Botulinum toxin assessment, intervention and after-care for upper limb hypertonicity in adults: international consensus statement.

Upper limb spasticity affecting elbow, wrist, and finger flexors can be safely and effectively reduced with injections of botulinum toxin type-A (BoNT-A). It has been best studied in adults in the context of post-stroke spasticity. The clinical benefits include reduction in pain and deformity, improvement in washing and dressing the upper limb, and a reduction in caregiver burden (Class I evidence, recommendation level A). Some patients show improvement in function performed by active movement of the affected upper limb (Class III evidence, recommendation C), but predicting and measuring this is difficult, and further research is needed. An individually based approach to treatment and outcome measurement is preferred (Class IV, recommendation U). More research is needed to resolve many unknown issues of assessment and treatment, using research methods appropriate to the question.

The effect of amantadine on levodopa-induced dyskinesias in Parkinson's disease: a double-blind, placebo-controlled study.

We performed a double-blind, placebo-controlled, crossover study to assess the effect of amantadine versus placebo on levodopa-induced dyskinesias in Parkinson's disease. We found a 24% reduction in the total dyskinesia score after amantadine administration (p = 0.004). This improvement was achieved without any influence on the severity of "on" period parkinsonism. The results confirm that amantadine reduces levodopa dyskinesias and support the hypothesis that dyskinesias can be reduced by blockade of excitatory pathways in the basal ganglia.

Evidence for impaired presynaptic dopamine function in parkinsonian patients with motor fluctuations.

We used [18F]6-fluorodopa (FD) positron emission tomography (PET) to examine the severity of nigrostriatal dopaminergic dysfunction in 67 patients with Idiopathic Parkinsonism (IP), 52 with fluctuations and 15 with a stable response to levodopa. FD uptake (Ki) was reduced by 12% in the caudate (p = 0.08) and by 28% in the putamen (p = 0.0004) of patients with fluctuations compared to those with a stable response. However, there was considerable overlap of FD Ki values between the two groups. The fluctuators had a longer symptom duration (11.6 +/- 5.7 years) than the patients with a stable response to levodopa (4.3 +/- 2.4 years; p < 0.0001) and the age of onset of symptoms was earlier in the fluctuators (43.9 +/- 8.9 versus 54.1 +/- 10.4; p = 0.0004). Similar reductions in FD Ki in the fluctuators persisted following adjustment for these variables (7.5% in the caudate and 26% in the putamen; p = n.s. and 0.007, respectively). When smaller groups (n = 15 each) were matched for duration of symptoms, the reduction in caudate Ki in the fluctuators was only 1.9% (p = n.s.), but there was still a 24% reduction in putamen Ki (p = 0.05). These findings suggest that fluctuators and non-fluctuators may differ in the severity of their nigrostriatal damage and provide modest support for the hypothesis that fluctuations may in part reflect altered "buffering" capacity of dopaminergic nerve terminals. However, the considerable overlap between groups suggests that other factors such as altered postsynaptic mechanisms and/or increased turnover of dopamine may make a substantial contribution to the development of motor fluctuations.

Pattern of dopaminergic loss in the striatum of humans with MPTP induced parkinsonism.

OBJECTIVES: To examine the distribution of striatal dopaminergic function in humans with parkinsonism induced by 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) to determine if there is a caudate-putamen gradient as is seen in idiopathic Parkinson's disease. METHODS: We scanned nine humans exposed to MPTP with parkinsonism ranging from minimal to severe using [(18)F]fluorodopa (FD) and high resolution PET. The results were compared with those of 10 patients with Parkinson's disease and six normal subjects. RESULTS: In the MPTP group there was an equal degree of reduction of dopaminergic function in the caudate and putamen. This was different from the greater putaminal than caudate loss in Parkinson's disease (p<0.001). CONCLUSIONS: Parkinson's disease is not caused by transient exposure to MPTP.

Long-term evaluation of bilateral fetal nigral transplantation in Parkinson disease.

