Danish Bhatti

Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson’s disease trial

A potential therapeutic role for immune transformation in Parkinson’s disease evolves from more than a decade of animal investigations demonstrating regulatory T cell (Treg) nigrostriatal neuroprotection. To bridge these results to human disease, we conducted a randomized, placebo-controlled double-blind phase 1 trial with a well-studied immune modulator, sargramostim (granulocyte-macrophage colony-stimulating factor). We enrolled 17 age-matched non-Parkinsonian subjects as non-treated controls and 20 Parkinson’s disease patients. Both Parkinson’s disease patients and controls were monitored for 2 months for baseline profiling. Parkinson’s disease patients were then randomized into two equal groups to self-administer placebo (saline) or sargramostim subcutaneously at 6 μg/kg/day for 56 days. Adverse events for the sargramostim and placebo groups were 100% (10/10) and 80% (8/10), respectively. These included injection site reactions, increased total white cell counts, and upper extremity bone pain. One urticarial and one vasculitis reaction were found to be drug and benzyl alcohol related, respectively. An additional patient with a history of cerebrovascular disease suffered a stroke on study. Unified Parkinson’s disease rating scale, Part III scores in the sargramostim group showed modest improvement after 6 and 8 weeks of treatment when compared with placebo. This paralleled improved magnetoencephalography-recorded cortical motor activities and Treg numbers and function compared with pretreated Parkinson’s disease patients and non-Parkinsonian controls. Peripheral Treg transformation was linked to serum tryptophan metabolites, including L-kynurenine, quinolinic acid, and serotonin. These data offer a potential paradigm shift in modulating immune responses for potential therapeutic gain for Parkinson’s disease. Confirmation of these early study results requires larger numbers of enrolled patients and further clinical investigation.Immune modulation: translating the benefitsThe immune system modulating drug sargramostim shows promising results in a small clinical trial with Parkinson’s disease (PD) patients. Previous studies have shown that sargramostim increases the number of regulatory T cells, attenuates immune responses, and confers neuroprotection in animal models of neurodegenerative disease. To determine whether these findings translate to humans, Howard E. Gendelman at the University of Nebraska Medical Center, USA, and colleagues examined the effects of sargramostim in 20 patients with PD. Despite the high number of mild to moderate reported adverse events, the drug was generally well tolerated and led to an increase in regulatory T cell number and activity. Moreover, preliminary assessments after 6 and 8 weeks of treatment suggested an overall improvement in the motor skills of patients that received the drug compared with those that received a placebo.

Utilization of rehabilitation therapy services in Parkinson disease in the United States

Objective: To examine rehabilitation therapy utilization for Parkinson disease (PD). Methods: We identified 174,643 Medicare beneficiaries with a diagnosis of PD in 2007 and followed them through 2009. The main outcome measures were annual receipt of physical therapy (PT), occupational therapy (OT), or speech therapy (ST). Results: Outpatient rehabilitation fee-for-service use was low. In 2007, only 14.2% of individuals with PD had claims for PT or OT, and 14.6% for ST. Asian Americans were the highest users of PT/OT (18.4%) and ST (18.4%), followed by Caucasians (PT/OT 14.4%, ST 14.8%). African Americans had the lowest utilization (PT/OT 7.8%, ST 8.2%). Using logistic regression models that accounted for repeated measures, we found that African American patients (adjusted odds ratio [AOR] 0.63 for PT/OT, AOR 0.63 for ST) and Hispanic patients (AOR 0.97 for PT/OT, AOR 0.91 for ST) were less likely to have received therapies compared to Caucasian patients. Patients with PD with at least one neurologist visit per year were 43% more likely to have a claim for PT evaluation as compared to patients without neurologist care (AOR 1.43, 1.30–1.48), and this relationship was similar for OT evaluation, PT/OT treatment, and ST. Geographically, Western states had the greatest use of rehabilitation therapies, but provider supply did not correlate with utilization. Conclusions: This claims-based analysis suggests that rehabilitation therapy utilization among older patients with PD in the United States is lower than reported for countries with comparable health care infrastructure. Neurologist care is associated with rehabilitation therapy use; provider supply is not.

