BACKGROUNDLevodopa is the main treatment for symptoms of Parkinson's disease. Determining whether levodopa also has a disease-modifying effect could provide guidance as to when in the course of the disease the treatment with this drug should be initiated. METHODSIn a multicenter, double-blind, placebo-controlled, delayed-start trial, we randomly assigned patients with early Parkinson's disease to receive levodopa (100 mg three times per day) in combination with carbidopa (25 mg three times per day) for 80 weeks (early-start group) or placebo for 40 weeks followed by levodopa in combination with carbidopa for 40 weeks (delayed-start group). The primary outcome was the between-group difference in the mean change from baseline to week 80 in the total score on the Unified Parkinson's Disease Rating Scale (UPDRS; scores range from 0 to 176, with higher scores signifying more severe disease). Secondary analyses included the progression of symptoms, as measured by the UPDRS score, between weeks 4 and 40 and the noninferiority of early initiation of treatment to delayed initiation between weeks 44 and 80, with a noninferiority margin of 0.055 points per week. RESULTS

BackgroundThe aim of this study is to investigate if early treatment with levodopa has a beneficial disease modifying effect on Parkinson’s disease (PD) symptoms and functional health, improves the ability to (maintain) work, and reduces the use of (informal) care, caregiver burden, and costs. Additionally, cost-effectiveness and cost-utility of early levodopa treatment will be assessed.MethodsTo differentiate between the direct symptomatic effects and possible disease modifying effects of levodopa, we use a randomised delayed-start double-blind placebo-controlled multi-centre trial design. Patients with early stage PD whose functional health does not yet necessitate initiation of PD-medication will be randomised to either 40 weeks of treatment with levodopa/carbidopa 100/25 mg TID including 2 weeks of dose escalation or to 40 weeks placebo TID. Subsequently, all patients receive levodopa/carbidopa 100/25 mg TID for 40 weeks. There are 8 assessments: at baseline and at 4, 22, 40, 44, 56, 68, and 80 weeks. The primary outcome measure is the difference in the mean total Unified Parkinson’s Disease Rating Scale scores between the early- and delayed-start groups at 80 weeks. Secondary outcome measures are rate of progression, the AMC Linear Disability Score, side effects, perceived quality of life with the Parkinson’s Disease Questionnaire-39, the European Quality of Life-5 Dimensions (EQ-5D), ability to (maintain) work, the use of (informal) care, caregiver burden, and costs. 446 newly diagnosed PD patients without impaired functional health need to be recruited in order to detect a minimal clinical relevant difference of 4 points on the total UPDRS at 80 weeks.DiscussionThe LEAP-study will provide insights into the possible disease modifying effects of early levodopa.Trial registrationISRCTN30518857, EudraCT number 2011-000678-72

BackgroundAlthough the treatment of Parkinson’s disease (PD) is very effective, in the course of the disease, 40% to 60% of patients develop dyskinesias. The pathophysiology of dyskinesias is still unclear. Results of preclinical research suggest that uptake and uncontrolled release of dopamine by serotonergic neurons is an important factor. Based on this model, we hypothesized that dyskinesias will develop predominantly in PD patients with a relatively preserved serotonergic system.MethodsBetween 1995 and 1998, 50 patients with early-stage untreated PD, diagnosed according to clinical criteria, and reduced striatal [123I]β-carboxymethyoxy-3-beta-(4-iodophenyl) tropane (CIT) single-photon emission computed tomography (SPECT) binding were recruited. To test our hypothesis, we retrospectively assessed baseline [123I]β-CIT SPECT scans for striatal dopamine transporter (DAT) and midbrain serotonin transporter (SERT) availability as well as the SERT-to-DAT ratios. We compared these data between patients that developed dyskinesias and patients that did not develop dyskinesias during a mean follow-up of 14.2 years.ResultsApproximately half of the PD patients developed dyskinesias. No differences in baseline [123I]β-CIT DAT availability, SERT availability, or SERT-to-DAT ratios were found between the dyskinetic and non-dyskinetic group. The development of dyskinesias was most strongly associated with the age of onset (P = 0.002).ConclusionsSERT-to-DAT ratios in early-stage untreated PD do not correlate with the future development of dyskinesias. However, our study does not exclude the possibility that SERT-to-DAT ratios increase with disease progression in patients that develop dyskinesias because of a slower rate of degeneration of the serotonergic system.

