Cerebrospinal Fluid Flow Cytometry: Utility in Central Nervous System Lymphoma Diagnosis.

BACKGROUND: Flow cytometry of the cerebrospinal fluid (CSF) is used in isolation or as an adjunct to cytology to increase the sensitivity of detecting central nervous system (CNS) lymphoma. We aimed to evaluate the sensitivity of CSF flow cytometry as a diagnostic screening tool for primary CNS lymphoma in patients presenting with undifferentiated neurologic symptoms. METHODS: We retrospectively reviewed all CSF samples received by the Calgary Laboratory Services Flow Cytometry Laboratory from 2012 to 2015. Clinical data, laboratory investigations, radiologic imaging studies, and pathological data were analyzed. Clinical review extended to 2 years post-CSF flow cytometric testing. RESULTS: Only 43/763 (5.6%) samples of CSF flow cytometry in 28/573 (4.9%) patients were found to be positive for a hematological malignancy in patients with undifferentiated neurologic symptoms. The overall sensitivity of the test was 13.8% with 25 patients with negative CSF flow cytometry later having a positive biopsy for CNS lymphoma. CSF flow cytometry was negative in all cases when at the time of CSF examination the patient did not have a previous hematological malignancy or findings of abnormal enhancement on MRI (n = 249). CONCLUSION: CSF flow cytometry has low utility in screening for primary CNS lymphoma in the absence of a previous history of hematologic malignancy or findings of abnormal enhancement on MRI.

Visual feedback improves propulsive force generation during treadmill walking in people with Parkinson disease.

Persons with Parkinson's disease experience gait alterations, such as reduced step length. Gait dysfunction is a significant research priority as the current treatments targeting gait impairment are limited. This study aimed to investigate the effects of visual biofeedback on propulsive force during treadmill walking in persons with Parkinson's. Sixteen ambulatory persons with Parkinson's participated in the study. They received real-time biofeedback of anterior ground reaction force during treadmill walking at a constant speed. Peak propulsive force values were measured and normalized to body weight. Spatiotemporal parameters were also assessed, including stride length and double support percent. Persons with Parkinson's significantly increased peak propulsive force during biofeedback compared to baseline (p <.0001, Cohen's dz = 1.69). Variability in peak anterior ground reaction force decreased across repeated trials (p <.0001, dz = 1.51). While spatiotemporal parameters did not show significant changes individually, stride length and double support percent improved marginally during biofeedback trials. Persons with Parkinson's can increase propulsive force with visual biofeedback, suggesting the presence of a propulsive reserve. Though stride length did not significantly change, clinically meaningful improvements were observed. Targeting push-off force through visual biofeedback may offer a potential rehabilitation technique to enhance gait performance in Persons with Parkinson's. Future studies could explore the long-term efficacy of this intervention and investigate additional strategies to improve gait in Parkinson's disease.

Acclimatization of force production during walking in persons with Parkinson's disease.

Individuals with Parkinson's disease walk slowly, with short strides resulting in decreased mobility. Treadmill walking assessments are utilized to understand gait impairment in persons with Parkinson's disease and treadmill-based interventions to mobility have become increasingly popular. While walking on a treadmill, there is a reported initial acclimatization period where individuals adjust to the speed and dynamics of the moving belt before producing consistent walking patterns. It is unknown how much walking time is required for individuals with Parkinson's disease to acclimate to the treadmill. We investigated how spatiotemporal parameters and ground reaction forces changed during treadmill acclimatization. Twenty individuals with idiopathic Parkinson's (15 Males, 5 Females) walked for a five-minute treadmill session on an instrumented treadmill while motion capture data were collected. The measures of interest included ground reaction force measures (peak propulsive force, peak braking force, propulsive impulse, and braking impulse) and spatiotemporal measures (stride length, stride time, or double support time). Analyses demonstrated significantly increased propulsive impulse (p <.001) after the first minute, with no significant difference for the remaining minutes (p ≥ 0.395). There were no significant changes in the spatiotemporal measures (P =.065). These results quantify the stabilization of ground reaction force during the treadmill acclimatization period. Based on our findings, if steady-state gait is desired, we recommend participants walk for at least two minutes before data collection. Future clinical investigations should consider ground reaction force as sensitive parameters for evaluating gait in persons with Parkinson's disease in treadmill-based assessments or interventional therapies.

