Faculty Bibliography

There are racial and socioeconomic disparities in the care of patients with Parkinson's disease (PD). Bellevue Hospital Center (BHC) in New York City is the oldest public hospital in the United States providing care to a multiracial, socioeconomically diverse and medically underserved population. We investigated racial and social disparities in providing care to patients with PD and related disorders at BHC compared to a NYU Langone Health, a Parkinson's Foundation Center of Excellence. Retrospective chart review of patients with diagnosis of PD or PD-related disorders evaluated at BHC or at NYU outpatient clinics from January 2012 to August 2017. 100 patients were enrolled from each site: BHC (55% men); NYU (49% men). The majority of patients at NYU were White (77%), compared to 14% at BHC; Hispanic patients comprised the majority at BHC (56%) (p < 0.001). BHC patients had more clinic visits per year compared to the NYU cohort (2.88 vs. 2.40, p = 0.001). BHC patients were less likely to self-report exercise (p = 0.047) or participation in physical therapy (p = 0.015). There were no clinically significant differences in diagnosis type, time to diagnosis, average Hoehn & Yahr or levodopa equivalent dose. Compared to a Parkinson's Foundation Center of Excellence, PD patients in a public hospital system are more racially diverse, are less likely to be insured, have higher rates of care utilization and are less likely to access necessary interventions such as physical therapy and exercise.

Advanced Parkinson's disease (PD) often brings a set of motor and non-motor features that are particularly challenging to manage. Medication options can be limited by side-effects and quality of life can be severely affected by an accumulating burden of nonmotor symptoms. Here, we reviewed the literature and our clinical experience with the aim of providing a practical approach to the management of advanced PD. We provide guidelines for treatment of physical and neurobehavioral concerns, that occur in advanced PD.

INTRODUCTION/BACKGROUND:This study aimed to assess the outcomes of mirabegron for the treatment of overactive bladder (OAB) symptoms in patients with Parkinson disease (PD). METHODS:A retrospective study was conducted including patients with PD who received mirabegron 50 mg once daily for OAB symptoms between 2012 and 2017. The primary endpoint was clinical success defined as any improvement in overactive bladder symptoms self-assessed by the patients 6 weeks after mirabegron initiation. Secondary endpoints included number of pads per day, number of nocturia episodes and adverse events. RESULTS:Fifty patients (mean 74 years old) were included. Before being treated with mirabegron, 56% had failed prior anticholinergic therapy. After 6 weeks of mirabegron 50 mg, five patients (11.4%) had a complete resolution of their OAB symptoms; 25 patients (50%) reported improvement, 23 (46%) reported no change and 2(4%) reported worsening of their OAB symptoms. The number of pads per day decreased from 1.5 to 0.9 (p = 0.01) and so did the number of nocturia episodes (from 3 to 2.6/night; p = 0.02). Only 2 adverse events were reported during mirabegron treatment (4%): one dizziness and one diaphoresis, that disappeared after mirabegron discontinuation. After a median follow-up of 19 months, 23 patients (46%) persisted on mirabegron. Persistence rates were 51.5%, 44.6% and 36.4% at 1, 2 and 3 years respectively. CONCLUSION/CONCLUSIONS:Mirabegron has an excellent safety profile and appears to be an effective treatment for overactive bladder symptoms in patients with PD. Further prospective randomized trials are needed to properly assess mirabegron in PD patients.

OBJECTIVE:To assess the safety and efficacy of intradetrusor onabotulinum toxin A injections for the treatment of overactive bladder (OAB) in patients with Parkinson's disease (PD). METHODS:All PD patients who underwent intradetrusor injections of onabotulinum toxin A (BoNT-A) for storage symptoms between 2010 and 2017 were included in a retrospective study. A 100 U dose of BoNT-A (Botox®, Allergan Irvine, CA) was used for the first injection in all patients. The primary endpoint was clinical success defined as any subjective improvement in OAB symptoms self-assessed by the patients 4 weeks after the injections. RESULTS:Out of 24 patients analyzed, 19 reported improvement of their OAB symptoms 4 weeks after the first injection (79.2%) with complete resolution of urgency urinary incontinence in seven patients (29.1%; P < 0.001). The average post-void residual (PVR) increased significantly after the first injection from 17.6 to 125.3 mL (P < 0.001). Three of the patients had to start clean intermittent catheterization (CIC) after the first injection (12.5%). Out of 49 injections in total, only five caused incomplete bladder emptying requiring the use of CIC (10.2%). Higher pre-injection PVR was significantly associated with both a lower chance of symptomatic improvement (P = 0.04) and a higher risk of incomplete bladder emptying with institution of CIC (P = 0.047). CONCLUSION/CONCLUSIONS:Intradetrusor injections of BoNT-A 100 U appeared as a safe and effective option in PD patients with OAB symptoms and a low PVR before the injection. Higher preoperative PVR was the strongest predictor of both treatment failure and postoperative urinary retention requiring CIC.

