Outpatient Physical Therapy for Functional Neurological Disorder: A Preliminary Feasibility and Naturalistic Outcome Study in a U.S. Cohort.

OBJECTIVE: Despite promising research and consensus recommendations on the important therapeutic role of physical therapy for motor functional neurological disorder (FND), little is known about the feasibility and potential efficacy of implementing physical therapy for this population in a U.S.-based outpatient program. Given health care system differences internationally, this is an important gap in the literature. METHODS: In this retrospective cohort study, the authors investigated the relationship between treatment adherence and clinical outcome in a hospital-based outpatient physical therapy clinical program. Medical records of 50 consecutive patients with motor FND referred from an FND clinical program were reviewed. The physical therapy intervention included a 1-hour initial assessment and the development of individualized treatment plans guided by published consensus recommendations. Statistical analyses included nonparametric, univariate screening tests followed by multivariate regression analyses. RESULTS: In univariate analyses, there was a statistically significant positive correlation between the number of sessions attended and clinical improvement. This relationship held when adjusting for demographic variables, concurrent psychogenic nonepileptic seizures, and other major neurological comorbidities. In a post hoc analysis of the subset of individuals with available gait speed data, posttreatment 10-meter gait speed times improved compared with baseline measurements. Baseline neuropsychiatric factors did not correlate with clinical improvement. CONCLUSIONS: This preliminary, retrospective cohort study demonstrated that treatment adherence to a U.S.-based outpatient physical therapy program was associated with clinical improvement. Prospective observational and randomized controlled trials are needed to further optimize physical therapy for patients with functional motor symptoms in the outpatient setting.

Parkinson disease phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations.

The phenotype of Parkinson's disease (PD) in patients with and without leucine-rich repeat kinase 2 (LRRK2) G2019S mutations reportedly is similar; however, large, uniformly evaluated series are lacking. The objective of this study was to characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). Glucocerebrosidase (GBA) mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the Geriatric Depression Scale (GDS) and the Non-Motor Symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. LRRK2 G2019S carriers (n = 97) and non-carriers (n = 391) were similar in age and age at onset of PD. Carriers had longer disease duration (8.6 years vs. 6.1 years; P < 0.001), were more likely to be women (51.5% vs. 37.9%; P = 0.015), and more often reported first symptoms in the lower extremities (40.0% vs. 19.2%; P < 0.001). In logistic models that were adjusted for age, disease duration, sex, education, and site, carriers were more likely to have lower extremity onset (P < 0.001), postural instability and gait difficulty (PIGD) (P = 0.043), and a persistent levodopa response for >5 years (P = 0.042). Performance on the UPDRS, MoCA, GDS, and NMS did not differ by mutation status. PD in AJ LRRK2 G2019S mutation carriers is similar to idiopathic PD but is characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.

ß-Glucocerebrosidase activity in GBA-linked Parkinson disease: The type of mutation matters.

OBJECTIVE: To test the relationship between clinically relevant types of GBA mutations (none, risk variants, mild mutations, severe mutations) and ß-glucocerebrosidase activity in patients with Parkinson disease (PD) in cross-sectional and longitudinal case-control studies. METHODS: A total of 481 participants from the Harvard Biomarkers Study (HBS) and the NIH Parkinson's Disease Biomarkers Program (PDBP) were analyzed, including 47 patients with PD carrying GBA variants (GBA-PD), 247 without a GBA variant (idiopathic PD), and 187 healthy controls. Longitudinal analysis comprised 195 participants with 548 longitudinal measurements over a median follow-up period of 2.0 years (interquartile range, 1-2 years). RESULTS: ß-Glucocerebrosidase activity was low in blood of patients with GBA-PD compared to healthy controls and patients with idiopathic PD, respectively, in HBS (p < 0.001) and PDBP (p < 0.05) in multivariate analyses adjusting for age, sex, blood storage time, and batch. Enzyme activity in patients with idiopathic PD was unchanged. Innovative enzymatic quantitative trait locus (xQTL) analysis revealed a negative linear association between residual ß-glucocerebrosidase activity and mutation type with p < 0.0001. For each increment in the severity of mutation type, a reduction of mean ß-glucocerebrosidase activity by 0.85 µmol/L/h (95% confidence interval, -1.17, -0.54) was predicted. In a first longitudinal analysis, increasing mutation severity types were prospectively associated with steeper declines in ß-glucocerebrosidase activity during a median 2 years of follow-up (p = 0.02). CONCLUSIONS: Residual activity of the ß-glucocerebrosidase enzyme measured in blood inversely correlates with clinical severity types of GBA mutations in PD. ß-Glucocerebrosidase activity is a quantitative endophenotype that can be monitored noninvasively and targeted therapeutically.

Glucocerebrosidase enzyme activity in GBA mutation Parkinson's disease.

Mutations in the glucocerebrosidase (GBA1) gene, the most common genetic contributor to Parkinson's disease (PD), are associated with an increased risk of PD in heterozygous and homozygous carriers. While glucocerebrosidase enzyme (GCase) activity is consistently low in Gaucher disease, there is a range of leukocyte GCase activity in healthy heterozygous GBA1 mutation carriers. To determine whether GCase activity may be a marker for PD with heterozygous GBA1 mutations (GBA1 mutation PD, GBA PD), GBA PD patients (n=15) were compared to PD patients without heterozygous GBA1 mutations (idiopathic PD; n=8), heterozygous GBA1 carriers without PD (asymptomatic carriers; n=4), and biallelic mutation carriers with PD (Gaucher disease with PD, GD1 PD; n=3) in a pilot study. GCase activity (nmol/mg protein/hour) in GD1 PD (median [interquartile range]; minimum-maximum: 6.4 [5.7]; 5.3-11) was lower than that of GBA PD (16.0 [7.0]; 11-40) (p=0.01), while GCase activity in GBA PD was lower than idiopathic PD (28.5 [15.0]; 16-56) (p=0.01) and asymptomatic carriers (25.5 [2.5]; 23-27) (p=0.04). Therefore, GCase activity appears to be a possible marker of heterozygous GBA1 mutation PD, and larger studies are warranted. Prospective studies are also necessary to determine whether lower GCase activity precedes development of PD.

The pull test: a history.

The pull test (PT) is used as a measure of postural instability in Parkinson's disease (PD) and other movement disorders. In 1987, it was incorporated into the Unified Parkinson's Disease Rating Scale (UPDRS), a scale used to measure the severity and treatment response in PD both in research studies and in clinical practice. However, the origins of the observation of postural instability in movement disorders and the attempt to quantify it are much older. Here, we trace the history of postural instability first described as a feature of PD by Romberg in 1853. Attempts to evaluate postural instability began with the first measurement by Charcot in the 1880s by pulling the clothes of patients and progressed to the push on the sternum by Hoehn and Yahr in the 1960s. Eventually, this evolved into the formal PT proposed by Fahn in the 1980s. Despite the widespread use of the PT as part of the UPDRS, variability exists in its execution. Recommendations have been made for training of examiners in clinical trials to improve its accuracy in assessing postural instability. We agree with improving PT technique for clinical trials and advocate for its routine use in clinical practice when diagnosing and treating movement disorders. Further, we propose the name "Fahn pull test" for the maneuver based on his significant contribution to its development.