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The term essential tremorhas been in regular use since the second half of the 20th century. To modern neurologists, the word “essential” may seem cryptic. The historical underpinnings of this term have not been examined.

Fragile X–associated tremor/ataxia syndrome (FXTAS) is a recently described, underrecognized neurodegenerative disorder of aging fragile X mental retardation 1 (FMR1) premutation carriers, particularly men. Core motor features are action tremor, gait ataxia, and parkinsonism. Carriers have expanded CGG repeats (55 to 200); larger expansions cause fragile X syndrome, the most common heritable cause of mental retardation and autism. This study determines whether CGG repeat length correlates with severity and type of motor dysfunction in premutation carriers.

For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse “Lewy body disorders” as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of α-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal α-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of α-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for α-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.

The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in ∼50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

To compare fMRI activation during two visual stimulation paradigms in Parkinson disease (PD) subjects with chronic visual hallucinations vs PD patients who had never hallucinated.

To define the long-term outcome in Gilles de la Tourette syndrome (GTS) using objective rating measures.

To examine the long-term outcome of PD patients with psychosis requiring antipsychotic therapy; to explore predictors of mortality, nursing home placement, dementia, and persistent psychosis; and to compare outcomes of those with persistent psychosis vs those whose psychosis resolved.

The authors studied the pharmacokinetics of levodopa (LD) with and without pramipexole (PPX) in men and postmenopausal women with PD. Patients on stable dose of carbidopa/LD were randomized to receive escalating doses of placebo or PPX over 7 weeks. LD and PPX pharmacokinetics were performed after a single test dose 25/100 of carbidopa/LD, before initiation of PPX or placebo, at 1.5 mg/d and 4.5 mg/d of PPX or placebo. Compared to men, women had greater LD bioavailability. PPX did not alter LD bioavailability, and PPX pharmacokinetics were equivalent in men and women.

To monitor the evolution of hallucinations over 4 years in a stratified sample of patients with PD.

To compare olanzapine and clozapine for safety and efficacy measures of psychosis and motor function in patients with PD and chronic hallucinations.

In the past, stereotactic surgery was a regular treatment for prominent unilateral tremor in Parkinson's disease (PD), but follow-up studies were usually short-term and always unblinded. We examined 17 PD patients in long-term follow-up (mean, 10.9 years after surgery) and used videotapes and the Unified Parkinson's Disease Rating Scale to blindly compare tremor ipsilateral and contralateral to the side of surgery. Since the patients were specifically selected for stereotactic surgery because of asymmetric tremor, and the surgical side chosen was contralateral to the predominant tremor, a sign of long-term efficacy would be current postoperative reversal of tremor side predominance. Upper extremity tremor was significantly better contralateral to the surgery compared with the ipsilateral side. We conclude that stereotactic surgery improved the absolute magnitude of tremor or ameliorated its rate of progression. Since asymmetric bradykinesia and dyskinesia were not a prerequisite for the choice of surgical side, we cannot make any conclusion about long-term impact of surgery on these features.

We studied the role of environment in the development of Parkinson's disease (PD) in China, where industrialization is relatively recent and the population geographically stable. Using a case-control method, we investigated the relationship between PD and exposure to the following factors before disease onset: place of residence, source of drinking water, environmental and occupational exposure to various agricultural and industrial processes. Occupational or residential exposure to industrial chemicals, printing plants, or quarries was associated with an increased risk of developing PD. In contrast, living in villages and exposure to the common accompaniments of village life, wheat growing and pig raising, were associated with a decreased risk for PD. PD cases and controls did not differ with respect to other factors investigated. These findings are consistent with the hypothesis that environmental exposure to certain industrial chemicals may be related to the development of PD.