Parkinson's disease (PD) is a complex, multisymptom, neurodegenerative disease affecting primarily older adults. With progression, many individuals become homebound and removed from coordinated, expert care, resulting in excess morbidity, mortality, and healthcare expenditures in acute care settings and institutions. Home visit care models have achieved the triple aim of improving individual and population health while reducing costs in many frail, community-dwelling geriatric cohorts. This study details a novel, interdisciplinary home visit program specifically designed for individuals with PD and related disorders and their family caregivers built upon best practice principles in the care of multimorbid older adults. At each quarterly home visit, a movement disorders-trained neurologist, social worker, and nurse work in parallel with the individual and caregiver to complete a history, physical, detailed medication reconciliation, psychosocial needs assessment, and home safety assessment. A comprehensive, person-centered plan is agreed upon, referrals to community resources are made, standardized documentation is shared, and follow-up communication is instituted. In the first 2 years, 272 visits were conducted with 85 individuals who represent one of the oldest, most disabled PD populations reported. Satisfaction with and retention in the program were high. This study represents the first translation of the success of interdisciplinary and home-based geriatric care models to a population with a specific neurological disease. Preliminary evidence supports the need for such programs in vulnerable populations. Future studies will prospectively assess person-centered outcomes, the effect of using telemedicine on sustainability, and cost effectiveness.

Cramp-fasciculation syndrome (CFS) is a rare muscle hyperexcitability syndrome that presents with muscle cramps, fasciculations, and stiffness, as well as pain, fatigue, anxiety, hyperreflexia, and paresthesias. Although familial cases have been reported, a genetic etiology has not yet been identified. We performed whole-exome sequencing followed by validation and cosegregation analyses on a father-son pair with CFS. Both subjects manifested other hypersensitivity-hyperexcitability symptoms, including asthma, gastroesophageal reflux, migraine, restless legs syndrome, tremor, cold hyperalgesia, and cardiac conduction defects. Most symptoms improved with carbamazepine, consistent with an underlying cation channelopathy. We identified a variant in the transient receptor potential ankyrin A1 channel (TRPA1) gene that selectively cosegregated with CFS and the other hypersensitivity-hyperexcitability symptoms. This variant (c.2755C>T) resulted in a premature stop codon at amino acid 919 (p.Arg919*) in the outer pore of the channel. TRPA1 is a widely distributed, promiscuous plasmalemmal cation channel that is strongly implicated in the pathophysiology of the specific hypersensitivity-hyperexcitability symptoms observed in these subjects. Thus, we have identified a novel TRPA1 variant that is associated with CFS as part of a generalized hypersensitivity-hyperexcitability disorder. These findings clarify the diverse functional roles of TRPA1, and underscore the importance of this channel as a potential therapeutic target.

Idiopathic normal pressure hydrocephalus (iNPH) is the most common cause of hydrocephalus in adults. The diagnosis may be challenging, requiring collaborative efforts between different specialists. According to the International Society for Hydrocephalus and Cerebrospinal Fluid Disorders, iNPH should be considered in the differential of any unexplained gait failure with insidious onset. Recognizing iNPH can be even more difficult in the presence of comorbid neurologic disorders. Among these, idiopathic Parkinson's disease (PD) is one of the major neurologic causes of gait dysfunction in the elderly. Both conditions have their peak prevalence between the 6th and the 7th decade. Importantly, postural instability and gait dysfunction are core clinical features in both iNPH and PD. Therefore, diagnosing iNPH where diagnostic criteria of PD have been met represents an additional clinical challenge. Here, we report a patient with parkinsonism initially consistent with PD who subsequently displayed rapidly progressive postural instability and gait dysfunction leading to the diagnosis of concomitant iNPH. In the following sections, we will review the clinical features of iNPH, as well as the overlapping and discriminating features when degenerative parkinsonism is in the differential diagnosis. Understanding and recognizing the potential for concomitant disease are critical when treating both conditions.

