Risk of Disabling Response Fluctuations and Dyskinesias for Dopamine Agonists Versus Levodopa in Parkinson's Disease.

BACKGROUND: Response fluctuations and dyskinesias develop during the use of both levodopa (LD) and dopamine agonists (DA), but may not be equally disabling. OBJECTIVE: To compare the risk and time of onset of disabling response fluctuations and dyskinesias (DRFD) among patients with Parkinson's disease (PD) who were initially treated with either LD or DA. METHODS: Open cohort study of all consecutive de-novo PD patients in routine clinical practice, included over a period of 15 years (median follow-up: 8.1 years, range 1.1-17.7), since embarking on LD or DA. Older patients and patients with more severe PD were started on LD (n = 77), younger patients on a DA (n = 50). Therapy was adjusted according to generally accepted guidelines. The primary endpoints were: the onset of response fluctuations, dyskinesias, and the moment when these complications became disabling (DRFD). RESULTS: LD-starters developed response fluctuations 0.8 years earlier than DA-starters (p = 0.07), while dyskinesias appeared around 2.5 years earlier (p = 0.003). However, the risk and time of onset of DRFD did not differ statistically between the groups (LD-starters: 60% , median interval 7.3 years, DA-starters: 52% , 6.1 years, p = 0.63). DA-starters displayed a 0.19 points lower adjusted mean improvement in motor scores than LD-starters (p = 0.002). Adjustments for age and severity of PD at start of dopaminergic therapy did not change these results. CONCLUSIONS: In routine clinical practice, the risk and time of onset of DRFD is comparable for LD-starters versus DA-starters, but motor functioning is worse in DA-starters. These results support the use of LD as initial therapy for PD.

Fetoscopic laser coagulation for severe twin-to-twin transfusion syndrome: factors influencing perinatal outcome, learning curve of the procedure and lessons for new centres.

OBJECTIVE: To evaluate the effects of operator experience on perinatal outcome in a single centre. DESIGN: Prospective consecutive cohort study. SETTING: Regional tertiary referral Fetal Medicine Centre in the UK. POPULATION: Pregnant women with monochorionic twin pregnancies complicated by severe twin-to-twin transfusion syndrome (TTTS) (at ≤26 completed weeks of gestatiuon) treated by fetoscopic laser coagulation (FLC) between October 2004 and November 2009. METHODS: Pregnancy characteristics and outcomes were collected. Logistic regression analysis was employed to determine the effect of a priori defined variables on outcome. MAIN OUTCOME MEASURE: Perinatal survival (survival to 28 days or beyond) for one or more twins. RESULTS: There were 164 consecutive sets of monochorionic twins. The median gestational age (GA) at FLC was 20.4 weeks (interquartile range 18-22.1 weeks), the median interval from FLC to delivery was 88.5 days (interquartile range 53-101 days) and the median GA at delivery was 33.2 weeks (interquartile range 29.7-34.9 weeks). The overall survival was 62%; perinatal survival of one or more twins was 85%. These outcomes improved after about 61 procedures were performed, and after about 3.4 years of experience. Univariate logistic regression analysis indicated that Quintero stage-IV disease decreased (OR 0.26; 95% CI 0.10-0.69) and prolongation of GA at delivery increased the survival of the twins (OR 1.34; 95% CI 1.12-1.60) (P < 0.01). Increasing experience of the procedure by operator led to a significant increase in perinatal survival (P < 0.01; OR 4.59; 95% CI 1.84-11.44). Multivariate logistic regression analysis indicated that only GA at delivery increased survival overall (OR 1.34; 95% CI 1.12-1.60; P = 0.01). CONCLUSIONS: These data indicate that both relatively large numbers treated and experience with FLC minimises any adverse outcome in monochorionic pregnancies with severe TTTS.

Timed motor tests can detect subtle motor dysfunction in early Parkinson's disease.

Early diagnosis of Parkinson's disease (PD) is important for putative neuroprotective therapies to be initiated in the earliest stage of the disease. We investigated whether a previously validated timed motor test (TMT) battery could detect subtle motor dysfunction in early PD patients and even in clinically unaffected limbs of strictly hemiparkinsonian patients. We assessed 107 PD patients (symptom duration

Pallidopyramidal disease: a misnomer?