Comorbid Conditions in Parkinson’s Disease: A Population-Based Study of Statewide Parkinson’s Disease Registry

Background/Aims: In 1996, Nebraska became the first state in the United States to establish a Parkinson’s disease (PD) Registry. The objectives of this study were to determine the most common comorbid conditions among PD patients receiving inpatient and outpatient services in Nebraska between 2004 and 2012, and to examine whether PD patients had increased risks of these conditions. Methods: Statewide linkage was performed between Nebraska PD Registry data and hospital discharge database. The cohort comprised of 3,852 PD inpatients and 19,260 non-PD inpatients, and 5,217 PD outpatients and 26,085 non-PD outpatients. Referent subjects were matched to PD patients by age at initial hospital admissions or visits, gender, and county of residence using systematic random-sampling method. Results: Compared to non-PD inpatients, PD inpatients were at higher risks for dementia (relative risk [RR] 2.29; 95% CI 2.14–2.45), mood disorders (RR 1.57; 95% CI 1.44–1.70), gastrointestinal disorders (RR 1.15; 95% CI 1.06–1.25), and urinary tract infections (RR 1.33; 95% CI 1.22–1.45), while PD outpatients had higher risks for spondylosis (RR 1.23; 95% CI 1.09–1.38), genitourinary disorders (RR 1.48; 95% CI 1.29–1.69), gastrointestinal disorders (RR 1.59; 95% CI 1.38–1.84), and dementia (RR 2.83; 95% CI 2.38–3.37) than non-PD outpatients. Conclusions: The findings highlight PD as a multisystem neurodegenerative disorder, and this information is crucial for creating strategies to better prevent and manage PD complications.

Rationale and patient selection for interventional therapies in Parkinson’s disease

ABSTRACT Introduction: Parkinson’s disease (PD) is increasing in prevalence due to a growing elderly population. Although there is no cure, there are exercise therapies and medications for mild to moderate disease. For more advanced disease, infusion or surgical interventions including deep brain stimulation surgery, levodopa carbidopa intestinal gel, and subcutaneous apomorphine infusion are considered. As these interventions become increasingly available, it is imperative for a neurologist involved in the care of advanced PD to be aware of the indications and timing for these interventions. Areas covered: This article attempts to identify different patient profiles and matches them with suggested advanced therapies for PD. There is limited literature providing guidance to a busy neurologist to match the most appropriate advanced therapy to the right patient profile. This article attempts to fill that void. Expert commentary: When matching patient profiles to therapy, several features must be considered: age, frailty, cognitive status, phenotype (predominant tremor vs. akinetic rigid), side effect or complication profile (dyskinesia, hallucinations, dysautonomia), and patient’s comfort with invasive therapy options.

Pathogenesis of Primary Orthostatic Tremor: Current Concepts and Controversies

Background Orthostatic tremor (OT), a rare and complex movement disorder, is characterized by rapid tremor of both legs and the trunk while standing. These disappear while the patient is either lying down or walking. OT may be idiopathic/primary or it may coexist with several neurological conditions (secondary OT/OT plus). Primary OT remains an enigmatic movement disorder and its pathogenesis and neural correlates are not fully understood. Methods A PubMed search was conducted in July 2017 to identify articles for this review. Results Structural and functional neuroimaging studies of OT suggest possible alterations in the cerebello-thalamo-cortical network. As with essential tremor, the presence of a central oscillator has been postulated for OT; however, the location of the oscillator within the tremor network remains elusive. Studies have speculated a possible dopaminergic deficit in the pathogenesis of primary OT; however, the evidence in favor of this concept is not particularly robust. There is also limited evidence favoring the concept that primary OT is a neurodegenerative disorder, as a magnetic resonance spectroscopic imaging study revealed significant reduction in cerebral and cerebellar N-acetyl aspartate (NAA) levels, a marker of neuronal compromise or loss. Discussion Based on the above, it is clear that the pathogenesis of primary OT still remains unclear. However, the available evidence most strongly favors the existence of a central oscillatory network, and involvement of the cerebellum and its connections.

Smartphone Apps Provide a Simple, Accurate Bedside Screening Tool for Orthostatic Tremor

Orthostatic Tremor (OT) is characterized by the presence of a sensation of instability while standing, associated with high frequency (13–18 Hz) lower extremity tremor. Diagnosis is confirmed with surface electromyography (EMG). An accurate screening tool that could be used in the routine clinical setting, without any specialized equipment, would be useful in earlier detection of OT and judicial use of additional testing.