We studied motor and psychomotor changes over 1 year after surgery in 7 patients with severe idiopathic Parkinson's disease (PD) who underwent intrastriatal autologous adrenal medulla transplant. Significant clinical improvements were present 1 year after surgery and primarily involved increased quantity of “on” time and increased quality of “off' time: “on” time increased from a mean 60.7 of the waking day to 82.7, and “off' function improved. In contrast, although “on” function also improved, statistically significant improvement occurred in only 1 measure, the Unified Parkinson's Disease Rating Scale activities of daily living subscale. Medications did not change, and motor fluctuations persisted. Improvement began several weeks after surgery, was maximal at 4 to 6 months, and was sustained thereafter. There was significant group improvement in quality of life measures of sleep and rest, social isolation, and ambulation. One patient had severe, recurrent depression postoperatively. The efficacy of adrenal transplant surgery is not transient, and specific functional improvements can be prolonged.

Ten patients with Parkinson's disease suffering severe motor fluctuations completed a double-blind, placebo-controlled, crossover trial of duodenal infusion of levodopa/carbidopa to determine if this technique improved the duration of functional time by reducing plasma levodopa level variability. With infusion, seven patients experienced increased functional “on” hours and decreased number of “off episodes; however, two patients were slightly worse and one patient experienced no benefit. All 10 patients had significantly decreased variability in levodopa levels permitting better titration of levodopa dosage to individual requirements. Five patients continued to use infusion 12 to 20 months after completion of this study. Selected patients with Parkinson's disease who experience severe motor fluctuations may benefit from duodenal infusion with an improved and prolonged response to medication.

The DATATOP database, which includes clinical information on 800 patients with early untreated Parkinson's disease (PD), is well suited to explore clinical heterogeneity in PD. Patients with early-onset PD (≤40 years, N 33) reached the same level of disability as the late-onset PD (≥70 years, N 85) group at a significantly slower rate (2.9 vs. 1.7 years). Early-onset PD patients functioned cognitively better than late-onset PD patients. Bradykinesia, and postural instability and gait difficulty (PIGD), were more common at onset in patients with a rapid rate of disease progression (“malignant PD”; duration of symptoms <1 year and Hoehnflahr stage of 2.5, N 11) as compared with those with a relatively slow rate of progression (“benign PD”; duration of symptoms >4 years, N 65). Comparisons of tremor-dominant PD (mean tremor score/ mean PIGD score ≤1.5, N 441) with the PIGD-dominant type (mean tremor score/mean PIGD score ≥1.0, N 233) provided support for the existence of clinical subtypes. The PIGD group reported significantly greater subjective intellectual, motor, and occupational impairment than the tremor group. Stage II patients had higher depression scores than stage I patients. Among the patients participating in the DATATOP, older age at onset with bradykinesia, or with the PIGD form of PD, is associated with more functional disability than when the symptoms are dominated by tremor or begin at a younger age.

Thirteen centers participated in a multicenter database with systematic evaluation of US and Canadian patients who had adrenal medullary transplantation for Parkinson's disease. This voluntary registry collected demographic, safety, and efficacy data using the same scoring measures over a 2-year follow-up period. Baseline data on 61 patients and 2-year follow-up data on 56 patients were compared. Eighteen percent died during the study period, and one-half of these deaths were related or questionably related to the surgery. Of the remaining 45 patients with data, global improvement, defined as an improved summed score of the “n” and “off” motor and activities of daily living functions from the Unified Parkinson's Disease Rating Scale, occurred in 32 of the patients at 2 years after surgery. At follow-up, significant group improvement persisted in the amount of daily “on” time and the quality of “off” function, but other measures were no better than baseline. When the global improvement calculation was based on the total sample and included deaths and patients lost to follow-up as “not improved,” only 19 were improved 2 years after surgery. Twenty-two percent of survivors had persistent psychiatric morbidity not present prior to surgery. These data document a modest group improvement in “off” function after neurotransplantation, but a serious level of mortality and morbidity.

