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Introduction: Orthostatic tremor (OT) is a rare neurological disorder characterized by a sensation of instability while standing. Very few clinical signs have been described for OT to date. Finding other symptoms and signs could prove valuable for this hard-to-recognized disease., Methods: This protocol is part of the University of Nebraska Medical Center Orthostatic Tremor longitudinal study. It was noted that OT patients flex their toes and sometimes the foot arch while standing (Plantar Grasp). They reported doing this to "grab" the floor and improve stability. This paper analyses the diagnostic test characteristics of the patient-self-reported Plantar Grasp, a new sign in OT., Results: There were 34 OT patients (88% females), and 20 controls (65% females). Eighty-eight percent of patients with OT reported the plantar grasp sign and none of the controls. The Plantar Grasp Sign was found to be very sensitive (88%), and extremely specific (100%) in our cohort. Non-weighted Negative Likelihood Ratio (NLR) was 0.12. And the 3% prevalence-weighted NLR was so low that the negative post-test probability was close to zero., Conclusion: Due to its high sensitivity, specificity, and ideal likelihood ratio, we propose that the Plantar Grasp sign could be considered to screen patients with possible OT. Further studies are needed to determine the specificity of this sign in OT versus other balance disorders., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: The initial COVID-19 pandemic shutdown led to the canceling of elective surgeries throughout most of the USA and Canada., Objective: This survey was carried out on behalf of the Parkinson Study Group (PSG) to understand the impact of the shutdown on deep brain stimulation (DBS) practices in North America., Methods: A survey was distributed through RedCap® to the members of the PSG Functional Neurosurgical Working Group. Only one member from each site was asked to respond to the survey. Responses were collected from May 15 to June 6, 2020., Results: Twenty-three sites participated; 19 (83%) sites were from the USA and 4 (17%) from Canada. Twenty-one sites were academic medical centers. COVID-19 associated DBS restrictions were in place from 4 to 16 weeks. One-third of sites halted preoperative evaluations, while two-thirds of the sites offered limited preoperative evaluations. Institutional policy was the main contributor for the reported practice changes, with 87% of the sites additionally reporting patient-driven surgical delays secondary to pandemic concerns. Pre-post DBS associated management changes affected preoperative assessments 96%; electrode placement 87%; new implantable pulse generator (IPG) placement 83%; IPG replacement 65%; immediate postoperative DBS programming 74%; and routine DBS programming 91%., Conclusion: The COVID-19 pandemic related shutdown resulted in DBS practice changes in almost all North American sites who responded to this large survey. Information learned could inform development of future contingency plans to reduce patient delays in care under similar circumstances., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Orthostatic tremor (OT) is characterized by a sensation of instability while standing, associated with high frequency (1318 Hz) tremor in the legs. Small retrospective series have reported electroencephalography (EEG) findings in OT with discordant results., Methods: We prospectively enrolled 30 OT subjects. Mean age = 68.3 (range 5487) with mean disease duration 16.3 years (range 444). A modified 1020 system EEG recording with additional midline electrodes was obtained. EMG electrodes were placed on quadricep muscles. EEG recording was performed at rest, during sleep and while standing unassisted., Results: In all subjects, EEG showed normal background, normal drowsiness and/or stage 2 sleep, and normal responses to hyperventilation and photic stimulation. These normal results persisted during stance. EEG abnormalities were found in 3 subjects (anterior-mid temporal slow activity), but were not position-dependent and were judged unlikely to be related to OT. Tremor artifact while standing was noted in all subjects, however it was measurable in 26 with frequency in the OT range in 25. When compared with EMG, the average difference in frequency was small at 1.2 Hz (range 0.52.5, p 0.46). Visual EEG analysis in OT patients did not reveal electrographic abnormalities even upon standing unassisted., Discussion: EEG was normal on this prospective, relatively large OT series. Clinicians interpreting video-EEGs should be aware of the OT artifact that can be seen in EEG and EKG leads mostly while standing., Competing Interests: The authors have no competing interests to declare., (Copyright: 2021 The Author(s).)

Background: The exact pathophysiology of primary Orthostatic Tremor (OT) is unknown. A central oscillator is assumed, and previous imaging studies show involvement of cerebellar pathways. However, the presence of ataxia on clinical exam is disputed. We set out to study ataxia in OT prospectively., Methods: EMG-confirmed primary OT subjects and spousal controls received a neurological exam with additional semiquantitative evaluations of ataxia as part of a multinational, prospective study. These included detailed limb coordination (DLC), detailed stance and gait evaluation (DS), and the Brief Ataxia Rating Scale (BARS). Intra- and inter-rater reliability were assessed and satisfactory., Results: 34 OT subjects (mean age = 67 years, 88% female) and 21 controls (mean age = 66 years, 65% male) were enrolled. Average disease duration was 18 years (range 4-44). BARS items were abnormal in 88% of OT patients. The OT subjects were more likely to have appendicular and truncal ataxia with significant differences in DLC, DS and BARS. Ocular ataxia and dysarthria were not statistically different between the groups., Discussion: Mild-to-moderate ataxia could be more common in OT than previously thought. This is supportive of cerebellar involvement in the pathophysiology of OT. We discuss possible implications for clinical care and future research., Highlights: Previous studies of Primary Orthostatic Tremor (OT) have proposed pathophysiologic involvement of the cerebellar pathways.However, presence of ataxia has not been systematically studied in OT.This is a prospective comprehensive ataxia assessment in OT compared to controls. Mild-to-moderate appendiculo-truncal ataxia was found to be common in OT., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2020 The Author(s).)