Introduction Non-invasive brain stimulation can be used in combination with rehabilitative therapies or physical exercises to enhance or improve function [1- 2]. It is believed that the combination of physical rehabilitation and brain stimulation may offer a greater or more sustained effect than either therapy alone [3]. The mechanisms underlying this potential synergistic effect are not fully known but may rely on associative plasticity [4]. It is known that task-specific training can induce task-specific neuronal changes based on use-dependent plasticity phenomena. However, training alone may produce a subliminal neural activation, resulting in only transient synaptic changes, whereas brain stimulation has been demonstrated effective to induce long-term potentiation (LTP)-like phenomena, presumably through Hebbian mechanisms [5]. In a previous study at our Lab, we demonstrated that repetitive transcranial magnetic stimulation (rTMS) could modulate motor memory in patients affected by Parkinson's disease (PD) [6]. Specifically, we showed that rTMS (and not sham), applied after the acquisition of a simple motor skill could increase motor skill retention. In our previous study, the effect of rTMS on skill retention was assessed through a visuomotor adaptation task consisting of a series of ballistic hand movements to reach a radially arrayed target by moving a cursor on a digitized tablet. Based on our promising results, we now plan to translate the paradigm into a clinical setting with the goal of improving functional restoration. To do so, we recently developed a novel non-invasive neuromodulation protocol pairing multiple, consecutive sessions of physical therapy (PT) for posture and gait rehabilitation back-to-back with rTMS sessions. Postural instability and gait disorders (PIGD) are the most important neurological risk factors for falls. In PD patients, PIGD are notoriously prevalent. Unfortunately, the available pharmacological treatments are scarcely effective, and PT is considered the standard of care [7]. The implementation of this translational study is primarily limited by its actual feasibility in everyday clinical settings. Here, we aimed to explore the feasibility of our protocol and its potential generalization in common clinical practice. This study is a collaborative effort between the Rusk Rehabilitation Institute and the Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders at NYU Langone Medical Center. We took advantage of a consolidated scientific partnership and a conveniently shared location in the same building to develop and test this new therapeutic paradigm. 2. Methods This is a double-blind, randomized, sham-controlled protocol for PD patients referred to PIGD-oriented rehabilitation. Inclusion criteria: age 35-89, diagnosis of PD, recent referral for PIGD-oriented PT at our institution's rehabilitation facilities, Hoehn and Yahr 2 through 4. Referred patients have been pre-screened for eligibility, including potential TMS contraindications, e.g. the presence of implanted devices or history of seizures. Prescreened subjects underwent formal screenings to assess eligibility. All patients provided written, informed consent. PT was delivered by an expert physical therapist on a one-to-one basis and specifically addressed PIGD rehabilitation. The experimental treatment was designed to follow the PT session without interfering with PT standard of care. Pre-established time window limit was 40 minutes maximum and session's frequency were matching PT (1 to 2 times weekly). Following each PT session, patients were immediately directed to our TMS lab to randomly receive rTMS or sham. TMS mapping and motor thresholds were performed at the first session. Clinical outcomes measures were obtained at baseline and following the final PT session. Both patients and PT providers were blinded to the TMS intervention. Preliminary data of feasibility, safety and adherence to the protocol were analyzed. 3. Results Nine patients were consecutively referred to PIGD-oriented PT from August to November 2016 from our Institute. Among these, 7 subjects were telephonically prescreened for the study and were invited to participate (2 were not reached prior to starting initial PT session). Five subjects (71%) were screened and enrolled (1 patient refused participation, and one patient received PT from another provider). The mean age of the sample was 74 +/-8.6 years (4 males). The mean disease duration was 9+/-4.6 years. The mean UPDRS-(III) score was 44.2 +/-10.5. The H&Y stages at screening were 2 (n=1) and 3(n=4). One subject withdrew consent, citing lack of motivation. In this case, the clinical severity of PIGD was very mild (Mini BESTest=26/28). The duration of each TMS or sham session was 20 minutes. The mean resting motor thresholds of the sample was 38%+/-9.8. The average time lapse between PT and TMS/sham delivery during the first session was 23minutes (min: 10 minutes and max: 40 minutes). At the following sessions, the average time lapse between PT and TMS/sham was 13.5 minutes (min: 5minutes and max: 25 minutes). There was 1 adverse event; the subject reported mild neck pain after one of the TMS/ sham sessions. There were no severe adverse events. There were no PT sessions without being followed by the experimental TMS/sham stimulation. A total of 28 paired sessions were completed with 100% compliance. 4. Discussion and Conclusion Our protocol was originally developed and tested in PD participants, but designed to be appropriate for more generalized use. Recently, it has been emphasized how the control of the temporal aspect between motor training and none-invasive brain stimulation is crucial for successful associative plasticity, as the latter is a time-dependent phenomenon [8]. Task execution (or motor training) and brain stimulation should therefore be coupled with proper timing to maximize the possibility of harnessing adequate long-term plastic changes. However, in order to pair rTMS with multiple PT sessions in clinical practice, some practical issues need to be preliminarily addressed. First, the rehabilitation setting where PT is performed should have, or be located near the TMS device. Furthermore, administering TMS after a PT session can present an additional burden for PD patients, whose tolerance and endurance may be limited by comorbid factors including chronic pain, anxiety, apathy and depression. Therefore, the possibility of drop-outs needs to be considered and appreciated. We designed our study so that administration of TMS pulses could promptly follow each PT session within a standardized temporal window of 40 minutes. Such a limited interval implies adequate logistics to ensure an effective, standardized and reproducible work flow. According to our preliminary data, systematic TMS adjuvancy in conjunction with multiple sessions of standard-of-care PT represents a feasible and safe paradigm with good adherence. Limitations of our current work include: small sample size that prevents comprehensive analysis on the efficacy of this paradigm for PIGD, and lack of available data for the paradigm with a wider temporal window. The latter could challenge the further applicability of our protocol in different settings where TMS device and PT practice are not conveniently co-located. Preliminary efficacy data will be analyzed for the generation of future large scale clinical trials. PT training is a fundamental strategy in neuro-rehabilitation, irrespectively to the nature of the damage occurred in the nervous system. If successful, our paradigm will contribute to the definition of new models of rehabilitation with promising, broad applications in different clinical settings