Background and objectives:The Levodopa in EArly Parkinson´s disease (LEAP) study enabled us to conduct post-hoc analyses concerning the effects of levodopa in patients with early Parkinson’s disease.Methods:The LEAP-study was a double-blind, placebo-controlled, randomized, delayed-start trial in which patients with early Parkinson’s disease were randomized to receive levodopa/carbidopa 300/75 mg daily for 80 weeks (early-start group) or to placebo for 40 weeks followed by levodopa/carbidopa 300/75 mg daily for 40 weeks (delayed-start group). We analyzed the effect of levodopa with the Unified Parkinson’s Disease Rating Scale on bradykinesia, rigidity, and tremor. At week 80, participants answered three questions regarding motor response fluctuations.Results:A total of 222 patients were randomized to the early-start group (mean±SD age at baseline 64.8±8.7 years; 71% male) and 223 to the delayed-start group (mean±SD age at baseline 65.5±8.8 years; 69% male). The difference between the early and delayed-start group in mean change from baseline to week four, expressed as Hedges’geffect size, was -0.33 for bradykinesia, -0.29 for rigidity, and -0.25 for tremor (for all symptoms indicating a small effect in favor of the early-start group); from baseline to week 22 respectively -0.49, -0.36, and -0.44 (small to medium effect); and from baseline to week 40 respectively -0.32, -0.19, and -0.27 (small effect). At 80 weeks, fewer patients in the early-start group (46 of 205 patients, 23%) experienced motor response fluctuations than patients in the delayed-start group (81 of 211, 38%; p<0.01).Discussion:In patients with early Parkinson’s disease levodopa improves bradykinesia, rigidity, and tremor to the same order of magnitude. For all three symptoms, effects were larger at 22 weeks compared to four weeks. At 80 weeks there were fewer patients with motor response fluctuations in the group that had started levodopa earlier.Classification of evidence:This study provides Class II evidence that the effect of levodopa on bradykinesia, rigidity and tremor is larger after 22 weeks compared to four weeks of treatment.Trial registration LEAP-study:ISRCTN30518857, EudraCT number 2011-000678-72

Purpose To determine the reliability of visual assessment of [ 123 I]FP-CIT SPECT imaging by non-experts in dopamine transporter (DAT) SPECT imaging in patients with early drug-naive Parkinson’s disease (PD). Also, we explored the indications of DAT SPECT imaging in clinical practice by neurologists. Methods We collected [ 123 I]FP-CIT SPECT scans of the Levodopa in EArly Parkinson’s disease (LEAP) trial participants that were made prior to recruitment, as part of routine clinical work-up. All scans were reassessed by an expert in DAT imaging. A survey on the use of DAT SPECT imaging was sent to all referring neurologists. Results The concordance of the initial local assessment and the expert reassessment was 98.7%. The survey showed that neurologists requested DAT SPECT imaging in only 73.6% of patients to differentiate between a neurodegenerative disease and non-neurodegenerative parkinsonism. Conclusions Visual assessment of [ 123 I]FP-CIT SPECT imaging by community nuclear medicine physicians in patients with early PD is reliable. Neurologists who request DAT SPECT scans are not always aware that the high accuracy is limited only to the differentiation between neurodegenerative and non-neurodegenerative parkinsonism. A significant portion of neurologists who request DAT SPECT scans is not always aware that the high accuracy is limited to the differentiation between neurodegenerative and non-neurodegenerative parkinsonism as DAT SPECT cannot reliably distinguish the various Parkinsonian syndromes.