Introduction: Orthostatic Tremor (OT) is a movement disorder characterized by a sensation of unsteadiness and tremors in the 13-18 Hz range present upon standing. The pathophysiology of OT is not well understood but there is a relationship between the sensation of instability and leg tremors. Despite the sensation of unsteadiness, OT patients do not fall often and balance in OT has not been formally assessed. We present a prospective blinded study comparing balance assessment in patients with OT versus healthy controls., Methods: We prospectively enrolled 34 surface Electromyography (EMG)-confirmed primary OT subjects and 21 healthy controls. Participants underwent evaluations of balance by blinded physical therapists (PT) with standardized, validated, commonly used balance scales and tasks., Results: OT subjects were mostly female (30/34, 88%) and controls were majority males (13/20, 65%). The average age of OT subjects was 68.5 years (range 54-87) and for controls was 69.4 (range 32-86). The average duration of OT symptoms was 18 years. OT subjects did significantly worse on all the balance scales and on most balance tasks including Berg Balance Scale, Functional Gait Assessment, Dynamic Gait Index, Unipedal Stance Test, Functional Reach Test and pull test. Gait speed and five times sit to stand were normal in OT., Conclusions: Common validated balance scales are significantly abnormal in primary OT. Despite the objective finding of impaired balance, OT patients do not commonly have falls. The reported sensation of unsteadiness in this patient population seems to be out of proportion to the number of actual falls. Further studies are needed to determine which components of commonly used balance scales are affected by a sensation of unsteadiness and fear of falling., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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., (© 2017 S. Karger AG, Basel.)

Background: 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., Objective: The objective of this study was to evaluate OT diagnostic test characteristics at bedside using iPhone's built-in accelerometer and available applications for tremor recordings., Methods: We obtained recordings using iPhones (Model 5, 5s, and 6) and free Applications ("LiftPulse" by LiftLabs [App1] and "iSeismometer" by ObjectGraph LLC [App2]) at default settings., Results: 24 EMG-confirmed OT subjects (mostly females, 22/24) and 15 age-matched controls (mostly males, 11/15) were evaluated. App1 detected OT range tremor in 22/24 patients and none of the controls. (Sensitivity = 92%, Specificity = 100%, NPV = 88%). App2 detected OT range tremor in 21/24 patients and in 1/13 controls (Sensitivity = 88%, Specificity = 92%, NPV = 80%). When combined, 24/24 patients and 1/13 controls had OT range tremor (Sensitivity = 100%, Specificity = 92%, NPV = 100%)., Conclusions: Smartphone apps that use the built-in accelerometer provide a simple, accurate and inexpensive bedside screening diagnostic tool for patients with OT.

Animal models and clinical studies have linked the innate and adaptive immune system to the pathology of Parkinson's disease (PD). Despite such progress, the specific immune responses that influence disease progression have eluded investigators. Herein, we assessed relationships between T cell phenotype and function with PD progression. Peripheral blood lymphocytes from two separate cohorts, a discovery cohort and a validation cohort, totaling 113 PD patients and 96 age- and environment-matched caregivers were examined by flow cytometric analysis and T cell proliferation assays. Increased effector/memory T cells (Tem), defined as CD45RO+ and FAS+ CD4+ T cells and decreased CD31+ and α4β7+ CD4+ T cells were associated with progressive Unified Parkinson's Disease Rating Scale III scores. However, no associations were seen between immune biomarkers and increased age or disease duration. Impaired abilities of regulatory T cells (Treg) from PD patients to suppress effector T cell function was observed. These data support the concept that chronic immune stimulation, notably Tem activation and Treg dysfunction is linked to PD pathobiology and disease severity, but not disease duration. The association of T cell phenotypes with motor symptoms provides fresh avenues for novel biomarkers and therapeutic designs.

Objective: To evaluate the possible association of Parkinson disease (PD) and melanoma in North America., Design, Setting, and Patients: Thirty-one centers enrolled patients with idiopathic PD. At visit 1, a neurologist obtained a medical history. At visit 2, a dermatologist recorded melanoma risk factors, performed a whole-body examination, and performed a biopsy of lesions suggestive of melanoma for evaluation by a central dermatopathology laboratory. We compared overall prevalence of melanoma with prevalence calculated from the US Surveillance Epidemiology and End Results (SEER) cancer database and the American Academy of Dermatology skin cancer screening programs., Results: A total of 2106 patients (mean [SD] age, 68.6 [10.6] years; duration of PD, 7.1 [5.7] years) completed the study. Most (84.8%) had received levodopa. Dermatology examinations revealed 346 pigmented lesions; dermatopathological findings confirmed 20 in situ melanomas (0.9%) and 4 invasive melanomas (0.2%). In addition, histories revealed 68 prior melanomas (3.2%). Prevalence (5-year limited duration) of invasive malignant melanoma in the US cohort of patients with PD (n = 1692) was 2.24-fold higher (95% confidence interval, 1.21-4.17) than expected in age- and sex-matched populations in the US SEER database. Age- or sex-adjusted relative risk of any melanoma for US patients was more than 7 times that expected from confirmed cases in American Academy of Dermatology skin cancer screening programs., Conclusions: Melanoma prevalence appears to be higher in patients with PD than in the general population. Despite difficulties in comparing other databases with this study population, the study supports increased melanoma screening in patients with PD.

