William C. Koller’s research while affiliated with Icahn School of Medicine at Mount Sinai and other places

Experimental studies suggest that deep brain stimulation (DBS) of the subthalamic nucleus (STN) induces impulsivity in patients with Parkinson's disease (PD). The purpose of this study was to assess various measures of impulse control in PD patients with STN DBS in comparison to patients receiving medical therapy. In a cross-sectional evaluation, 53 consecutively eligible patients were assessed for impulsivity with the Barratt Impulsiveness Scale, for impulse control disorders (ICDs) using the Minnesota Impulsive Disorders Interview, and for obsessive-compulsive symptoms using the Maudsley Obsessional-Compulsive Inventory. Independent samples t-tests revealed that compulsivity scores were not different between DBS patients and patients without DBS. However, impulsivity scores were significantly higher in DBS patients. Additionally, ICDs were observed in 3 of 16 (19%) DBS patients and in 3 of 37 (8%) medically treated patients. No association was found between the use of dopamine agonists and impulsivity in DBS patients. Our data suggest that screening for impulsivity and ICDs should be performed prior to DBS, and that patients should be monitored for these problems during follow-up. Prospective trials are needed to confirm the findings of this exploratory study and to elucidate the reasons of a possible induction of impulsivity by STN DBS.

To determine the effects of dopaminergic medication withdrawal in an elderly, demented and minimally ambulatory nursing home population with parkinsonism in New York City. In our double-blind, randomized study, 11 patients (7 males, 4 females) were randomized into 2 groups: one group underwent levodopa medication withdrawal (experimental group) and the other group continued on their levodopa (control group). Patients were evaluated weekly over the course of a month with a neurologic examination and a series of assessment tools, including the motor UPDRS (Unified Parkinson's disease rating scale), Hoehn and Yahr staging scale, the Mini-Mental State Examination (MMSE) and the Nursing Assistant Behavioral Detection Form. An academic nursing home in New York City. The patients had a mean age of 82.00 +/- 10.14 years, with a mean MMSE score of 9.50 +/- 6.60 out of 30.00 maximum. The control and experimental groups did not differ significantly with respect to age (P = .52), dementia severity (P = .35), nor severity of PD symptoms as measured by the UPDRS (P = .22) and Hoehn and Yahr staging (P = .65). Overall, no significant changes were observed between the control and experimental groups in cognitive, behavioral, and motor function across each time period. Of interest, 2 of the drug withdrawal patients showed modest improvements in cognitive function as measured by the MMSE. Our findings suggest that in patients with advanced parkinsonism and dementia, dopaminergic medication withdrawal may be a feasible way to reduce polypharmacy and potential medication-related side effects, with a minimal risk of worsening motor deterioration. Therefore, our findings may have potential implications for a medication intervention that could prevent potential deleterious side effects and improve health-related quality of life in this frail population.

Tremor is a common neurologic symptom that can also be incapacitating to the patient, so effective therapy is needed. The causes of tremor are heterogeneous. Essential tremor (ET) and the tremor associated with Parkinson's disease (PD) are the most common encountered in clinical practice. β-Adrenergic blockers and primidone remain the mainstay of treatment for ET, whereas carbidopa/levodopa and anticholinergics are most beneficial in PD. However, the efficacy of various other medications has been studied in ET and PD, and also in patients with tremor resulting from other conditions, with varying results.

We studied the prevalence of movement disorders in a large nursing home population (397 patients, mean age 86 years) in New York City. Patients were first evaluated by specially trained research coordinators and final clinical diagnoses were confirmed by a movement disorder specialist. A movement disorder was identified in 21% of patients (83/397). The most frequent movement disorders were essential tremor (ET) (8.8%) and parkinsonism (7.1%). Only half of those admitted with a diagnosis of parkinsonism were confirmed in their diagnosis by the movement disorder specialists. Three percent of patients exhibited drug-induced tremor, 1.3% had dystonia, 0.5% had myoclonus and 0.3% had generalized dyskinesias. Overall, our findings underline the high frequency of movement disorders in a nursing home population. The discrepancy between our findings and the prevalence rates for parkinsonism reported on the initial transfer diagnosis emphasizes the difficulty of accurate diagnosis of movement disorders and in particular parkinsonism.