Background: In clinical trials that recruited patients with early Parkinson’s disease (PD), 4–15% of the participants with a clinical diagnosis of PD had normal dopamine transporter single photon emission computed tomography (DAT SPECT) scans, also called “scans without evidence of dopaminergic deficit” (SWEDD). Objective: To investigate in patients with a clinical diagnosis of PD, if specific clinical features are useful to distinguish patients with nigrostriatal degeneration from those that have no nigrostriatal degeneration. Methods: We performed a diagnostic test accuracy study. Patients that participated in the Levodopa in Early Parkinson’s disease trial, a clinical trial in patients with early PD, were asked to participate if they had not undergone DAT SPECT imaging earlier. The index tests were specific clinical features that were videotaped. A panel of six neurologists in training (NT), six general neurologists (GN), and six movement disorders experts (MDE) received a batch of ten videos consisting of all SWEDD subjects and a random sample of patients with abnormal DAT SPECT scans. The raters analyzed the videos for presence of specific signs and if they suspected the patient to have SWEDD. The reference test was visually assessed DAT SPECT imaging. Results: Of a total of 87 participants, three subjects were SWEDDs (3.4%). The overall intraclass correlation coefficient (ICC) of the Parkinsonian signs was poor to moderate with ICCs ranging from 0.14 to 0.67. NT correctly identified 50.0% of the SWEDD subjects, GN 33.3%, and MDE 66.7%. Conclusion: Our study suggests that the selected videotaped clinical features cannot reliably distinguish patients with a clinical diagnosis of PD and an abnormal DAT SPECT from patients with clinical PD and a SWEDD.

Background. Differentiating Parkinson's disease (PD) from multiple system atrophy (MSA) can be challenging especially early in the course of the disease. Previous studies have shown that midbrain serotonin transporter (SERT) availability in patients with established MSA was significantly lower compared to PD. It is unknown if this is also true for early-stage patients. Methods. 77 early-stage, untreated PD patients were recruited between 1995 and 1998, underwent [123I]β-CIT SPECT imaging, and were followed for at least five years. 16 patients were lost to followup, and in 4 the diagnosis was changed to another atypical parkinsonian syndrome, but not in MSA. In 50 patients, the PD diagnosis was unchanged at followup. In seven patients, the diagnosis was changed to MSA at followup. We retrospectively assessed baseline midbrain SERT availability as well as midbrain SERT-to-striatal dopamine transporter (DAT) ratios. Results. No difference in baseline [123I]β-CIT SERT availability was found. The midbrain SERT-to-striatal DAT ratio for whole striatum was significantly lower in patients with PD compared to MSA (P = 0.049). However, when adjusting for the disease duration at imaging this difference is not significant (P = 0.070). Conclusion. Midbrain SERT availability is not different between early-stage PD and MSA. Therefore, SERT imaging is not useful to differentiate between early PD and MSA.

Background Seizures can be part of the clinical presentation of central nervous system (CNS) infections. We describe patients suspected of a neurological infection who present with a seizure and study diagnostic accuracy of clinical and laboratory features predictive of CNS infection in this population. Methods We analyzed all consecutive patients presenting with a seizure from two prospective Dutch cohort studies, in which patients were included who underwent cerebrospinal fluid (CSF) examination because of the suspicion of a CNS infection. Results Of 900 episodes of suspected CNS infection, 124 (14%) presented with a seizure. The median age in these 124 episodes was 60 years (IQR 45–71) and 53% of patients was female. CSF examination showed a leukocyte count ≥ 5/mm3 in 41% of episodes. A CNS infection was diagnosed in 27 of 124 episodes (22%), a CNS inflammatory disorder in 8 (6%) episodes, a systemic infection in 10 (8%), other neurological disease in 77 (62%) and in 2 (2%) episodes another systemic disease was diagnosed. Diagnostic accuracy of clinical and laboratory characteristics for the diagnosis of CNS infection in this population was low. CSF leukocyte count was the best predictor for CNS infection in patients with suspected CNS infection presenting with a seizure (area under the curve 0.94, [95% CI 0.88 – 1.00]). Conclusions Clinical and laboratory features fail to distinguish CNS infections from other causes of seizures in patients with a suspected CNS infection. CSF leukocyte count is the best predictor for the diagnosis of CNS infection in this population.