Double blind, nonrandomized crossover study of active recharge biphasic deep brain stimulation for primary dystonia.

BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is an effective therapy for select patients with primary dystonia. DBS programming for dystonia is often challenging due to variable time to symptomatic improvement or stimulation induced side effects (SISE) such as capsular or optic tract activation which can prolong device optimization. OBJECTIVE: To characterize the safety and tolerability of active recharge biphasic DBS (bDBS) in primary dystonia and to compare it to conventional clinical DBS (clinDBS). METHODS: Ten subjects with primary dystonia and GPi DBS underwent a single center, double blind, nonrandomized crossover study comparing clinDBS versus bDBS. The testing occurred over two-days. bDBS and clinDBS were administered on separate days and each was activated for 6 h. Rating scales were collected by video recording and scored by four blinded movement disorders trained neurologists. RESULTS: The bDBS paradigm was safe and well-tolerated in all ten subjects. There were no persistent SISE reported. The mean change in the Unified Dystonia Rating Scale after 4 h of stimulation was greater in bDBS when compared to clinDBS (-6.5 vs 0.3, p < 0.04). CONCLUSION: In this pilot study, we demonstrated that biphasic DBS is a novel stimulation paradigm which can be administered safely. The biphasic waveform revealed a greater immediate improvement. Further studies are needed to determine whether this immediate improvement persists with chronic stimulation or if clinDBS will eventually achieve similar levels of improvement to bDBS over time.

Type, Timing, Frequency, and Durability of Outcome of Physical Therapy for Parkinson Disease: A Systematic Review and Meta-Analysis.

Importance: Parkinson disease (PD) is a neurodegenerative syndrome affecting approximately 1% of the population older than 60 years, and a major goal of treatment is preservation of physical function through physical therapy (PT). Although PT outcomes for PD are well documented, aggregate information on the parameters of PT are needed to guide implementation. Objective: To evaluate current evidence on the types, timing, frequency, duration, and outcomes of PT regimens applied for PD. Data Sources: PubMed, Embase, Medline, and the Web of Science Core Collection were searched for articles published from January 1, 2000, to August 10, 2022. Search terms included terms related to Parkinson disease, PT interventions, and PT-related outcomes. Study Selection: Included studies were peer-reviewed randomized clinical trials available in English of any PT intervention for patients with PD that included PT-related outcomes. The Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline was followed. Data Extraction and Synthesis: Two reviewers extracted data and assessed quality using the Cochrane Risk of Bias Tool. Data were analyzed using a random-effects model. Main Outcomes and Measures: A meta-analysis compared outcomes of nonstandard PT vs standard PT and standard PT vs no intervention for Unified Parkinson's Disease Rating Scale (UPDRS) score and measures of gait and balance. Results: A total of 46 trials with 3905 patients were included (range of mean ages, 61-77 years). Ten trials (22%) compared 2 types of nonstandard PT interventions; 26 (57%), nonstandard PT vs standard PT; and 10 (22%), PT vs no intervention. The most common nonconventional PT intervention was aquatic physiotherapy (5 trials [11%]). Durations of PT regimen ranged from 2 to 12 weeks in 39 trials (85%), and PT was most commonly performed with frequencies of either twice or 3 times weekly (27 [59%]). In most trials (39 [85%]), PT session length ranged from 30 to 60 minutes. Across trials, PT outcomes were reported for gait (14 trials [30%]), balance (10 [22%]), quality of life (3 [9%]), and cognition (1 [2%]). Approximately half of the trials (22 [48%]) documented durability of some level of benefit after completion of the prescribed regimen. Meta-analysis showed no significant difference for PT vs no intervention in UPDRS scores (standardized mean difference [SMD], -1.09; 95% CI, -2.50 to 0.33) or for nonstandard PT vs standard PT in measures of gait (SMD, 0.03; 95% CI, -0.53 to 0.59), balance (SMD, 0.54; 95% CI, -0.03 to 1.12), and UPDRS score (SMD, -0.49; 95% CI, -1.04 to 0.06). Meta-analytic regression of moderators revealed no significant differences in outcomes by frequency of PT per week (SMD, 0.17; 95% CI, -0.03 to 0.36). Conclusions and Relevance: The findings suggest that although a wide range of types and regimens of PT for PD have been tested, comparative effectiveness of different models of care and implementation strategies as well as long-term durability of their outcomes remain undetermined.