To further explore the efficacy and safety of subcutaneous apomorphine (APO) in treating off episodes in APO-naïve patients with advanced Parkinson's disease (PD). 56 patients receiving optimized oral anti-PD medication were evaluated on separate days for response to single increasing doses of APO. Acute response to oral anti-PD medication and APO dose escalation (2-10 mg) was evaluated under unblinded conditions. At the 4 mg APO dose, placebo was randomly introduced under double-blind crossover conditions. Mean changes from pre-dose in Unified Parkinson's Disease Rating Scale motor scores indicated significant improvement following APO 4 mg versus placebo at 20 min (p=0.0002), 40 min (p<0.0001; maximum improvement) and 90 min (p=0.0229). Improvements showed significant dose-response at 20 min, 40 min (both p<0.0001) and 90 min (p=0.0049). Adverse events were more common with APO than placebo, and also showed significant dose-response (p<0.0001). Common adverse events associated with APO included yawning, dizziness, nausea, somnolence and dyskinesias, and were generally mild to moderate. There were no significant differences between APO and placebo in the incidence of hypotension associated with a postural change from a sitting to standing position. Subcutaneous APO provided rapid, effective relief of off episodes associated with advanced PD.

Welding fume contains manganese (Mn) which is known to be bio-available to and neurotoxic for the central nervous system. Although an essential metal, Mn overexposure may cause manganism, a parkinsonian syndrome. The present welder study sought to improve the clinical portrait of manganism and to determine dose-effect relationships. The welders were employed in the construction of the new Bay Bridge (San Francisco) and welded in confined spaces for up to 2 years with minimal protection and poor ventilation. Neurological, neuropsychological, neurophysiological, and pulmonary examinations were given to 49 welders. Clinical cases were selected on the basis of apriori defined criteria pertaining to welding history and neurological/neuropsychological features. Among the 43 eligible welders, 11 cases of manganism were identified presenting with the following symptoms: sleep disturbance, mood changes, bradykinesia, headaches, sexual dysfunction, olfaction loss, muscular rigidity, tremors, hallucinations, slurred speech, postural instability, monotonous voice, and facial masking. Significant associations between outcome variables and cumulative exposure index (CEI) or blood Mn (MnB) were obtained with CEI for variables implicating attention and concentration, working and immediate memory, cognitive flexibility, and verbal learning; and with MnB for executive function, cognitive flexibility, visuo-spatial construction ability, and visual contrast sensitivity. This study strongly suggests that neuropsychological features contribute in a dose-effect related way to the portrait of manganism usually characterized by tremor, loss in balance, diminished cognitive performance, and signs and symptoms of parkinsonism.