Objective: To identify a genetic cause for familial cramp-fasciculation syndrome (CFS). Background: CFS is a muscle hyperexcitability syndrome that may present not only with muscle cramps, stiffness, and fasciculations, but also with pain, generalized fatigue, anxiety, hyperreflexia, and paresthesias. The clinical features of CFS and improvement with carbamazepine suggest that it may represent a cation channelopathy. Although familial cases have been reported, a genetic etiology for CFS has yet to be identified. Design/Methods: Whole exome sequencing was performed on a father-son pair with carbamazepine-responsive CFS. After filtering for common genetic variations, only seven candidate single nucleotide variants were validated and found to be present in both affected subjects. Disease segregation analyses carried out in four unaffected family members were used to reduce this to a single disease-segregating mutation. An ethnicity-matched control population was used to assess the pathogenicity of this mutation. Results: We identified a novel mutation in the transient receptor potential ankyrin 1 ion channel (TRPA1; MIM #615040) gene in subjects with CFS. This disease-segregating TRPA1 mutation (c.2755C>T) resulted in a premature stop codon at amino-acid 919 (p.Arg919Stop), and was found to be absent in the control population. TRPA1 is a widely distributed, promiscuous plasmalemmal cation channel activated by endogenous and environmental irritants. TRPA1 has been associated with the pathogenesis of pain, paresthesias, and inflammation, and is therefore under investigation as a potential therapeutic target for pain and muscle cramps. The identified mutation was localized to the putative selectivity filter of TRPA1, a region implicated in the pore dilatation process, and thus the degree to which TRPA1 is activated by noxious stimuli. Conclusions: Autosomal dominant CFS is associated with a novel mutation in the putative selectivity filter of TRPA1. These findings further clarify the functional role of human TRPA1, and underscore the importance of this ion channel as a potential therapeutic target