Background: The role of monoamine oxidase type B inhibitors in the treatment of Parkinson's disease has expanded with the new monoamine oxidase B inhibitor rasagiline and a new formulation, selegiline oral disintegrating tablets. As primary therapy in early disease monoamine oxidase B inhibitors reduce motor disability and delay the need for levodopa. In more advanced disease requiring levodopa, adjunctive monoamine oxidase B inhibitors reduce 'off' time and may improve gait and freezing., Objective: Rasagiline and selegiline oral disintegrating tablets may reduce the safety risks associated with the amfetamine and methamfetamine metabolites of conventional oral selegiline while retaining or improving therapeutic efficacy., Methods: Articles were identified by searches of PubMed and searches on the Internet and reviewed. All articles and other referenced materials were retrieved using the keywords 'Parkinson's disease', 'treatment' and 'monoamine oxidase B inhibitor' and were published between 1960 and 2007, with older references selected for historical significance. Only papers published in English were reviewed., Conclusion: Accumulating data support the use of monoamine oxidase B inhibitors as monotherapy for early and mild Parkinson's disease and as adjunctive therapy for more advanced Parkinson's disease with levodopa-associated motor fluctuations. The recently released monoamine oxidase B inhibitor rasagiline and a new formulation, selegiline oral disintegrating tablets, have potential advantages over conventional oral selegiline.

We examined a sample of individuals in the Nebraska State Parkinson's Disease Registry (NSPDR) to determine what proportion meets standard criteria for Parkinson's disease (PD). The NSPDR was established in 1996 in an effort to understand the high prevalence of PD in Nebraska. Only minimal demographic data are included for each entrant. Subjects enter the NSPDR by means of diagnosing physicians, pharmacists dispensing anti-PD medications and the patients themselves. A series of 356 registrants diagnosed between 1997 and 2001 were contacted and invited to participate in a case-control study. Medical records were reviewed by a single abstractor in a standard manner. When patients consented, history was filled in by interview. A subset of patients were examined by a movement disorders specialist, who assigned all patients a probability of PD. Where sufficient information was available, 78% of registrants were confirmed to have PD (i.e., percent probability > 50%), including 83% of the patients previously diagnosed by a neurologist. Tremor was an initial symptom in 72% of confirmed versus 39% of excluded cases, and resting tremor was present in 86% of those that were confirmed. The most frequent reasons for exclusion were drug-induced Parkinsonism, multiple systems atrophy, vascular disease, and essential tremor. Use of the NSPDR for epidemiologic study requires careful review of the data set before assignment of cases. When histories are compiled in a standardized, comprehensive manner, the necessity for actual patient examinations can be minimized.

Zydis selegiline dissolves on contact with saliva and undergoes pregastric absorption. This minimizes first-pass metabolism and provides high plasma concentrations of selegiline. In this study, the efficacy and safety of Zydis selegiline was assessed in Parkinson's disease (PD) patients who were experiencing motor fluctuations with levodopa. Patients were randomly assigned to either drug or placebo in a 2:1 ratio in this double-blind, multicenter trial. Significant reductions in daily off time occurred at 4 to 6 weeks with the 1.25 mg dose (9.9%, P = 0.003) and 10 to 12 weeks with the 2.5 mg dose (13.2%, P < 0.001). The total number of off hours was reduced by 2.2 hours at Week 12 from baseline (compared with 0.6 hours in the placebo group). The average number of dyskinesia-free on hours for the Zydis selegiline patients increased by 1.8 hours at Week 12. There was no change in mean percentage of "Asleep" time throughout the study. No apparent differences were detected in the occurrence of drug-related adverse events between the Zydis selegiline group and placebo-treated groups. Adverse events were consistent with known effects of levodopa therapy. Zydis selegiline safely reduces daily off time when used as adjunctive therapy with levodopa in patients with PD., (Copyright 2004 Movement Disorder Society)

A solid understanding of the descriptive epidemiology of a disease is essential in etiologic investigations; this includes prevalence and incidence, as well as groups within the larger community who may have noticeably lower or higher rates. We ascertained the usefulness of a non-traditional registry in describing Parkinson's disease (PD) patterns in a community. A passive surveillance PD registry in Nebraska began data collection on 1 January 1997. All physicians were required to report PD diagnosis, pharmacists reported new prescriptions of anti-PD drugs (PD cases were confirmed later with the prescribing physician), and there was a patient self-report mechanism. The overlap of reporting by the sources allowed estimation of the number not reported by any source, using the statistical technique "capture-recapture." As of January 2000, the Nebraska PD Registry had reports of 5,062 PD patients. The number not reported by any Registry reporting source was calculated to be 117, leading to an estimated total of 5,179 cases and a prevalence of 329.3 per 100,000 population. Tabulations of age- and gender-specific prevalence rates, as well as county-level estimates, allow examination of areas of elevated or lowered prevalence. The combination of a passive surveillance system and capture-recapture technique presents a useful method for epidemiologic description, and more traditional survey methods could benefit by including capture-recapture capability., (Copyright 2003 Movement Disorder Society)

Objective: To review the use of the antiepileptic drug gabapentin for the treatment of various types of tremor., Data Sources: A search of biomedical literature was completed through MEDLINE and EMBASE (1993-May 2002) to identify all clinical trials pertaining to the use of gabapentin for the treatment of tremor in humans., Data Synthesis: Outcome data from the few published studies have varied widely. Patient groups have been small, and conclusions have been based largely on subjective patient and investigator ratings., Conclusions: A trial of gabapentin is warranted in patients who fail therapy with traditional agents. Improvement should be measured by a patient's perceived functional ability.