The accuracy of the clinical diagnosis of corticobasal degeneration (CBD) is unknown.To determine its diagnostic accuracy, we presented 105 cases with known neuropathologic diagnoses, including CBD (n = 10), progressive supranuclear palsy (PSP, n = 24), Parkinson's disease (n = 15), diffuse Lewy body disease (n = 14), multiple system atrophy (n = 16), postencephalitic parkinsonism (n = 7), Pick's disease (n = 7), Creutzfeldt-Jakob disease (n = 4), Alzheimer's disease (n = 4), vascular parkinsonism (n = 3), and Whipple's disease (n = 1), as clinical vignettes to six neurologists unaware of the autopsy findings. Reliability was measured with the kappa statistics. The neurologists' clinical diagnoses were compared with clinicopathologic diagnoses for sensitivity, specificity, and positive predictive values at first and last clinic visits. The group reliability for the diagnosis of CBD significantly improved from moderate for the first visit (mean = 34 months after onset) to substantial for the last (68 months after onset). For the first visit, mean sensitivity for CBD was low (35%), but specificity was near-perfect (99.6%). For the last visit, mean sensitivity minimally increased (48.3%), and specificity remained stable. False-negative misdiagnoses mainly occurred with PSP. False-positive diagnoses were rare. The extremely low sensitivity of the clinical diagnosis of CBD suggests that this disorder is markedly underdiagnosed. Although the validity of the clinical diagnosis might have been improved if neurologists could have examined these patients, more important is that this disorder was misdiagnosed by the primary neurologists. In our data set, the best predictors for the diagnosis of CBD included limb dystonia, ideomotor apraxia, myoclonus, and asymmetric akinetic-rigid syndrome with late onset of gait or balance disturbances.

To study specific serotonin (5-hydroxytryptamine [5-HT]) receptor subtype antagonists in an animal model of posthypoxic myoclonus.

long-acting levodopa/carbidopa combination (CR-CSinemet) was compared with traditional levodopa/carbidopa (Sinemet) open label in 20 patients with Parkinson's disease and “wearing-off” phenomena. After 4 to 6 weeks of therapy with CR-4-Sinemet, the number of daily doses of medication dropped significantly compared with traditional Sinemet, disability improved, and “on” time increased. In nine patients receiving CR-4-Sinemet for 3 months, the number of daily doses and the on time without chorea remained significantly improved. CR-4-Sinemet peaked in plasma after 2 hours, and moderately high levels remained at 4 hours after the dose. Side effects were similar between traditional Sinemet and CR-4 Sinemet.

We studied 58 adults with Gilles de la Tourette's syndrome diagnosed during childhood. Tics persisted in all patients but were moderate/severe in only 24, compared with 60 at the time of worst function. Coprolalia persisted in 4, compared with 22 at the time of worst function. For most patients, worst function occurred in adolescence (mode 13 years). In spite of a high frequency of school and behavioral problems during development, 98 graduated high school and 90 were full-time students or fully employed. Features predictive of mild tic severity in adulthood were mild tics during the patient's worst pre-adulthood function and mild tics during early and late adolescence. Childhood tic severity had no predictive value, and likewise, coprolalia during development did not increase the risk for adult moderate/severe tics.

Several studies have evaluated the reliability and validity of the clinical diagnosis of Alzheimer's disease (AD) using well-defined neuropathologic criteria, but none has attempted to evaluate the diagnostic accuracy of Pick's disease. We determined the accuracy of the clinical diagnosis of Pick's by presenting 105 autopsy-confirmed cases of Pick's (n = 7) and related disorders (non-Pick's, n = 98) as clinical vignettes in randomized order to six neurologists who were unaware of the autopsy findings. The group of raters had moderate to fair agreement for the diagnosis of Pick's as measured by the κ statistics. The sensitivity for the diagnosis of Pick's for the first visit (mean, 53 months after onset) and last visit (mean, 78 months after onset) was low (range, 0 to 71%), but specificity was near-perfect. Median positive predictive values at both visits were 83 to 85%. False-negative misdiagnoses mainly involved AD. False-positive diagnoses were rare and occurred with corticobasal degeneration (first visit) and with dementia with Lewy bodies (last visit). Pick's was also misdiagnosed by primary neurologists. The best clinical predictors for the early diagnosis of Pick's included "frontal" dementia, early "cortical" dementia with severe frontal lobe disturbances, absence of apraxia, and absence of gait disturbance at onset. However, the first neurologic evaluation in some of the Pick's cases took place in advanced stages of the disease. Our findings suggest that this disorder is underdiagnosed in clinical practice. Although the low sensitivity for the clinical diagnosis of Pick's is disappointing, our data suggest that when clinicians suspect Pick's, their diagnosis is almost always correct. Absence of awareness of the main features of this disorder and of specificity of the frontal lobe syndrome may partially explain the low detection of Pick's disease.

