Jeff M. Bronstein

Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease

BACKGROUND Deep-brain stimulation is the surgical procedure of choice for patients with advanced Parkinsons disease. The globus pallidus interna and the subthalamic nucleus are accepted targets for this procedure. We compared 24-month outcomes for patients who had undergone bilateral stimulation of the globus pallidus interna (pallidal stimulation) or subthalamic nucleus (subthalamic stimulation). METHODS At seven Veterans Affairs and six university hospitals, we randomly assigned 299 patients with idiopathic Parkinsons disease to undergo either pallidal stimulation (152 patients) or subthalamic stimulation (147 patients). The primary outcome was the change in motor function, as blindly assessed on the Unified Parkinsons Disease Rating Scale, part III (UPDRS-III), while patients were receiving stimulation but not receiving antiparkinsonian medication. Secondary outcomes included self-reported function, quality of life, neurocognitive function, and adverse events. RESULTS Mean changes in the primary outcome did not differ significantly between the two study groups (P=0.50). There was also no significant difference in self-reported function. Patients undergoing subthalamic stimulation required a lower dose of dopaminergic agents than did those undergoing pallidal stimulation (P=0.02). One component of processing speed (visuomotor) declined more after subthalamic stimulation than after pallidal stimulation (P=0.03). The level of depression worsened after subthalamic stimulation and improved after pallidal stimulation (P=0.02). Serious adverse events occurred in 51% of patients undergoing pallidal stimulation and in 56% of those undergoing subthalamic stimulation, with no significant between-group differences at 24 months. CONCLUSIONS Patients with Parkinsons disease had similar improvement in motor function after either pallidal or subthalamic stimulation. Nonmotor factors may reasonably be included in the selection of surgical target for deep-brain stimulation. (ClinicalTrials.gov numbers, NCT00056563 and NCT01076452.)

CNS Myelin and Sertoli Cell Tight Junction Strands Are Absent in Osp/Claudin-11 Null Mice

Oligodendrocyte-specific protein (OSP)/claudin-11 is a recently identified transmembrane protein found in CNS myelin and testis with unknown function. Herein we demonstrate that Osp null mice exhibit both neurological and reproductive deficits: CNS nerve conduction is slowed, hindlimb weakness is conspicuous, and males are sterile. Freeze fracture reveals that tight junction intramembranous strands are absent in CNS myelin and between Sertoli cells of mutant mice. Our results demonstrate that OSP is the mediator of parallel-array tight junction strands and distinguishes this protein from other intrinsic membrane proteins in tight junctions. These novel results provide direct evidence of the pivotal role of the claudin family in generating the paracellular physical barrier of tight junctions necessary for spermatogenesis and normal CNS function.

Deep Brain Stimulation for Parkinson Disease: An Expert Consensus and Review of Key Issues

OBJECTIVE To provide recommendations to patients, physicians, and other health care providers on several issues involving deep brain stimulation (DBS) for Parkinson disease (PD). DATA SOURCES AND STUDY SELECTION An international consortium of experts organized, reviewed the literature, and attended the workshop. Topics were introduced at the workshop, followed by group discussion. DATA EXTRACTION AND SYNTHESIS A draft of a consensus statement was presented and further edited after plenary debate. The final statements were agreed on by all members. CONCLUSIONS (1) Patients with PD without significant active cognitive or psychiatric problems who have medically intractable motor fluctuations, intractable tremor, or intolerance of medication adverse effects are good candidates for DBS. (2) Deep brain stimulation surgery is best performed by an experienced neurosurgeon with expertise in stereotactic neurosurgery who is working as part of a interprofessional team. (3) Surgical complication rates are extremely variable, with infection being the most commonly reported complication of DBS. (4) Deep brain stimulation programming is best accomplished by a highly trained clinician and can take 3 to 6 months to obtain optimal results. (5) Deep brain stimulation improves levodopa-responsive symptoms, dyskinesia, and tremor; benefits seem to be long-lasting in many motor domains. (6) Subthalamic nuclei DBS may be complicated by increased depression, apathy, impulsivity, worsened verbal fluency, and executive dysfunction in a subset of patients. (7) Both globus pallidus pars interna and subthalamic nuclei DBS have been shown to be effective in addressing the motor symptoms of PD. (8) Ablative therapy is still an effective alternative and should be considered in a select group of appropriate patients.

Parkinson's Disease and Residential Exposure to Maneb and Paraquat From Agricultural Applications in the Central Valley of California

Evidence from animal and cell models suggests that pesticides cause a neurodegenerative process leading to Parkinsons disease (PD). Human data are insufficient to support this claim for any specific pesticide, largely because of challenges in exposure assessment. The authors developed and validated an exposure assessment tool based on geographic information systems that integrated information from California Pesticide Use Reports and land-use maps to estimate historical exposure to agricultural pesticides in the residential environment. In 1998-2007, the authors enrolled 368 incident PD cases and 341 population controls from the Central Valley of California in a case-control study. They generated estimates for maneb and paraquat exposures incurred between 1974 and 1999. Exposure to both pesticides within 500 m of the home increased PD risk by 75% (95% confidence interval (CI): 1.13, 2.73). Persons aged < or =60 years at the time of diagnosis were at much higher risk when exposed to either maneb or paraquat alone (odds ratio = 2.27, 95% CI: 0.91, 5.70) or to both pesticides in combination (odds ratio = 4.17, 95% CI: 1.15, 15.16) in 1974-1989. This study provides evidence that exposure to a combination of maneb and paraquat increases PD risk, particularly in younger subjects and/or when exposure occurs at younger ages.

Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders: Report of the Guideline Development Subcommittee of the American Academy of Neurology

Objective: To determine the efficacy of medical marijuana in several neurologic conditions. Methods: We performed a systematic review of medical marijuana (1948–November 2013) to address treatment of symptoms of multiple sclerosis (MS), epilepsy, and movement disorders. We graded the studies according to the American Academy of Neurology classification scheme for therapeutic articles. Results: Thirty-four studies met inclusion criteria; 8 were rated as Class I. Conclusions: The following were studied in patients with MS: (1) Spasticity: oral cannabis extract (OCE) is effective, and nabiximols and tetrahydrocannabinol (THC) are probably effective, for reducing patient-centered measures; it is possible both OCE and THC are effective for reducing both patient-centered and objective measures at 1 year. (2) Central pain or painful spasms (including spasticity-related pain, excluding neuropathic pain): OCE is effective; THC and nabiximols are probably effective. (3) Urinary dysfunction: nabiximols is probably effective for reducing bladder voids/day; THC and OCE are probably ineffective for reducing bladder complaints. (4) Tremor: THC and OCE are probably ineffective; nabiximols is possibly ineffective. (5) Other neurologic conditions: OCE is probably ineffective for treating levodopa-induced dyskinesias in patients with Parkinson disease. Oral cannabinoids are of unknown efficacy in non–chorea-related symptoms of Huntington disease, Tourette syndrome, cervical dystonia, and epilepsy. The risks and benefits of medical marijuana should be weighed carefully. Risk of serious adverse psychopathologic effects was nearly 1%. Comparative effectiveness of medical marijuana vs other therapies is unknown for these indications.

Randomized trial of deep brain stimulation for Parkinson disease: Thirty-six-month outcomes

Objectives: Our objective was to compare long-term outcomes of deep brain stimulation (DBS) of the globus pallidus interna (GPi) and subthalamic nucleus (STN) for patients with Parkinson disease (PD) in a multicenter randomized controlled trial. Methods: Patients randomly assigned to GPi (n = 89) or STN DBS (n = 70) were followed for 36 months. The primary outcome was motor function on stimulation/off medication using the Unified Parkinsons Disease Rating Scale motor subscale. Secondary outcomes included quality of life and neurocognitive function. Results: Motor function improved between baseline and 36 months for GPi (41.1 to 27.1; 95% confidence interval [CI] −16.4 to −10.8; p < 0.001) and STN (42.5 to 29.7; 95% CI −15.8 to −9.4; p < 0.001); improvements were similar between targets and stable over time (p = 0.59). Health-related quality of life improved at 6 months on all subscales (all p values significant), but improvement diminished over time. Mattis Dementia Rating Scale scores declined faster for STN than GPi patients (p = 0.01); other neurocognitive measures showed gradual decline overall. Conclusions: The beneficial effect of DBS on motor function was stable and comparable by target over 36 months. Slight declines in quality of life following initial gains and gradual decline in neurocognitive function likely reflect underlying disease progression and highlight the importance of nonmotor symptoms in determining quality of life. Classification of Evidence: This study provides Class III evidence that improvement of motor symptoms of PD by DBS remains stable over 3 years and does not differ by surgical target. Neurology® 2012;79:55–65

Parkinson’s disease risk from ambient exposure to pesticides

Due to the heavy and expanding agricultural use of neurotoxic pesticides suspected to affect dopaminergic neurons, it is imperative to closely examine the role of pesticides in the development of Parkinson’s disease (PD). We focus our investigation on pesticide use in California’s heavily agricultural central valley by utilizing a unique pesticide use reporting system. From 2001 to 2007, we enrolled 362 incident PD cases and 341 controls living in the Central Valley of California. Employing our geographic information system model, we estimated ambient exposures to the pesticides ziram, maneb, and paraquat at work places and residences from 1974 to 1999. At workplaces, combined exposure to ziram, maneb, and paraquat increased risk of PD three-fold (OR: 3.09; 95% CI: 1.69, 5.64) and combined exposure to ziram and paraquat, excluding maneb exposure, was associated with a 80% increase in risk (OR:1.82; 95% CI: 1.03, 3.21). Risk estimates for ambient workplace exposure were greater than for exposures at residences and were especially high for younger onset PD patients and when exposed in both locations. Our study is the first to implicate ziram in PD etiology. Combined ambient exposure to ziram and paraquat as well as combined ambient exposure to maneb and paraquat at both workplaces and residences increased PD risk substantially. Those exposed to ziram, maneb, and paraquat together experienced the greatest increase in PD risk. Our results suggest that pesticides affecting different mechanisms that contribute to dopaminergic neuron death may act together to increase the risk of PD considerably.