Developmental changes in auditory brainstem responses (ABRs) to clicks and tone bursts were studied in genetically hypothyroid Tshr mutant mice that were homozygous for the hypothyroid trait (hyt/hyt), as well as in euthyroid individuals that were heterozygous for the trait (+/hyt). The developmental role of maternal thyroid hormones was determined by comparing homozygotes that were offspring of euthyroid (hyt/hyt(c)) or hypothyroid (hyt/hyt(h)) dams; all heterozygotes were born to euthyroid dams (+/hyt(e)). Clear responses to high-level stimuli were recorded from heterozygotes on postnatal day 12 (P12) for most stimulus conditions, and thresholds, response amplitudes, interpeak intervals, and latencies developed normally, achieving nearly adult properties by P21. Most hyt/hyt(h) animals were unresponsive to acoustic stimulation throughout the period of study. Grossly immature responses to high-level stimuli were observed in many hyt/hyt(e) pups on P15; however, clear, low-amplitude responses were not routinely observed until P21. Thresholds improved with age in +/hyt(e) and hyt/hyt(e) individuals, and latency-level curves were relatively steep in young animals and developed normally in +/hyt(e) mice with the most significant changes occurring between P15 and P21. In general, hyt/hyt(e) mice exhibited prolonged latencies, interpeak intervals, and central conduction times throughout the age range studied, and slopes of latency-level curves remained abnormally steep through P28. Response amplitudes were generally larger in heterozygotes than in hyt/hyt(e) mice, regardless of level. Replacement of thyroxin during the first 10 postnatal days in hyt/hyt(h) pups had little to no effect on the development of auditory function, although more animals from this group were responsive at very high stimulation levels. We conclude that auditory function is impaired in hypothyroid Tshr animals throughout development and that impairment is profound when individuals are not exposed to maternal thyroid hormone, i.e., a clear thyroxin-dependent critical prenatal period exists in the Tshr mutant mouse.

Based on previous work, it is clear that genetically hypothyroid Tshr(hyt) mutant mice are congenitally deaf [O'Malley et al. (1995) Hear. Res. 88: 181-189, Sprinkle et al. 2001b, J. Assoc. Res. Otolaryngol. DOI: 10.1007/s101620010077]. However, the extent to which auditory development is dependent on the availability of thyroxin (T4) during specific developmental stages is unknown. The aim of this study was to determine the relative importance of prenatal and postnatal thyroxin on the ontogeny of hearing in the hyt mouse. Experimental hypothyroid subjects were offspring of hyt/hyt breeders implanted with T4 or placebo controlled-release pellets 14 days prior to mating. Pups received T4 or saline placebo injections from birth through postnatal day 14 (P14) or the time of testing on P28. In the absence of exogenous T4 replacement, very high stimulus levels (>80 dB SPL) were required to elicit responses. Remarkably, T4 treatment confined to the postnatal period failed to significantly improve auditory function relative to untreated animals, while response thresholds, latencies, and amplitudes of mice born to dams that received T4 during pregnancy were significantly improved relative to both of the untreated groups. Response thresholds were improved somewhat when maternal T4 replacement was followed by treatment during the first 14 days of life, and animals treated throughout prenatal and postnatal life were comparable to those of age-matched euthyroid individuals. Findings from this study show that treatment of hyt/hyt mice with exogenous T4 significantly attenuates hypothyroid-induced otopathology in a develop-mental-stage-dependent manner. In addition, we demonstrate that postnatal development is critically dependent on prenatal exposure to thyroxin and that the critical window of T4 dependence extends throughout development.

The otological consequences of hypothyroidism and the outcome of thyroxin (T4) administration during the developmental period preceding the onset of hearing were examined in mice that express a point mutation in the gene encoding the thyrotropin receptor (Tshr), the so-called hyt mouse. Progeny of sires homozygous for the trait and heterozygous dams were injected with T4 or saline placebo from birth through the tenth postnatal day and auditory-evoked brainstem responses (ABRs) to acoustic clicks and tone bursts were recorded from young adults. Mutant (hyt/hyt) mice exhibited a distinctive pattern of sensory pathology that was characterized by their insensitivity to sound, prolonged response latencies, reduced peak amplitudes, and steep latency-intensity curves relative to the phenotypically normal, euthyroid, +/hyt littermates. Following thyroxin treatment, hyt/hyt mice responded to acoustic stimuli more frequently, were more sensitive to tone bursts throughout their audiometric range, and exhibited decreased latencies and increased amplitudes when compared with placebo-treated homozygous mutants. Although thresholds to acoustic stimuli were improved relative to the untreated group, T4-treated homozygotes were less sensitive than normal, euthyroid individuals. In addition, energy consumption by auditory brainstem nuclei, measured by 2-deoxyglucose (2-DG) uptake, was significantly lower in hyt/hyt mice compared with heterozygotes, and T4 treatment increased the level of 2-DG utilization. Moreover, mean ages for eye-opening and pinna-raising were delayed in animals that were homozygous for the hyt allele. When T4 was administered to hyt/hyt animals, pinna-raising occurred earlier than in untreated animals. A subset of homozygotes exhibited circling behavior, indicative of vestibular and/or motor dysfunction, even though all individuals assumed a normal righting reflex. These findings, including recruitment-like behavior and the restoration of response magnitude at high levels but not low, suggest that the cochlear amplifier is the primary locus of an enduring otological defect associated with hypothyroidism in the Tshr mouse.