Sixteen patients with advanced Parkinson's disease (PD) and motor fluctuations were evaluated throughout 12 months of open label therapy on CR4-Sinemet. Reduced dosage frequency and significant motor improvement with reduced fluctuation occurred and were maintained with CR4-Sinemet compared with baseline on Sinemet. In a double-blind protocol using CR4-Sinemet in 20 stable PD patients, CR4-Sinemet was given twice daily and compared with Sinemet given four times daily. Patients remained stable without improvement or deterioration when the long-acting drug was substituted at 50 frequency. Plasma levodopa levels with CR4-Sinemet were smoother than with Sinemet. Although some patients receiving CR4-Sinemet found they functioned more slowly in the morning, the easier dosing schedule and improved amount of "on" time in fluctuators suggest that this formulation may become increasingly useful in managing PD.

We evaluated the ability of nurse clinicians to assess parkinsonian signs in older persons with a modified version of the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS). After completing a structured training protocol, three nurse clinicians and a neurologist with expertise in movement disorders administered a modified UPDRS to 75 older persons. The nurses repeated the assessment about 3 weeks later. Inter-rater agreement and short-term temporal stability were estimated for each item, the total modified UPDRS score, and for summary measures of bradykinesia, postural reflex impairment, rigidity, and tremor, and a global parkinsonian sign score. We performed our assessment in Catholic religious communities in the Chicago area, using consecutive subjects at four communities participating in the Religious Orders Study, a longitudinal, clinical-pathologic study of older persons. Our results showed that nurses were not a significant source of variability, with intraclass correlations exceeding 0.97 for all items, and they showed good to excellent agreement with the neurologist for most modified UPDRS items. Correlations between nurses and neurologist exceeded 0.90 for the total modified UPDRS, ranged from 0.76 to 0.95 for the four parkinsonian domain scores, and exceeded 0.90 for the global parkinsonian sign score. Nurses showed fair to good agreement with themselves over the 3-week interval for most modified UPDRS items. Correlations over the 3-week interval exceeded 0.90 for the total modified UPDRS score, ranged from 0.70 to 0.95 for the four domain scores, and exceeded 0.90 for the global parkinsonian sign score. Ratings of parkinsonian signs by nurse clinicians corresponded closely to those of a neurologist with expertise in movement disorders and showed good inter-rater agreement and temporal stability. With appropriate training, nurse clinicians can reliably administer the modified UPDRS.

The authors examined age effects on adverse events from two randomized, controlled trials of rasagiline, comparing younger (younger than70 years) and older (70 years and older) subjects. Older patients were more prone to serious adverse effects than younger patients, but there was no statistical interaction between age and rasagiline exposure. This absence of an age-rasagiline interaction suggests that rasagiline does not require special safety precautions for elderly subjects with Parkinson disease.

Recently, the authors demonstrated linkage in idiopathic PD to a region on chromosome 8p that contains the N-acetyltransferase genes, NAT1and NAT2. The authors examined NAT1and NAT2for association with PD using family-based association methods and single nucleotide polymorphisms (SNPs). The authors did not find evidence for association with increased risk for PD between any individual NAT1or NAT2SNP or acetylation haplotype (N 397 families, 1,580 individuals).

The authors describe a 37-year-old woman with early-onset hemiparkinsonism (HP) and ipsilateral body hemiatrophy (HA). Genetic analysis revealed a missense mutation (Arg275Trp) and a duplication of exon 7 of parkin. The complementary metabolic and receptor pattern of PET ligands corresponded to that typically found in idiopathic PD, although tracer binding asymmetry was lacking. Parkinmutations should be considered in HPHA, particularly when there is a younger age at onset and dystonia is an early sign.