Although adverse neuropsychological and neurological health effects are well known among workers with high manganese (Mn) exposures in mining, ore-processing and ferroalloy production, the risks among welders with lower exposures are less well understood. Confined space welding in construction of a new span of the San Francisco-Oakland Bay Bridge without adequate protection was studied using a multidisciplinary method to identify the dose-effect relationship between adverse health effects and Mn in air or whole blood. Bridge welders (n = 43) with little or no personal protection equipment and exposed to a welding fume containing Mn, were administered neurological, neuropsychological, neurophysiological and pulmonary tests. Outcome variables were analysed in relation to whole blood Mn (MnB) and a Cumulative Exposure Index (CEI) based on Mn-air, duration and type of welding. Welders performed a mean of 16.5 months of welding on the bridge, were on average 43.8 years of age and had on average 12.6 years of education. The mean time weighted average of Mn-air ranged from 0.11-0.46 mg/m(3) (55% >0.20 mg/m(3)). MnB >10 microg/l was found in 43% of the workers, but the concentrations of Mn in urine, lead in blood and copper and iron in plasma were normal. Forced expiratory volume at 1s: forced vital capacity ratios (FEV(1)/FVC) were found to be abnormal in 33.3% of the welders after about 1.5 years of welding at the bridge. Mean scores of bradykinesia and Unified Parkinson Disease Rating Scale exceeded 4 and 6, respectively. Computer assisted tremor analysis system hand tremor and body sway tests, and University of Pennsylvania Smell Identification Test showed impairment in 38.5/61.5, 51.4 and 88% of the welders, respectively. Significant inverse dose-effect relationships with CEI and/or MnB were found for IQ (p<or=0.05), executive function (p<or=0.03), sustaining concentration and sequencing (p<or=0.04), verbal learning (p<or=0.01), working (p<or=0.04) and immediate memory (p<or=0.02), even when adjusted for demographics and years of welding before Bay Bridge. Symptoms reported by the welders while working were: tremors (41.9%); numbness (60.5%); excessive fatigue (65.1%); sleep disturbance (79.1%); sexual dysfunction (58.1%); toxic hallucinations (18.6%); depression (53.5%); and anxiety (39.5%). Dose-effect associations between CEI and sexual function (p<0.05), fatigue (p<0.05), depression (p<0.01) and headache (p<0.05) were statistically significant. Confined space welding was shown to be associated with neurological, neuropsychological and pulmonary adverse health effects. A careful enquiry of occupational histories is recommended for all welders presenting with neurological or pulmonary complaints, and a more stringent prevention strategy should be considered for Mn exposure due to inhalation of welding fume.

The objective of this study is to conduct a dose-finding study of sarizotan in Parkinson's disease (PD) patients with dyskinesia to identify a safe dose and to identify a sensitive dyskinesia rating measure. Sarizotan is a novel compound with full 5-HT(1A) agonist properties and additional high affinity for D(3) and D(4) receptors. An open label study documented improvements in PD patients with levodopa-induced dyskinesia. There is no precedent for study designs or outcome measures in pivotal trials of antidyskinesia therapies. The approach used here was a multicenter, randomized, placebo-controlled, double-blind, parallel study. Included were PD patients optimized to levodopa and dopaminergic drugs with moderately disabling dyskinesias present greater than or equal to 25% of the waking day. Interventions included sarizotan 2, 4, or 10 mg/day or matching placebo, given in two doses. There were two outcome measures: the primary measure was change from baseline in diary-based on time without dyskinesia; the secondary measures were change from baseline in scores on the Abnormal Involuntary Movement Scale (AIMS), the composite score of Unified Parkinson's Disease Rating Scale (UPDRS) Items 32+33 (dyskinesia duration and disability) and total UPDRS. A total of 398 subjects were randomized, with 381 included in the intention-to-treat population. No significant changes occurred on sarizotan compared to placebo on any diary-based measure of dyskinesia or the AIMS score. The composite score of UPDRS Items 32+33 was significantly improved with 2 mg/day sarizotan, with a trend at 10 mg/day. Adverse events were not significantly different in sarizotan- and placebo-treated patients, but off time significantly increased with sarizotan 10 mg/day. Sarizotan 2 mg/day is a safe agent in PD patients with dyskinesia. To test its role in abating dyskinesia, future studies should focus on this dose and will use the composite score of UPDRS Items 32+33 as the primary outcome.

Levodopa revolutionized the symptomatic treatment of Parkinson's disease (PD). It is considered the most efficacious drug for PD as it consistently provides better symptom control. Dopamine agonists allow symptoms of PD to be satisfactorily controlled during the first years of disease; however, nearly all dopamine agonist-treated patients require levodopa supplementation. However, the limitations and shortcomings of levodopa therapy are also evident. The disease process has been the subject of considerable controversy. Long-term levodopa treatment contributes to the early development of motor complications and in particular dyskinesias. Motor complications tend to compromise patient's functionality and well-being. However, despite these complications, due to its more favorable side-effect profile and its higher efficacy, levodopa administration is considered a rational choice for individual patients, even in the earlier stages of disease progression. This holds in particular for older de novo patients with less risk for the development of motor complications than patients with early onset of PD.