The authors of this paper view Parkinson's disease (PD) as a clinically defined progressive syndrome of resting limb tremor, bradykinesia, muscle rigidity, and a shuffling unsteady gait that responds well to dopaminergic medications. Parkinson's disease is a not a single entity, but rather a syndrome with diverse causes, with both genetic and environmental risk factors. The clinician's concern is to rule out other entities, especially those having another specific treatment, and to give PD patients the best short- and long-term benefit, with the least possible unwanted side effects.

We present two cases of hyperacute ischemic stroke that were initially missed by diffusion-weighted imaging; abnormalities in locations corresponding to focal neurologic deficits were discovered by MR angiography and perfusion-weighted imaging. Within hours, follow-up diffusion-weighted scans revealed partial conversion of the hypoperfused regions to complete stroke. These cases illustrate the potential for a nonresolving stroke-in-evolution to go undetected by diffusion-weighted imaging at hyperacute timepoints.

Objective: To evaluate ropinirole hydrochloride as dopaminergic monotherapy in patients with early Parkinson disease., Design: A 6-month extension of a double-blind, placebo-controlled study., Setting: Ambulatory care at 22 different sites in the United States., Patients: Patients who successfully completed the initial 6-month study could enter the 6-month extension study (ropinirole, n = 70; placebo, n = 77)., Intervention: Use of ropinirole or placebo therapy., Main Outcome Measures: The efficacy variables were the number of patients who successfully completed the 12-month study and did not require supplemental levodopa, the number of patients requiring supplemental levodopa, and the proportion of patients having an insufficient therapeutic response., Results: Significantly fewer ropinirole-treated patients met criteria for insufficient therapeutic response (23 [19.8%] of 116) or required the initiation of levodopa therapy (22 [19%] of 116) compared with placebo-treated patients (60 [48%] of 125 patients for insufficient therapeutic response; 57 [45.6%] of 125 patients for additional levodopa). Significantly more ropinirole-treated patients (51 [44.0%] of 116) successfully completed the 12-month study and did not require supplemental levodopa compared with placebo-treated patients (28 [22.4%] of 125). The incidence of adverse experiences and patient withdrawals was low., Conclusion: Ropinirole was effective and well tolerated as monotherapy for 12 months in patients with early Parkinson disease.

Background and Objective: In preparation for analytic study we undertook to describe areas of relative excess and deficit of Parkinson's Disease (PD) in Nebraska and tested two methodologic tools for inexpensive assessment of descriptive epidemiology of PD., Methods: In lieu of large-scale population screening and diagnosis, we obtained sales information of anti-PD drugs in the state in 1988-1990 as well as listings of all people dying from 1984 to 1993 who had Parkinson's Disease mentioned anywhere on their death certificate. The anti-PD drug sales data are intended as a proxy for prevalence, while the death certificate data are intended as a proxy for incidence., Results: Sales divided by population over age 54 indicates where anti-PD drug sales differ from expected. We found high correlation of drug sales rates with several farming exposures. Age-adjusted death rates, however, showed a low degree of association with sales or farming variables. This may be attributable to differences in death certificate completion or in underlying incidence versus prevalence., Conclusions: These techniques provide a useful tool for delineating possible differences in incidence and prevalence. While not as accurate as full community survey with expert diagnosis, they are not as expensive, and can be followed by local cluster investigations and individual-level etiologic studies to test hypotheses resulting from the initial study.

In vivo ethanol exposure reduces in vitro Na+,K(+)-adenosine triphosphatase (Na+,K(+)-ATPase) sensitivity to ethanol in some animal models, but very little is known about the effects of ethanol on human brain Na+,K(+)-ATPase. Cerebral cortex homogenates from 13 male alcoholic and 9 control subjects were assayed for K(+)-p-nitrophenylphosphatase (K(+)-pNPPase, a measure of Na+,K(+)-ATPase) and Mg(2+)-pNPPase activities at 37 degrees for 20 min in 75 mM imidazole-HCl (pH 7.4), 5 mM p-nitrophenylphosphate, 5 mM MgCl2, and 20 mM KCl, with or without 1 mM ouabain. Native K(+)-pNPPase activites were similar in control and alcoholic brains (61.5 +/- 3.5 vs 55.3 +/- 3.1 nmol/mg/min). In vitro exposure to a near lethal ethanol level (0.5%, or 110 mM) was without effect, whereas 5% ethanol inhibited K(+)-pNPPase activity by about 28% (P < 0.001) in both groups. Both 0.5 and 5% ethanol in vitro significantly stimulated Mg(2+)-pNPPase activity (1-2% and 19-20%, respectively). By comparison, mouse brain K(+)-pNPPase was inhibited significantly by in vitro ethanol, and Mg(2+)-pNPPase activity was unaffected. Ethanol levels attainable in humans may not be sufficient to alter significantly brain Na+,K(+)-ATPase activity.