Questionnaire studies have found that parkinsonism worsens in women during the premenstrual period, when estrogen and progesterone levels are presumably at their nadir. To assess this patient-based observation and correlate motor signs with hormonal levels, the authors prospectively studied 10 menstruating women with PD in their “off” state, on 5 successive weeks. Although PD severity fluctuated during the study period, there was no significant correlation between the objective or subjective measures of parkinsonism and estrogen and progesterone levels.–1574

In five nondemented Parkinson's disease patients with daily visual hallucinations, we tested whether high-dose IV levodopa (LD) infusions precipitated hallucinations. Two infusion paradigms were studied, each with 1.5-mg/kg hourly dose for 4 hours-steady infusion and pulse infusion of the full hour dose over 5 minutes each hour. In both protocols, plasma LD levels changed significantly during the infusion protocol. The cumulative area under the curve was equivalent for the two infusions. All patients remained alert, and none developed visual hallucinations. The two patients with peak-dose dyskinesias on oral LD developed prominent dyskinesias during the infusion. Visual hallucinations do not relate simply to high levels of LD or to sudden changes in plasma levels.

We studied 10 regular exercising men with Parkinson's disease on levodopa (LD) under two conditions–no exercise and vigorous exercise started 1 hour after LD ingestion. We compared LD levels and motor scores on the Unified Parkinson's Disease Rating Scale (UPDRS). There was a high degree of agreement between plasma LD level and the patients' UPDRS scores 30 minutes later (mean Eta20.84) in both conditions, with no difference between the two. We conclude that LD levels accurately reflect UPDRS motor function in these patients, and that vigorous exercise started 1 hour after LD ingestion does not influence LD or motor scores.

We studied whether Parkinson's disease patients who had lost efficacy from pergolide (PERG) could benefit if transferred to bromocriptine (BCT) therapy. Using paired t-tests, we compared motor scores at baseline (when patients were still on PERG) and after 6 months of BCT therapy in 11 patients. No significant improvement occurred in any measure on BCT therapy (mean dose 33.6 mg/day), although patients remained stable. In 6 patients on whom “on/off” data were obtained, decreased “off” time and increased “on” time without chorea occurred, but these changes were not statistically significant. The side effect profile was similar with the 2 drugs.

To determine the effect of central dopaminergic stimulation with apomorphine on speech in PD.

To improve the specificity and sensitivity of the clinical diagnosis of progressive supranuclear palsy (PSP, Steele-Richardson-Olszewski syndrome), the National Institute of Neurological Disorders and Stroke (NINDS) and the Society for PSP, Inc. (SPSP) sponsored an international workshop to develop an accurate and universally accepted set of criteria for this disorder. The NINDS-SPSP criteria, which were formulated from an extensive review of the literature, comparison with other previously published sets of criteria, and the consensus of experts, were validated on a clinical data set from autopsy-confirmed cases of PSP. The criteria specify three degrees of diagnostic certainty: possible PSP, probable PSP, and definite PSP. Possible PSP requires the presence of a gradually progressive disorder with onset at age 40 or later, either vertical supranuclear gaze palsy or both slowing of vertical saccades and prominent postural instability with falls in the first year of onset, as well as no evidence of other diseases that could explain these features. Probable PSP requires vertical supranuclear gaze palsy, prominent postural instability, and falls in the first year of onset, as well as the other features of possible PSP. Definite PSP requires a history of probable or possible PSP and histopathologic evidence of typical PSP. Criteria that support the diagnosis of PSP, and that exclude diseases often confused with PSP, are presented. The criteria for probable PSP are highly specific, making them suitable for therapeutic, analytic epidemiologic, and biologic studies, but not very sensitive. The criteria for possible PSP are substantially sensitive, making them suitable for descriptive epidemiologic studies, but less specific. An appendix provides guidelines for diagnosing and monitoring clinical disability in PSP.