The combination of recessive early-onset parkinsonism and pyramidal tract signs caused by pallidopyramidal degeneration is known as pallidopyramidal disease or syndrome (PPD/S). We investigated whether patients diagnosed as Davison's PPD/S showed any definite proof of pyramidal and pallidal involvement, without findings suggestive of other nosological entities. Since Davison's original description, 15 other PPD/S cases have been reported, yet all lack proof of pyramidal or pallidal degeneration. Because of the dopa-responsiveness in all patients subsequent to Davison's report, we argue that these patients probably suffered from early-onset nigral parkinsonism or dopa-responsive dsystonia, rather than pallidal parkinsonism; in such cases, the presumed pyramidal Babinski could be a pseudobabinski ("striatal toe"). Secondary pallidopyramidal syndromes do occur, for example, in multiple system atrophy or Wilson's disease, but in these patients additional findings indicate diseases other than Davison's PPD/S. We conclude that the existence of PPD/S as a distinct clinico-pathological nosological entity, as proposed by Davison, is doubtful. In cases reported as Davison's PPD/S, the description "pallidopyramidal" seems to be a misnomer.

Paramedical treatment in primary dystonia: a systematic review.

Dystonia is a disabling movement disorder with a significant impact on quality of life. The current therapeutic armamentarium includes various drugs, botulinum toxin injections, and occasionally (neuro)surgery. In addition, many patients are referred for paramedical (including allied health care) interventions. An enormous variation in the paramedical treatment is provided, largely because evidence-based, accepted treatment regimes are not available. We have conducted a systematic review of studies that explored the effect of various paramedical interventions in primary dystonia. Only studies that have used clinical outcome measures were included. There were no class A1 or A2 studies and therefore, level 1 or 2 practice recommendations for a specific intervention could not be deducted. Many papers were case reports, mostly with a very limited number of patients and a clear publication bias for beneficial effects of a particular paramedical intervention. Some potentially interesting interventions come from class B studies, which include physical therapy in addition to botulinum toxin injections (BoNT-A) in cervical dystonia; sensorimotor training and transcutaneous electrical nerve stimulation (TENS) in writer's cramp; and speech therapy added to BoNT-A injections in laryngeal dystonia. Good quality clinical studies are therefore warranted, which should have the aim to be generally applicable. A design in which the paramedical intervention is added to a current gold standard, for example, BoNT-A injections in cervical dystonia, is recommended.

Comparison of a timed motor test battery to the Unified Parkinson's Disease Rating Scale-III in Parkinson's disease.

The most widely used scale currently available for the clinical evaluation of motor dysfunction in Parkinson's disease (PD)-the Unified Parkinson's Disease Rating Scale-III (UPDRS-III) -is time-consuming, subjective, and has suboptimal sensitivity. A brief timed motor test (TMT) battery could possibly overcome these drawbacks. Two hundred eighty-eight PD patients (disease duration 3.1 years; preceding dopaminergic treatment initiation) were assessed with the UPDRS-III and nine TMTs based on aspects of (a) walking, (b) writing, (c) single and double-handed pegboard performance, (d) finger tapping, and (e) rapid alternating forearm movements. We investigated validity, reliability, responsiveness, and feasibility. Completing the TMT battery took less than 5 minutes. The TMT correlated well with UPDRS-III and disease duration. Two factors explained 61% of the TMT variance, the first represented mainly upper extremity function, the second mainly axial/lower extremity function. Cronbach's alpha was equal for the TMT and the UPDRS-III (0.8). Test-retest reliability of the TMT sumscore was 0.93 to 0.89 for measurements separated by 3 up to 24 months, whereas UPDRS-III correlations were 0.88 to 0.84. At group level, a trial using "change from baseline" as endpoint requires only 75% of the patients needed with the UPDRS-III when applying the TMT battery, and 57% using the pegboard dexterity test. At patient level, TMT and UPDRS-III were equally responsive. The TMT battery described here is valid, reliable, and feasible. Compared to the UPDRS-III, it is more objective and more sensitive to change. Therefore, it could be a useful tool for both practical and scientific purposes. (c) 2008 Movement Disorder Society.

Gender differences in Parkinson's disease.