Objective: To identify a possible gene defect in a large kindred with atypical Creutzfeldt-Jakob disease (CJD)., Subjects: Over 360 kindred members, with and without progressive dementia., Methods: Family, hospital, and clinic records were reviewed. The DNA was extracted from paraffin-embedded brain tissue of two deceased patients, and from blood leukocytes of nine healthy persons at risk. DNA was subjected to polymerase chain reaction and then analyzed by restriction endonuclease and single nucleotide primer extension., Results: Nine family members had progressive fatal neurological disease consistent with CJD without myoclonus or typical electroencephalographic findings. Supranuclear gaze palsy was present in all five patients who underwent eye examinations. Two neuropathologically confirmed cases and five of nine at-risk family members had an identical mutation (GAG to AAG, glutamic acid to lysine) in codon 200 of the amyloid gene (PRNP) on chromosome 20., Conclusions: Clinically atypical CJD with early supranuclear gaze palsy but without myoclonus or characteristic electroencephalographic periodicity patterns is associated with the codon 200Lys mutation in the largest CJD kindred yet reported. The clinical concept of familial CJD should be enlarged to include this unusual phenotype.

The effects of changes in photoperiod length upon body weight; spleen, thymus, and testis weights; testis protein content; testis cation pump enzyme activities; and plasma testosterone were studied in the developing Siberian hamster, Phodopus sungorus. Male hamsters were exposed to a cycle of 16L:8D (long-day), until Day 18 when half were switched to a 10L:14D (short-day) cycle, until killed 0, 2, 4, 7, 10, 12, or 15 days later. Body weight and relative testis weight (expressed as percentage of body weight) increased steadily during the first week of exposure. After 10 days, the long-day hamsters consistently weighed more (p less than 0.05). Relative testis weights in the short-day group began to decrease (p less than 0.005) within 10 days and continued to decline. Testis homogenate K(+)-pNPPase- (as a measure of Na+,K(+)-ATPase) and Mg(2+)-pNPPase-specific activities closely paralleled testis weight, with the short-day animals (p less than 0.05) differing after 10 days. Plasma testosterone levels remained below adult levels through exposure Day 15, but were relatively lower (p less than 0.05) in the short-day group after 10 days. Spleen weights were similar for the long- and short-day groups. The short-day group had larger thymus weights after 12 days (p less than 0.05), but thymus enzyme activities did not differ between the two groups. We conclude that cation pump activities in the Siberian hamster testis are significantly affected by changes in photoperiod length.

PET has a promising role in neuroradiology for accurate diagnosis and prognostication of malignant tumors as well as differential diagnosis of radiation necrosis and recurrent tumors. Particularly, PET has proven its ability to accurately differentiate radiation necrosis from recurrent brain tumor. Active tumors have accelerated glycolysis, and a remarkable accumulation of FDG radiotracer in high grade brain tumors is evident on PET images. Tumor metabolism also proportionally increases with increasing pathologic grades of brain tumor, and accelerated tumor metabolism indicates a poor prognosis for the tumor.

The impact of low level lead exposure on human central nervous system function is a major public health concern. This study addresses the inhibition of the cation pump enzyme Na, K-ATPase by low level lead. Human brain tissue was obtained at autopsy and frozen until use. Brain homogenates were preincubated with PbCl2 for 20 min at 0 degrees C. Inhibition of K-paranitrophenylphosphatase (pNPPase), a measure of the dephosphorylation step of Na,K-ATPase, reached steady state within 10 min. K-pNPPase activity, expressed (mean +/- SEM) as a percentage of control (45.2 +/- 2.7 nmol/mg/min), fell to 96.3 +/- 0.9% at 0.25 uM [PbCl2] to 82.0 +/- 1.6% at 2.5 uM [PbCl2] in homogenates prepared from normal brain. Similar results were obtained with homogenates prepared from brains of patients with a history of alcohol abuse and of those with other miscellaneous conditions. Since the mean blood level of lead in the United States has ranged recently from 9.2 to 16.0 ug/dl (0.44 to 0.77 uM), these results indicate that current in vivo levels of lead exposure may impair important human brain function.

The effects of different light wavelengths at equal irradiance on testis weight, testis protein content, and testis K-paranitrophenylphosphatase (K-pNPPase) activity were studied in the Syrian hamster. One group (long photoperiod) was maintained on a light:dark cycle of 14:10, and another group (short photoperiod) on a cycle of 10:14. Five other groups were maintained on a cycle of 10:14 but with a one hour pulse of equally intense illumination in the middle of the dark period with UV, blue, green, yellow or red light. Animals exposed to a long photoperiod or UV, blue or green light pulses had significantly greater testis weights--up to eightfold greater than those in the yellow or red or short photoperiod groups. Organ protein content closely paralleled organ weight, but the protein/wet weight ratio was consistently higher in the large organ groups. K-pNPPase and Mg-pNPPase activities were significantly higher in the large organ groups, even when expressed per mg protein. Therefore, at a balanced irradiance of 0.2uW/cm2, light wavelength exerts a profound effect on testicular weight, protein content, and K-pNPPase and Mg-pNPPase activities. Testicular involution is a process that is selective with regard to protein biosynthesis.

The myelographic contrast agent, metrizamide, causes a temporary confusional state in many patients. Since metrizamide is a 2-deoxyglucose analogue, it was tested for inhibitory effects on glucose metabolism. The Michaelis constant (Km) of human brain hexokinase for glucose rose from 0.039 to 0.24 and 0.47 mM with final metrizamide concentrations of 0, 16 and 32 mM, respectively. The maximal velocity did not change. Since metrizamide is injected into the human CSF in concentrations of up to 780 mM, impairment of brain glucose metabolism can be expected. These effects could be largely counteracted if metrizamide were injected in a 100 mM glucose solution.