To determine if ventricular cerebrospinal fluid (vCSF) alpha-tocopherol levels in Parkinson's disease (PD) patients can be increased by oral alpha-tocopherol supplementation and whether vCSF levels are linearly related to plasma alpha-tocopherol levels. Background: In spite of its putative neuroprotective properties, alpha-tocopherol has failed to alter PD clinical progression. However, the ability of supplemental alpha-tocopherol to affect brain or vCSF levels has never been assessed in humans nor has a dose-response curve for alpha-tocopherol in vCSF been established. Methods: Five PD patients with Ommaya catheters received oral dl-alpha-tocopherol over 5 months. Each patient ingested alpha-tocopherol daily with monthly dosage increases (400, 800, 1,600, 3,200, 4,000 IU/day). Plasma and vCSF samples were obtained at baseline and at the end of each month. Alpha-tocopherol levels were determined in triplicate by high-pressure liquid chromatography with fluorometric and electrochemical detection. Results: At baseline, endogenous alpha-tocopherol was detected in plasma and vCSF, with a greater than one-hundred-fold difference between the fluid compartments (mean plasma level 18.76 micro Meter/l (SD +/- 4.69) versus mean CSF level 0.114 micro Meter/l (SD +/- 0.084). A clear dose-response curve occurred in plasma, with statistically significant increases over baseline developing even with 400 IU/d. With higher doses, a significant increase continued without evidence of saturation. However, there was no significant increase in vCSF alpha-tocopherol levels at any dose, including the supraclinical (4,000 IU/d). There was no correlation between plasma and vCSF alpha-tocopherol levels. Conclusion: Oral alpha-tocopherol supplementation, even at supraclinical doses, fails to increase vCSF alpha-tocopherol levels. This lack of change may be due to limited passage across the blood-brain barrier or very rapid alpha-tocopherol metabolism. All prior negative studies on efficacy of alpha-tocopherol in PD may need reevaluation in light of these pharmacologic data.

We assessed the validity and interrater reliability of neurologists who, using four different sets of previously published criteria for the clinical diagnosis of progressive supranuclear palsy (PSP), also called Steele-Richardson-Olszewski syndrome, rated 105 autopsy-proven cases of PSP (n equals 24), Lewy body disease (n equals 29), corticobasal ganglionic degeneration (n equals 10), postencephalitic parkinsonism (n equals 7), multiple system atrophy (n equals 16), Pick's disease (n equals 7), and other parkinsonian or dementia disorders (n equals 12). Cases were presented in random order to six neurologists. Information from each patient's first and last visits to the medical center supplying the case was presented sequentially to the rater, and the rater's diagnosis was compared with the neuropathologic diagnosis of each case. Interrater agreement for the diagnosis of PSP varied from substantial to near perfect, but none of the criteria had both high sensitivity and high predictive value. Because of these limitations, we used a logistic regression analysis to identify the variables from the data set that would best predict the diagnosis. This analysis identified vertical supranuclear palsy with downward gaze abnormalities and postural instability with unexplained falls as the best features for predicting the diagnosis. From the results of the regression analysis and the addition of exclusionary features, we propose optimal criteria for the clinical diagnosis of PSP.

We performed the first double-blind, crossover comparison between levodopa/carbidopa (LD/CD) in optimized liquid versus tablet doses to measure plasma LD levels and relative effects on disabilities (motor function, fluctuations, and dyskinesias) in patients with Parkinson's disease. Twenty-three subjects with motor fluctuations were optimized with open-label LD/CD tablets and liquid. In a double-dummy design, patients randomly received 2 weeks of liquid and 2 weeks of tablet LD/CD. Twice during each arm, we evaluated patients hourly 9 AM to 4 PM with the use of plasma LD levels, the Unified Parkinson's Disease Rating Scale, a dyskinesia rating scale, and "on-off" ratings. Patients receiving liquid LD/CD ingested significantly higher doses and had significantly improved motor function and total "on" time, without an increase in dyskinesia severity. The number of motor fluctuations in the two phases was not significantly different. LD levels and variability were also equivalent with the two formulations. At optimized dosing, liquid LD/CD offers a means to significantly improve motor disability in patients with Parkinson's disease without exacerbating dyskinesia.