OBJECTIVE: To investigate gender differences in basic disease characteristics, motor deterioration and nigrostriatal degeneration in Parkinson's disease (PD). METHODS: We studied 253 consecutive PD patients who were not receiving levodopa or dopamine agonists (disease duration < or = 10 years). We investigated the influence of gender and oestrogen status on: (1) age at onset, (2) presenting symptom, (3) severity and progression of motor symptoms (Unified Parkinson's Disease Rating Scale III (UPDRS-III) scores) and (4) amount and progression of nigrostriatal degeneration ([123I]FP-CIT single photon emission computed tomography measurements). RESULTS: Age at onset was 2.1 years later in women (53.4 years) than in men (51.3 years). In women, age at onset correlated positively with parity, age at menopause and fertile life span. Women more often presented with tremor (67%) than men (48%). Overall, patients presenting with tremor had a 3.6 year higher age at onset and a 38% slower UPDRS-III deterioration. Mean UPDRS-III scores at disease onset were equal for both genders, as was the rate of deterioration. Women had a 16% higher striatal [123I]FP-CIT binding than men at symptom onset and throughout the course of PD. CONCLUSIONS: Our results suggest that, in women, the development of symptomatic PD may be delayed by higher physiological striatal dopamine levels, possibly due to the activity of oestrogens. This could explain the epidemiological observations of a lower incidence and higher age at onset in women. Women also presented more often with tremor which, in turn, is associated with milder motor deterioration and striatal degeneration. Taken together, these findings suggest a more benign phenotype in women with PD.

Ambulatory motor assessment in Parkinson's disease.

We developed an algorithm that distinguishes between on and off states in patients with Parkinson's disease during daily life activities. Twenty-three patients were monitored continuously in a home-like situation for approximately 3 hours while they carried out normal daily-life activities. Behavior and comments of patients during the experiment were used to determine the on and off periods by a trained observer. Behavior of the patients was measured using triaxial accelerometers, which were placed at six different positions on the body. Parameters related to hypokinesia (percentage movement), bradykinesia (mean velocity), and tremor (percentage peak frequencies above 4 Hz) were used to distinguish between on and off states. The on-off detection was evaluated using sensitivity and specificity. The performance for each patient was defined as the average of the sensitivity and specificity. The best performance to classify on and off states was obtained by analysis of movements in the frequency domain with a sensitivity of 0.97 and a specificity of 0.97. We conclude that our algorithm can distinguish between on and off states with a sensitivity and specificity near 0.97. This method, together with our previously published method to detect levodopa-induced dyskinesia, can automatically assess the motor state of Parkinson's disease patients and can operate successfully in unsupervised ambulatory conditions.

Cerebrospinal fluid analysis differentiates multiple system atrophy from Parkinson's disease.

We investigated whether cerebrospinal fluid (CSF) analysis discriminates between idiopathic Parkinson's disease (PD; n = 35) and multiple system atrophy (MSA; n = 30). The median CSF concentration of the neurotransmitter metabolites 5-hydroxyindolacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) was reduced significantly (49-70%) in MSA compared to PD. In contrast, several brain-specific proteins (tau, neuron-specific enolase, myelin basic protein) were elevated (130-230%) in MSA compared with those in PD. A combination of CSF tau and MHPG discriminated PD from MSA (adjusted odds ratios: tau, 27.2; MHPG, 0.14). Our data suggest that the more progressive and widespread neurodegenerative nature of MSA, as compared with PD, is reflected in the composition of CSF. We propose that CSF analysis may become part of the diagnostic work-up of patients with parkinsonian syndromes.

Striatal dopamine and learning strategy-an (123)I-FP-CIT SPECT study.

UNLABELLED: Patients with Parkinson's disease (PD) have difficulty in processing learning tasks that lack external guidelines and, consequently, necessitate the subjects to generate their own problem-solving strategy. While the contribution of striatal dopaminergic deficiency to PD-specific motor symptoms is well established, its role in the PD-characteristic deviant learning style remains unclear. The aim of this study was to assess the relation between striatal dopamine activity as revealed by single photon emission computed tomography (SPECT) with (123)I-FP-CIT, a ligand for the dopamine transporter (DaT), and type of learning strategy, as identified by the California Verbal Learning Task (CVLT) in 19 patients with probable PD. The results showed a robust inverse correlation between striatal dopamine DaT binding and the externally guided, serial learning strategy: the lower the DaT in caudate nucleus as well as in putamen, the more the patient group appeared to rely on externally structured learning. Additionally, a significant positive correlation was found between caudatal DaT activity and the internally generated, semantic learning strategy. Unlike these strategic learning characteristics, IQ equivalent and recall total score appeared to vary independently from striatal DaT availability. CONCLUSION: our findings provide direct evidence that striatal dopaminergic activity is specifically involved in the regulation of strategic learning processes.