The Human Tic Detector: An automatic approach to tic characterization using wearable sensors.

OBJECTIVE: Current rating scales for Tourette syndrome (TS) are limited by recollection bias or brief assessment periods. This proof-of-concept study aimed to develop a sensor-based paradigm to detect and classify tics. METHODS: We recorded both electromyogram and acceleration data from seventeen TS patients, either when voluntarily moving or experiencing tics and during the modified Rush Video Tic Rating Scale (mRVTRS). Spectral properties of voluntary and tic movements from the sensor that captured the dominant tic were calculated and used as features in a support vector machine (SVM) to detect and classify movements retrospectively. RESULTS: Across patients, the SVM had an accuracy, sensitivity, and specificity of 96.69 ± 4.84%, 98.24 ± 4.79%, and 96.03 ± 6.04%, respectively, when classifying movements in the test dataset. Furthermore, each patient's SVM was validated using data collected during the mRVTRS. Compared to the expert consensus, the tic detection accuracy was 85.63 ± 15.28% during the mRVTRS, while overall movement classification accuracy was 94.23 ± 5.97%. CONCLUSIONS: These results demonstrate that wearable sensors can capture physiological differences between tic and voluntary movements and are comparable to expert consensus. SIGNIFICANCE: Ultimately, wearables could individualize and improve care for people with TS, provide a robust and objective measure of tics, and allow data collection in real-world settings.

A randomized clinical trial of burst vs. spaced physical therapy for Parkinsons disease.

INTRODUCTION: The optimal timing for physical therapy (PT) delivery in Parkinson's disease (PD) is unknown. Our objective was to determine whether spacing physical therapy visits over a longer period of time is beneficial for maintenance of physical function in PD. METHODS: A single center, single-blinded, randomized controlled trial of PD participants. Participants (n = 30) were randomized to either burst (two PT sessions weekly for 6 weeks) or spaced (one PT session every 2 weeks for 6 months) PT. 11 participants in each arm completed the study and were analyzed. The primary outcome measure was the Timed Up and Go (TUG) test at baseline and 6 months. The burst group had an additional outcome measure timepoint at the completion of PT at 6 weeks. RESULTS: Neither group achieved a minimal clinically significant benefit in the TUG score (3.5s) at 6 months. The spaced PT TUG scores were maintained when comparing baseline (7.8 ± 1.5s) and 6 month timepoints (7.8 ± 2.6s, p = 0.594). The burst group TUG scores comparing baseline (9.8 ± 3.8s) to 6 weeks (9.1 ± 3.0s) also was maintained (p = 0.365). The burst group worsened, however, when measuring the period from 6 weeks to 6 months (12.1 ± 7.6s, p = 0.034). CONCLUSIONS: The spaced PT group had stability of the TUG mobility measure at 6 months, while the burst group had a significant worsening once PT was discontinued after 6 weeks. It is feasible to test these approaches in a future larger comparative effectiveness study.

Rhabdomyolysis secondary to severe tic fits.

Tourette syndrome (TS) is a condition wherein motor and vocal tics occur, provoked by an urge, but often not able to be completely voluntarily controlled. Tics are known to cause physical and emotional risks to quality of life, and in rare extreme cases, may have permanent consequences. We report the first cases, to our knowledge, of rhabdomyolysis due to extreme tic fits in two distinct patients with TS. Both patients presented with severe tics, leading to elevated creatine kinase and a diagnosis of rhabdomyolysis requiring hospitalisation and intravenous fluids. Neither had neuroleptic malignant syndrome. One patient was on concurrent neuroleptic therapy, but his laboratory parameters improved when tics subsided despite continued neuroleptic use. Our cases highlight the potential complication of rhabdomyolysis secondary to severe tic fits independent of neuroleptic use.