Single physiological doses of epinephrine did not affect the blood sugar level of human volunteers though they caused a marked tachycardia that was accompanied by a strong transient sensation, typically described as fullness in the chest. Epinephrine did not cause the release of norepinephrine and/or dopamine in man, in contrast to three other vertebrates (lamprey, eel, and rat). In the human, as in the rat and cyclostomes, the glycemic effect of epinephrine occurs only during stress and/or unphysiological conditions, while the chronotropic effects are probably physiological from cyclostomes to man.

In an attempt to find a simple, noninvasive method for estimating the plasma free concentration (CPf) of phenytoin (PHT), the relationship between urine PHT concentration (Cu) and CPf was studied in 40 epileptic patients who were 6 to 50 yr old. Cu was determined by gas-liquid chromatography and CPf by equilibrium dialysis at 37 degrees. Cu was generally greater than CPf, but correlation between the two was strong (r2 = 0.876) and in the same range as previously published results for saliva and CPf. Correlation of Cu with CPf was not influenced by patient age, urine pH, or urine flow rate. In 24 patients timed urine collections were obtained and calculated renal clearances of PHT were shown to increase in proportion to urine flow rates. Although it is not known if renal impairment and albuminuria will alter the relationship between Cu and CPf it appears that Cu may be useful in estimating the concentration of pharmacologically active PHT in plasma.

Rat brain homogenates were preincubated with lead chloride for 20 min at 0 degrees C. Inhibition of K-pnitrophenylphosphatase (K-pNPPase), which measures the dephosphorylation step of Na,K-ATPase, reached steady state within 10 min and was readily reversible. The activity in brain, homogenates prepared from 60-day-old rats, expressed (mean +/- SE) as a percentage of control (100.0 +/- 0.48%), fell to 89.4 +/- 0.52% at 0.25 microM [Pb] to 64.2 +/- 1.65% at 5 microM [Pb]. However, between 5 and 25 microM [Pb] K-pNPPase activity significantly increased (to 85.4 +/- 3.14% at 25 microM) before it again fell above 30 microM. Similar results were obtained with brain homogenates prepared from 10-day-old rats. The multiphasic nature of this dose-response curve did not change with changes in buffer, substrate, anion, test tube order, or test tube composition (glass vs plastic), and appeared to be intrinsic to homogenate-Pb interactions. Microsomal preparations also exhibited multiphasicity, but with a shift in the inflection points. However, there was no multiphasicity with commercial hog brain Na,K-ATPase, suggesting an interaction between a component in the rat brain preparations and lead ion. Addition of boiled rat brain homogenate to commercial Na,K-ATPase resulted in partial protection from lead inhibition but did not produce multiphasicity over the ranges tested. Bovine serum albumin provided less protection. We conclude that there is a complex interaction among K-pNPPase activity, some factor in the rat brain homogenate, and low levels of lead ion.

Seven affected individuals from three generations in a kindred having over 250 members were identified as having possible, probable, or definite Creutzfeldt-Jakob disease. Spongiform encephalopathy was found at postmortem examination in two cases. Detailed inpatient neurological examinations were performed on four of the subjects, three of whom were first observed with supranuclear gaze paralysis, gait ataxia, and rapidly progressive dementia. Supranuclear gaze paresis can be seen as an early feature of Creutzfeldt-Jakob disease, although it has been regarded as a late sign. In this, the largest reported kindred of Creutzfeldt-Jakob disease, most of the affected patients were farmers. Possible modes of infection are discussed.

The effects of mild periodate exposure on the kinetics of (Na+ + K+)-ATPase and K+-p-nitrophenylphosphatase were studied using rat cerebral microsome preparations. Fifty percent inhibition of both enzyme activities was attained near 3 microM periodate concentrations. This inhibition was biphasic with time. Mg2+-ATPase and Mg2+-p-nitrophenylphosphatase activities were much less inhibited by periodate. Periodate inhibition was partially reversed by dimercaprol and dithiothreitol but not by diffusion. The possible reaction products formic acid, formaldehyde, glyceraldehyde, and acetaldehyde had no inhibitory effects in similar concentrations. Periodate exposure produced no detectable changes in the activation of (Na+ + K+)-ATPase by Na+, K+, Mg2+, or ATP. Residues shared by both (Na+ + K+)-ATPase and K+-p-nitrophenylphosphatase are both critical to hydrolytic function and sensitive to mild oxidation by periodate.

Marked asterixis occurred in two patients following metrizamide myelography. One also suffered generalized seizures and the other had severe stuttering speech for seven days. The spectrum of toxic manifestations of metrizamide is reviewed with emphasis on the unusual lethargy and other depressive effects seen with this relatively safe agent. The hypothesis that metrizamide exerts a ouabain-like effect on the cortical surface was tested. Metrizamide in concentrations as high as 20 mM had no inhibitory effect on rat cerebral K+-para-nitrophenylphosphatase, a partial reaction of (Na+K+)-adenosine triphosphatase. Because metrizamide is a 2-deoxyglucose analogue, a competitive inhibition of hexokinase at the first step in glycolysis was also postulated. Metrizamide was found to competitively inhibit commercial (microbial) hexokinase. The Michaelis constant for glucose rises from 0.13 to 0.25 to 0.33 to 0.91 mM in the presence of 0, 0.4, 1.0, and 2.0 mM metrizamide, respectively. Since the concentration of metrizamide over the cerebral cortex after routine myelography may be approximately 50 mM compared with a glucose concentration of only 3.6 mM (65 mg/dl), it is postulated that impaired brain glucose metabolism may be responsible for some of the toxic effects of metrizamide.