How much phenotypic variation can be attributed to parkin genotype?

To establish phenotype-genotype correlations in early-onset parkinsonism, we have compared the phenotype of a large series of 146 patients with and 250 patients without parkin mutations. Although no single sign distinguished the groups, patients with mutations had significantly earlier and more symmetrical onset, dystonia more often at onset and hyperreflexia, slower progression of the disease, and a tendency toward a greater response to levodopa despite lower doses. After forward stepwise multiple logistic regression analysis, dystonia at onset and brisk reflexes were not longer significantly different but were correlated with age at onset rather than the presence of the parkin mutation. Age at onset in carriers of parkin mutations varied as did the rate of progression of the disease: the younger the age at onset the slower the evolution. The genotype influenced the phenotype: carriers of at least one missense mutation had a higher United Parkinson's Disease Rating Scale motor score than those carrying two truncating mutations. The localization of the mutations was also important because missense mutations in functional domains of parkin resulted in earlier onset. Patients with a single heterozygous mutation had significantly later and more asymmetrical onset and more frequent levodopa-induced fluctuations and dystonia than patients with two mutations.

Movement parameters that distinguish between voluntary movements and levodopa-induced dyskinesia in Parkinson's disease.

It is well known that long-term use of levodopa by patients with Parkinson's disease causes dyskinesia. Several methods have been proposed for the automatic, unsupervised detection and classification of levodopa induced dyskinesia. Recently, we have demonstrated that neural networks are highly successful to detect dyskinesia and to distinguish dyskinesia from voluntary movements. The aim of this study was to use the trained neural networks to extract parameters, which are important to distinguish between dyskinesia and voluntary movements. Thirteen patients were continuously monitored in a home-like situation performing in about 35 daily life tasks for a period of approximately 2.5 h. Behavior of the patients was measured using triaxial accelerometers, which were placed at six different positions of the body. A neural network was trained to assess the severity of dyskinesia. The neural network was able to assess the severity of dyskinesia and could distinguish dyskinesia from voluntary movements in daily life. For the trunk and the leg, the important parameters appeared to be the percentage of time that the trunk or leg was moving and the standard deviation of the segment velocity of the less dyskinetic leg. For the arm, the combination of the percentage of time, that the wrist was moving, and the percentage of time, that a patient was sitting, explained the largest part of the variance of the output. Dyskinesia differs from voluntary movements in the fact that dyskinetic movements tend to have lower frequencies than voluntary movements and in the fact that movements of different body segments are not well coordinated in dyskinesia.

Automatic assessment of levodopa-induced dyskinesias in daily life by neural networks.

We developed an objective and automatic procedure to assess the severity of levodopa-induced dyskinesia (LID) in patients with Parkinson's disease during daily life activities. Thirteen patients were continuously monitored in a home-like situation for a period of approximately 2.5 hours. During this time period, the patients performed approximately 35 functional daily life activities. Behavior of the patients was measured using triaxial accelerometers, which were placed at six different positions on the body. A neural network was trained to assess the severity of LID using various variables of the accelerometer signals. Neural network scores were compared with the assessment by physicians, who evaluated the continuously videotaped behavior of the patients off-line. The neural network correctly classified dyskinesia or the absence of dyskinesia in 15-minute intervals in 93.7, 99.7, and 97.0% for the arm, trunk, and leg, respectively. In the few cases of misclassification, the rating by the neural network was in the class next to that indicated by the physicians using the AIMS score (scale 0-4). Analysis of the neural networks revealed several new variables, which are relevant for assessing the severity of LID. The results indicate that the neural network can accurately assess the severity of LID and could distinguish LID from voluntary movements in daily life situations.