Geospatial Analysis of Persons with Movement Disorders Living in Underserved Regions.

Background: Movement disorders persons from underserved areas have increased barriers to access tertiary care. There is currently limited data on the geographic and demographic profile of movement disorders persons from underserved areas. Methods: A retrospective chart review of the geographic and demographic profile of consecutive cases seen between 2002-2017 at the University of Florida Norman Fixel Institute for Neurological Diseases (UF-NFIND) was performed. Information collected included age, sex, diagnosis, zip code, treatment received, and insurance information. The distances between each person's home residence and the nearest movement disorders center of excellence (MDC) as well as the distance to the UF-NFIND were calculated using ArcGIS 10.3. Results: A total of 5.2% (355/6867) of the sample population were identified as a Medicaid/self-pay population and classified as underserved. The most common diagnoses were tic disorder (19.2%), dystonia (18.3%), and Parkinson's disease (14.3%). In underserved persons, the median distances from their homes to the UF-NFIND (82.19 [45.79-176.93] km) vs. their nearest MDC (63.34 [26.91-121.43] km) were significantly different (p < 0.001). Discussion: Underserved persons in our study travelled further to receive subspecialty care at UF-NFIND than closer MDCs. Potential reasons for underutilization of closer care could possibly include research opportunities, availability of specific treatments or procedures, insurance restrictions, and limited specialist availability. Despite this observation, underserved persons were underrepresented at our institution compared to the proportion of Medicaid/uninsured patients in Florida. Our results highlight the need for increased awareness of care options for underserved movement disorders populations.

Globus Pallidus Internus (GPi) Deep Brain Stimulation for Parkinson's Disease: Expert Review and Commentary.

INTRODUCTION: The globus pallidus internus (GPi) region has evolved as a potential target for deep brain stimulation (DBS) in Parkinson's disease (PD). DBS of the GPi (GPi DBS) is an established, safe and effective method for addressing many of the motor symptoms associated with advanced PD. It is important that clinicians fully understand this target when considering GPi DBS for individual patients. METHODS: The literature on GPi DBS in PD has been comprehensively reviewed, including the anatomy, physiology and potential pitfalls that may be encountered during surgical targeting and post-operative management. Here, we review and address the implications of lead location on GPi DBS outcomes. Additionally, we provide a summary of randomized controlled clinical trials conducted on DBS in PD, together with expert commentary on potential applications of the GPi as target. Finally, we highlight future technologies that will likely impact GPi DBS, including closed-loop adaptive approaches (e.g. sensing-stimulating capabilities), advanced methods for image-based targeting and advances in DBS programming, including directional leads and pulse shaping. RESULTS: There are important disease characteristics and factors to consider prior to selecting the GPi as the DBS target of PD surgery. Prior to and during implantation of the leads it is critical to consider the neuroanatomy, which can be defined through the combination of image-based targeting and intraoperative microelectrode recording strategies. There is an increasing body of literature on GPi DBS in patients with PD suggesting both short- and long-term benefits. Understanding the GPi target can be useful in choosing between the subthalamic (STN), GPi and ventralis intermedius nucleus as lead locations to address the motor symptoms and complications of PD. CONCLUSION: GPi DBS can be effectively used in select cases of PD. As the ongoing DBS target debate continues (GPi vs. STN as DBS target), clinicians should keep in mind that GPi DBS has been shown to be an effective treatment strategy for a variety of symptoms, including bradykinesia, rigidity and tremor control. GPi DBS also has an important, direct anti-dyskinetic effect. GPi DBS is easier to program in the outpatient setting and will allow for more flexibility in medication adjustments (e.g. levodopa). Emerging technologies, including GPi closed-loop systems, advanced tractography-based targeting and enhanced programming strategies, will likely be future areas of GPi DBS expansion. We conclude that although the GPi as DBS target may not be appropriate for all PD patients, it has specific clinical advantages.

Systematic review of the clinical spectrum of CASPR2 antibody syndrome.