A 27-year-old woman who had undergone extensive small bowel resection at age 14 months developed kyphoscoliosis, ocular palsies, constricted visual fields, retinitis pigmentosa, progressive ataxia, muscular weakness, nearly absent vibration and impaired position sense, areflexia, extensor plantar responses, and macrocytic anemia. Her condition closely resembled Bassen-Kornzweig disease, but lipoprotein electrophoresis was normal. Mild fat malabsorption, lactic acidosis, and severe deficiency of vitamins A and E and carotene were documented. Serum B12 and folic acid levels were normal. During vitamin A and E therapy sufficient to elevate serum levels to the normal range, there was improvement of visual fields and visual acuity in dim light, lactic acidosis, and red cell volume. Progression of symptoms was halted during vitamin replacement therapy, and her gait improved. This syndrome is the human counterpart to vitamin E deficiency in experimental animals.

We have compared the competitive inhibitory effects of 2-deoxyglucose, glucosamine, N-acetylglucosamine, N-benzoylglucosamine, and the commonly used radiographic and density gradient agent metrizamide (2-[3-acetamido-2,4,6-triiodo-5-(N-methylacetamido) benzamido]-2-deoxyglucose) on the mitochondrial and soluble forms of human brain hexokinase. Metrizamide produces a classical competitive inhibition with glucose for human brain hexokinase, with Kis of 2.8 and 2.5 mM, respectively, for the mitochondrial and soluble forms. Glucosamine exhibited Kis of 0.58 and 0.29 mM, while 2-deoxyglucose exhibited Kis of 0.074 and 0.15 mM and N-acetylglucosamine 0.098 and 0.092 mM for these two forms, respectively. N-Benzoylglucosamine was by far the most effective inhibitor tested, with Ki values of 0.0086 and 0.022 mM, respectively. In order of increasing potency as a competitive inhibitor for mitochondrial hexokinase are metrizamide, glucosamine, N-acetylglucosamine, 2-deoxyglucose, and N-benzoylglucosamine. For the soluble form of the enzyme in increasing potency are metrizamide, glucosamine, 2-deoxyglucose, N-acetylglucosamine, and N-benzoylglucosamine. Since N-benzoylglucosamine was over 100 times more potent than metrizamide, some of the effects of metrizamide could be due to contamination by N-benzoylglucosamine. However, gas chromatography-mass spectrometry analysis of metrizamide did not indicate the presence of N-benzoyl-glucosamine. In addition, column chromatographic separation of commercially available metrizamide and reconstitution of freeze-dried eluate fractions localized the inhibitory effect to the metrizamide peak.

The effects of metrizamide on the kinetics of rat brain hexokinase were compared in vitro with those of 2-deoxyglucose and glucosamine. Although metrizamide, 2-deoxyglucose, and glucosamine are known to be competitive inhibitors of approximately equal potency for glucose of yeast hexokinase (Ki approximately 0.7 mM for all three), metrizamide is a much weaker competitive inhibitor (Ki about 20 mM) of rat brain hexokinase than either 2-deoxyglucose or glucosamine (Ki about 0.3 mM for both). This indicates a greater active site specificity of rat brain hexokinase than of yeast hexokinase. Rat brain hexokinase activity is enhanced approximately threefold in the presence of 0.05, 0.2, and 0.8 mg/ml bovine serum albumin, while yeast hexokinase is only enhanced by 50% under these conditions. Despite the high Ki value for metrizamide, interference with glucose metabolism may occur whenever metrizamide is present in much higher concentrations than glucose. Myelography in humans is one such situation.

We compared the effect of metrizamide and its parent compound glucosamine on the kinetics of dog brain hexokinase. The Michaelis constant (Km) for glucose rose from 0.065 to 0.15 to 0.28 mM in the presence of 0, 16, and 32 mM metrizamide, respectively. For 0, 1.5, and 3.7 mM glucosamine, the Km values were 0.065, 0.4, and 1.3 mM. No change was found in the maximal velocity with either inhibitor. Metrizamide is therefore a rather weak competitive inhibitor of brain hexokinase. However, since the brain or spinal cord may be exposed to metrizamide concentrations near 780 mM during myelography, it is predictable that glucose metabolism may be significantly impaired under these conditions. This may be the mechanism for some cases of metrizamide encephalopathy.

This was a search for endogenous inhibitors of the cation pump enzyme in normal and ischemic gerbil brain. The first model of ischemia was bilateral common carotid clamping for 30 minutes followed by reperfusion periods of 0, 1, 2.5, and 4 hours. After bilateral clamping, K-paranitrophenylphosphatase (K-pNPPase) activity fell significantly after 0, 1, and 2.5 hours of reflow but only slightly by 4 hours. The second model was decapitation with timed delays of 0, 15, 60 and 240 minutes. There was no decline in K-pNPPase activity after total ischemia produced by decapitation. Thus, the model of partial ischemia was more deleterious to the cation pump enzyme than was the model of total ischemia. All brains contained endogenous K-pNPPase inhibitors. Boiled supernatant fractions inhibited K-pNPPase activity by about 50-60% while Amicon filtrates of brain homogenate inhibited about 12%. Factors in normal and ischemic brain may modify the activity of the cation pump enzyme, but no differences in inhibitory effects were found between normal and ischemic brain extracts.