Background: Neuroinflammation plays a key role in PD pathogenesis, and allogeneic bone marrow–derived mesenchymal stem cells can be used as an immunomodulatory therapy.Objective: The objective of this study was to prove the safety and tolerability of intravenous allogeneic bone marrow–derived mesenchymal stem cells in PD patients.Methods: This was a 12‐month single‐center open‐label dose‐escalation phase 1 study of 20 subjects with mild/moderate PD assigned to a single intravenous infusion of 1 of 4 doses: 1, 3, 6, or 10 × 10⁶ allogeneic bone marrow–derived mesenchymal stem cells/kg, evaluated 3, 12, 24, and 52 weeks postinfusion. Primary outcome safety measures included transfusion reaction, study‐related adverse events, and immunogenic responses. Secondary outcomes included impact on peripheral markers, PD progression, and changes in brain perfusion.Results: There were no serious adverse reactions related to the infusion and no responses to donor‐specific human leukocyte antigens. Most common treatment‐emergent adverse events were dyskinesias (20%, n = 4) with 1 emergent and 3 exacerbations; and hypertension (20%, n = 4) with 3 transient episodes and 1 requiring medical intervention. One possibly related serious adverse event occurred in a patient with a 4‐year history of lymphocytosis who developed asymptomatic chronic lymphocytic leukemia. Peripheral inflammation markers appear to be reduced at 52 weeks in the highest dose including, tumor necrosis factor‐α (P < 0.05), chemokine (C‐C motif) ligand 22 (P < 0.05), whereas brain‐derived neurotrophic factor (P < 0.05) increased. The highest dose seems to have demonstrated the most significant effect at 52 weeks, reducing the OFF state UPDRS motor, −14.4 (P < 0.01), and total, −20.8 (P < 0.05), scores.Conclusion: A single intravenous infusion of allogeneic bone marrow–derived mesenchymal stem cells at doses of 1, 3, 6, or 10 × 10⁶ allogeneic bone marrow–derived mesenchymal stem cells/kg is safe, well tolerated, and not immunogenic in mild/moderate PD patients. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Case Report from JAMA Neurology — Isolated Central Nervous System Histoplasmosis Presenting With Ischemic Pontine Stroke and Meningitis in an Immune-Competent Patient

Neuromodulation of subcortical areas of the brain as therapy to reduce Parkinsonian motor symptoms was developed in the mid-twentieth century and went through many technical and scientific advances that established specific targets and stimulation parameters. Deep Brain Stimulation (DBS) was approved by the FDA in 2002 as neuromodulation therapy for advanced Parkinson’s disease, prompting several randomized controlled trials that confirmed its safety and effectiveness. The implantation of tens of thousands of patients in North America and Europe ignited research into its potential role in early disease stages and the therapeutic benefit of DBS compared to best medical therapy. In 2013 the EARLY-STIM trial provided Class I evidence for the use of DBS earlier in Parkinson’s disease. This finding led to the most recent FDA approval in patients with at least 4 years of disease duration and 4 months of motor complications as an adjunct therapy for patients not adequately controlled with medications. This following review highlights the historical development and advances made overtime in DBS implantation, the current application, and the challenges that come with it.

Motor classifications of Parkinson's Disease (PD) have been widely used. This paper aims to update a subtype classification using the MDS-UPDRS-III and determine if cerebrospinal neurotransmitter profiles (HVA and 5-HIAA) differ between these subtypes in a cohort from the Parkinson's Progression Marker Initiative (PPMI). UPDRS and MDS-UPDRS scores were collected for 20 PD patients. Akinetic-rigid (AR), Tremor-dominant (TD), and Mixed (MX) subtypes were calculated using a formula derived from UPDRS, and a new ratio was developed for subtyping patients with the MDS-UPDRS. This new formula was subsequently applied to 95 PD patients from the PPMI dataset, and subtyping was correlated to neurotransmitter levels. Data were analyzed using receiver operating characteristic models and ANOVA. Compared to previous UPDRS classifications, the new MDS-UPDRS TD/AR ratios produced significant areas under the curve (AUC) for each subtype. The optimal sensitivity and specificity cutoff scores were ≥0.82 for TD, ≤0.71 for AR, and >0.71 and <0.82 for Mixed. Analysis of variance showed that the AR group had significantly lower HVA and 5-HIAA levels than the TD and HC groups. A logistic model using neurotransmitter levels and MDS-UPDRS-III could predict the subtype classification. This MDS-UPDRS motor classification system provides a method to transition from the original UPDRS to the new MDS-UPDRS. It is a reliable and quantifiable subtyping tool for monitoring disease progression. The TD subtype is associated with lower motor scores and higher HVA levels, while the AR subtype is associated with higher motor scores and lower 5-HIAA levels.

Objective To assist in the assessment of intrathecal baclofen (ITB) therapy risks and benefits by providing surgical intervention rate, safety, and elective device replacement rate data. Materials and Methods An ongoing prospective, long‐term, multicenter Product Surveillance Registry (PSR) (NCT01524276) enrolled consented patients implanted with the SynchroMed II infusion system. Pump and catheter performance data were collected, with patients followed prospectively for events related to the device, procedure, and therapy. Investigators provided event descriptions, patient symptoms, and patient outcomes. Results We analyzed registry data from 1743 patients (77% adult, 46.8% female) treated with ITB for severe spasticity at 53 registry sites between August 2003 and October 2017, for an accumulated 6481 patient‐years. Discontinuation from the registry was largely (58.6% of discontinued patients) due to study site closure and patient relocation; exit due to an adverse event was limited to 0.3%. After 10 years, 87.2% of adult and 76.3% of pediatric patients continued with ITB. Overall, 99.1% of pumps reaching end of battery life were replaced at the time of explant. Conclusions ITB therapy for the treatment of severe spasticity requires surgical implantation of a programmable infusion system for chronic drug delivery. If complications arise, many necessitate surgical intervention for correction. For spinal and cerebral spasticity in pediatric and adult patients, discontinuation rates due to an adverse event were low (0.3%), and there was high acceptance (99.1%) of surgical intervention for therapy continuation. Patient/caregiver willingness to accept surgical and other risks for therapy continuation was extremely high.