa infusion, JLI (LID/JLI). 62 patients were not affected by LID (NLID) and all of them were on therapy only with oral drugs. The overall prevalence of clinically significant ICRB was 34% (95% CI = 26% to 43%) and the mean value (±SD) of QUIP-RS total score was 5.4±8.5. Prevalence of clinically significant ICRB, as well as severity of ICRB, was higher in patients with LID compared to NLID patients (p  = 0.016 and p  < 0.001, respectively). When considering LID/JLI, LID/OT and NLID groups, QUIP-RS total score was significantly higher in LID/OT patients compared to LID/JLI (10.4±11.8 vs. 4.9±6.0, p  = 0.019) and NLID (10.4±11.8 vs. 2.5±4.8, p  < 0.001) groups. Conclusion: PD patients with LID show ICRB more frequently and more severely than patients without LID. Among LID patients, those treated by JLI showed a lower severity of ICRB than those on OT, suggesting a potential protective effect of JLI on ICRB. Show more

Keywords: Dyskinesia, Parkinson’s disease, dopamine, ICD, impulse control disorders, repetitive behavior disorders, levodopa

DOI: 10.3233/JPD-191833

Citation: Journal of Parkinson's Disease, vol. 10, no. 3, pp. 927-934, 2020

Authors: Moes, Harmen R. | Groenendal-Laurensse, Jerney W.M.J. | Drent, Martje | Tissingh, Gerrit | van Laar, Teus

Article Type: Research Article

Abstract: Background: Continuous intra-duodenal infusion of levodopa-carbidopa intestinal gel (LCIG) is a well-established therapy for patients with advanced Parkinson’s disease (PD) suffering from motor complications despite optimized treatment with oral dopaminomimetics. However, time to discontinuation of treatment with LCIG varies considerably between patients, ranging from a few months to more than ten years. To improve the selection of candidates for LCIG, knowledge of prognostic factors is of paramount importance. Objective: To explore baseline predictors of time to discontinuation of LCIG. Methods: In this two-center retrospective cohort study, we reviewed the medical files of 98 PD patients treated …with LCIG between April 2006 and December 2015 (53% male; mean age: 66.2 years; mean disease duration: 12.3 years). Baseline patient characteristics were used as covariates in Cox regression models. Results: During follow-up (mean observation time: 2.6 years; range: 0.1–9.3) eighteen patients discontinued treatment (18.4%), while seven patients died (7.1%). Median duration of treatment with LCIG, estimated with Kaplan-Meier analysis, was 7.8 years (95% CI: 6.7–9.0). Disease duration (in years) at baseline was a statistically significant predictor of time to discontinuation of LCIG (HR: 0.85; 95% CI: 0.75–0.96, p  = 0.006). All other characteristics studied, e.g. age >70 years, did not show statistically significant associations with the total duration of treatment with LCIG. Conclusion: Our findings show a low overall rate of discontinuation of LCIG infusion, with a median duration of treatment of 7.8 years. Shorter disease duration at baseline appeared to be a predictor of earlier discontinuation of LCIG. Show more

Keywords: Parkinson disease, carbidopa, levodopa drug combination, duodopa, treatment adherence, drug-related side effects and adverse reactions, survival analysis, Kaplan-Meier estimate, regression analysis, observational study, retrospective study

DOI: 10.3233/JPD-201978

Citation: Journal of Parkinson's Disease, vol. 10, no. 3, pp. 935-944, 2020

Authors: Jackson, Lauren | Turcano, Pierpaolo | Stitt, Derek | Coon, Elizabeth | Savica, Rodolfo

Article Type: Short Communication

Abstract: Background: Scans without evidence of dopaminergic deficit (SWEDDS) on 123 I-FP-CIT SPECT (DAT) can occur in patients with clinical evidence of Parkinsonism. In this patient population, autonomic function testing may elucidate the underlying clinical disorder. Objective: To evaluate SWEDD patients undergoing autonomic testing and determine the severity and pattern of autonomic dysfunction. Methods: All patients with a diagnosis of SWEDD and formal autonomic function testing at Mayo Clinic, MN were retrospectively reviewed. Autonomic failure was quantified using composite autonomic severity score (CASS). The Modified Hoehn and Yahr score (HYS) determined Parkinsonism severity. Results: Of …1,874 patients with DAT imaging at Mayo Clinic, 13 met diagnostic criteria of SWEDD. The median age of symptom onset was 56.0 (IQR 40.5–75.5). Autonomic dysfunction was present in 12/13 on ARS and/or TST. The median CASS was 2.50 (IQR 1.00–3.00). Distal anhidrosis was most common (7/13) while 3/13 had widespread anhidrosis on TST and/or QSART testing. Patients with a distal pattern of anhidrosis had a median score of 3.0 (IQR 2.38–4.25) on the HYS versus 2.0 (IQR 1.00–2.00) for those with a diffuse pattern (p  = 0.048). Patients with more advanced Parkinsonism were more likely to respond to L-Dopa, with higher HYS in the dopa-responsive versus non-Dopa-responsive (p  = 0.026). No correlation existed between severity of Parkinsonism, and CASS (p  = 0.39). Conclusion: Autonomic function testing may detect autonomic dysfunction in most patients with SWEDD. The pattern of dysfunction is suggestive of the degree of clinical Parkinsonism, and autonomic testing may predict whether patients with SWEDD respond to L-Dopa. Show more

Keywords: Scans without evidence of dopaminergic deficit, parkinsonism, autonomic reflex screen, thermoregulatory sweat test, composite autonomic scoring scale, Hoehn and Yahr scale, quantitative sudomotor axon reflex test

DOI: 10.3233/JPD-201944

Citation: Journal of Parkinson's Disease, vol. 10, no. 3, pp. 945-949, 2020

Authors: Vilas, Dolores | Tolosa, Eduard | Quintana, María | Pont-Sunyer, Claustre | Santos, Meritxell | Casellas, Aina | Valldeoriola, Francesc | Compta, Yaroslau | Martí, María José | Mullol, Joaquim

Article Type: Research Article

Abstract: Background: Studies on olfaction in LRRK2 -associated Parkinson’s disease (LRRK2 -PD) have yielded variable results. The impact of smell dysfunction upon daily life activities have been rarely assessed in PD. Objective: To characterize the olfactory deficit in LRRK2 -PD and its impact on daily life activities. Methods: Twenty-four LRRK2 -PD, 40 idiopathic PD (IPD), and 49 age-sex-matched controls were interviewed about olfactory characteristics and the impact of smell on daily life activities. The Barcelona Smell Identification test (BAST-24) and the Spanish-version of the 40-item University of Pennsylvania smell test (UPSIT) were applied. Results: Nineteen …(79.2%) LRRK2 -PD patients reported subjective smell impairment with a low impact upon daily living activities. UPSIT score was higher in LRRK2- PD than in IPD (22.54±7.98 vs 18.84±6.03; p  = 0.042). All IPD and 95.8% LRRK2 -PD patients had hyposmia/anosmia, assessed by means of the UPSIT. No differences were found between LRRK2 -PD and IPD regarding smell detection, memory or forced-choice identification. Conclusion: Most LRRK2 -PD patients reported subjective smell impairment and presented hyposmia, according to validated smell tests, with a low impact of the smell dysfunction on daily life activities. Show more

Keywords: Parkinson’s disease, LRRK2, olfaction, hyposmia

DOI: 10.3233/JPD-201972

Citation: Journal of Parkinson's Disease, vol. 10, no. 3, pp. 951-958, 2020