Nonsteroidal anti-inflammatory drugs may protect against Parkinson disease

Objective: Markers of neuroinflammation, including activated microglia and increased levels of circulating proinflammatory cytokines, have been observed in the brains and CSF of patients with Parkinson disease (PD). Yet the link between anti-inflammatory agents and PD in humans remains uncertain, despite indications that neuroinflammation may contribute to cell death in the PD brain and experimental evidence of anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) exerting neuroprotective effects in animal models. Methods: Using a population-based approach, we studied NSAID use among 293 incident idiopathic PD cases and 286 age-, race-, and gender-matched controls from three rural California counties. Results: Our data suggested a decreased risk of PD among regular (≥2 pills/week for at least 1 month) aspirin NSAID users (OR, 0.80; 95% CI, 0.56 to 1.15). A stronger protective effect was observed for regular nonaspirin NSAID users (OR, 0.52; 95% CI, 0.35 to 0.79), particularly those who reported 2 or more years of use (OR, 0.44; 95% CI, 0.26 to 0.74). The aspirin effect estimates differed by gender, showing a protective effect only in women, especially among long term (≥24 months) regular users (OR, 0.51; 95% CI, 0.26 to 1.02). Conclusion: Our study contributes to the growing body of literature suggesting a protective role for nonsteroidal anti-inflammatory drugs (NSAIDs) in Parkinson disease (PD). Given our results and the biologic plausibility of a neuroprotective function for NSAIDs there is a pressing need for further studies elucidating the protective role such drugs may play in PD. GLOSSARY: MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NSAIDs = nonsteroidal anti-inflammatory drugs; PD = Parkinson disease.

Dopamine Transporter Genetic Variants and Pesticides in Parkinson's Disease

Background Research suggests that independent and joint effects of genetic variability in the dopamine transporter (DAT) locus and pesticides may influence Parkinson’s disease (PD) risk. Materials Methods: In 324 incident PD patients and 334 population controls from our rural California case–control study, we genotyped rs2652510, rs2550956 (for the DAT 5′ clades), and the 3′ variable number of tandem repeats (VNTR). Using geographic information system methods, we determined residential exposure to agricultural maneb and paraquat applications. We also collected occupational pesticide use data. Employing logistic regression, we calculated odds ratios (ORs) for clade diplotypes, VNTR genotype, and number of susceptibility (A clade and 9-repeat) alleles and assessed susceptibility allele–pesticide interactions. Results PD risk was increased separately in DAT A clade diplotype carriers [AA vs. BB: OR = 1.66; 95% confidence interval (CI), 1.08–2.57] and 3′ VNTR 9/9 carriers (9/9 vs. 10/10: OR = 1.8; 95% CI, 0.96–3.57), and our data suggest a gene dosing effect. Importantly, high exposure to paraquat and maneb in carriers of one susceptibility allele increased PD risk 3-fold (OR = 2.99; 95% CI, 0.88–10.2), and in carriers of two or more alleles more than 4-fold (OR = 4.53; 95% CI, 1.70–12.1). We obtained similar results for occupational pesticide measures. Discussion Using two independent pesticide measures, we a) replicated previously reported gene–environment interactions between DAT genetic variants and occupational pesticide exposure in men and b) overcame previous limitations of nonspecific pesticide measures and potential recall bias by employing state records and computer models to estimate residential pesticide exposure. Conclusion Our results suggest that DAT genetic variability and pesticide exposure interact to increase PD risk.

Clinical Characteristics in Early Parkinson’s Disease in a Central California Population-Based Study

There is considerable variation in the phenotypic appearance of individuals with idiopathic Parkinsons disease (PD), which may translate into differences in disease progression in addition to underlying disease etiology. In this publication, we report on the demographic and clinical characteristics of 162 individuals diagnosed with clinically probable PD from January 1998 to June 2003 who resided in predominantly rural communities in central California. The majority of the subjects were Caucasian, male, and between 60 and 79 years of age. The akinetic–rigid and tremor‐dominant subtypes were more common than the mixed subtype. The majority of subjects displayed motor signs of rigidity (92.0%), bradykinesia (95.7%), and gait problems (87.0%), whereas less than half (43.3%) of the subjects displayed a tremor. Three fourths of patients received a Hoehn and Yahr Scale score of Stage 2 or higher. One third of the patients were treated with levodopa, and patients under 60 years of age were more likely to be treated with dopamine agonists. Within 3 years after first diagnosis, 13% of subjects showed some signs of depression and 17% of subjects met criteria for mild dementia. Among our subjects, 17.3% reported a family history of PD in first‐ or second‐degree relatives,15.4% a family history of essential tremor, and 14.2% of Alzheimers disease. This study represents the most extensive phenotypic description of rural U.S. residents in the initial stages of PD who were recruited in a population‐based manner; future follow‐up may provide valuable information regarding the prognostic indication of these symptoms/signs and improve our understanding of the underlying etiology of PD.