BACKGROUND: Contactin-associated protein-like 2 (CASPR2) autoantibody disease has a variable clinical phenotype. We present a case report and performed a systematic review of the literature to summarize: (1) the clinical phenotype of patients with CASPR2 antibodies, (2) the findings in neurological investigations, and (3) the associated neuroimaging findings. METHODS: A chart review was performed for the case report. A systematic review of the medical literature was performed from first available to June 13, 2018. Abstracts were screened, and full-text peer-reviewed publications for novel patients with CASPR2 positivity in serum or cerebrospinal fluid (CSF) were included. Selected publications were reviewed, and relevant information was collated. Data were analyzed to determine overall frequency for demographic information, clinical presentations, and investigation findings. RESULTS: Our patient was a previously healthy 61-year-old male with both serum and CSF CASPR2 antibodies who presented with limbic encephalitis and refractory epilepsy. He was successfully treated with immunosuppression. For our systematic review, we identified 667 patients from 106 studies. Sixty-nine percent were male. Median age was 54 years (IQR 39-65.5). Median disease duration was 12 months (IQR 5.6-20). Reported overall clinical syndromes were: autoimmune encephalitis [69/134 (51.5%)], limbic encephalitis [106/274 (38.7%)], peripheral nerve hyperexcitability [72/191 (37.7%)], Morvan syndrome [57/251 (22.7%)], and cerebellar syndrome [24/163 (14.7%)]. Patients had positive serum [642/642 (100%)] and CSF [87/173 (50.3%)] CASPR2 antibodies. MRI was reported as abnormal in 159/299 patients (53.1%), and the most common abnormalities were encephalitis or T2 hyperintensities in the medial temporal lobes, or hippocampal atrophy, mesial temporal sclerosis, or hippocampal sclerosis. FDG-PET was abnormal in 30/35 patients (85.7%), and the most common abnormality was temporomesial hypometabolism. The most commonly associated condition was myasthenia gravis (38 cases). Thymoma occurred in 76/348 patients (21.8%). Non-thymoma malignancies were uncommon [42/397 (10.6%)]. CONCLUSIONS: Most patients have autoimmune or limbic encephalitis and corresponding abnormalities on neuroimaging. Other presentations include peripheral nerve hyperexcitability or Morvan syndromes, cerebellar syndromes, behavioral and cognitive changes, and more rarely movement disorders. The most commonly associated malignancy was thymoma and suggests a role for thymoma screening in CASPR2-related diseases.

Motor outcomes and adverse effects of deep brain stimulation for dystonic tremor: A systematic review.

Dystonic tremor (DT) is defined as the tremor in body parts affected by dystonia. Although deep brain stimulation (DBS) has been used to manage medically-refractory DT patients, its efficacy has not been well established. The objective of this study is to provide an up-to-date systematic review of DBS outcomes for DT patients. We conducted a literature search using Medline, Embase, and Cochrane Library databases in February 2020 according to the PRISMA guidelines. From 858 publications, we identified 30 articles involving 89 DT patients who received DBS of different targets. Thalamic DBS was the most common (n = 39) and improved tremor by 40-50% potentially in the long-term over five years with variable effects on dystonic symptoms. Globus pallidus internus (GPi), subthalamic, and subthalamic nucleus (STN) DBS improved both tremor and dystonic symptoms; however, data were limited. A few studies have reported better tremor and dystonia outcomes with combinations of different targets. Concerning adverse effects, gait/balance disorders, and ataxia seemed to be more common among patients treated with thalamic or subthalamic DBS, whereas parkinsonian adverse effects were observed only in patients treated with subthalamic or GPi DBS. Comparative benefits and limitations of these targets remain unclear because of the lack of randomized controlled trials. In conclusion, DBS of these targets may improve tremor with a variable effect on dystonia with different adverse effect profiles. The shortcomings in the literature include long-term motor outcomes, quality of life outcomes, optimal DBS targeting, and DBS programming strategy.

Timing of Physical Therapy Sessions for Individuals With Parkinson Disease May Unlock Benefits.

This Viewpoint advocates for careful consideration in the timing of physical therapy for individuals with Parkinson disease as a possible avenue toward improved outcomes.