BACKGROUND: Parkinson disease (PD) is associated with a progressive loss of nigrostriatal dopamine neurons. Medication therapy provides adequate control of symptoms for several years, but long-term treatment is complicated by progressive disability and the development of motor fluctuations and dyskinesias. In animal models of PD, fetal nigral transplants have been shown to survive grafting into the striatum, provide extensive striatal reinnervation, and improve motor function. In patients with PD, cell survival and clinical benefit have been observed following fetal nigral grafting, but results have been inconsistent. OBJECTIVE: To evaluate the safety and efficacy of bilateral fetal nigral transplantation into the postcommissural putamen in patients with advanced PD complicated by motor fluctuations and dyskinesias. PATIENTS AND METHODS: Six patients with advanced PD underwent bilateral fetal nigral transplantation. Each patient received solid grafts derived from donors aged 6 1/2 to 9 weeks after conception stereotactically implanted into the postcommissural putamen using 3 to 4 donors per side. Cyclosporine was administered for approximately 6 months to provide immune suppression. Clinical evaluations included the Unified Parkinson's Disease Rating Scale (UPDRS), Schwab-England Activities of Daily Living Scale, and timed tests of motor function conducted during both the "off' and "on" states at baseline and at 1, 3, 6, 9, 12, 18, and 24 months following transplantation. Percentage of time off and percentage of time on with and without dyskinesia were recorded at half-hour intervals using home diaries during the week prior to each evaluation. 18F-fluorodopa positron emission tomographic scans were performed at baseline, and at 6 months and 1 year following transplantation. RESULTS: Patients have been followed up for a mean+/-SD of 20.5+/-5.5 months. Complications related to surgery were mild and transient. Activities of daily living, motor, and total (activities of daily living plus motor) UPDRS scores during the off state improved significantly (P<.05, Wilcoxon signed rank test) at final visit in comparison with baseline. Mean total UPDRS off score improved 32%, and each patient experienced at least a 19% improvement. Mean percentage of time on without dyskinesia during the waking day improved from 22% to 60% (P<.05). Mean putamenal fluorodopa uptake on positron emission tomography increased significantly at 6 and 12 months in comparison with baseline (P<.001, 2-tailed t test). This increase correlated with clinical improvement. Two patients died 18 months after transplantation from causes unrelated to the surgical procedure. In both cases, histopathological examination showed robust survival of tyrosine hydroxylase immunoreactive cells and abundant reinnervation of the postcommissural putamen. CONCLUSIONS: Fetal nigral tissue can be transplanted into the postcommissural putamen bilaterally in patients with advanced PD safely and with little morbidity. In this open-label pilot study we observed consistent long-term clinical benefit and increased fluorodopa uptake on positron emission tomography. Clinical improvement appears to be related to the survival and function of transplanted fetal tissue.

Long-term follow-up of levodopa responsiveness in generalized dystonia.

OBJECTIVES: To assign an accurate diagnosis to patients with dystonia based on the presence of sustained levodopa responsiveness and to determine whether motor fluctuations occur in patients with dystonia who are withheld from levodopa. PATIENTS AND METHODS: Patients with generalized dystonia who responded to treatment in the 1970s with levodopa/carbidopa were surveyed by phone and then examined during a 3-day levodopa holiday. Functional imaging with fluorodopa positron emission tomography was performed on a subset of patients. RESULTS: In the phone interview, 4 of 7 patients with a diagnosis of dopa-responsive dystonia reported the wearing-off effect a short while (within 4-8 hours) after missing a dose of levodopa. Five patients with dopa-responsive dystonia were examined repetitively during levodopa withdrawal, and 3 developed recurrent symptoms of dystonia as the drug was withheld. In each case, worsening of dystonia did not occur until 29 hours or more after levodopa withdrawal, providing evidence for a response profile similar to the long duration response described in Parkinson disease. No significant changes were seen in the dystonia scores of the 3 patients with idiopathic torsion dystonia who were withheld from levodopa. CONCLUSIONS: We suggest that the subjective feeling of wearing off experienced by our patients with dopa-responsive dystonia may have been for one of the nonmotor effects of levodopa, such as mood elevation. Our data provide objective evidence for the often-repeated assertion that motor fluctuations (analogous to those in levodopa-treated patients with Parkinson disease) do not occur in patients with dopa-responsive dystonia.

Age-dependent decline of dopamine D1 receptors in human brain: a PET study.

Radioligand binding studies in animals have demonstrated age-related loss of dopamine receptors in the caudate and putamen. In humans, while age-related declines in dopamine D2 receptors have been consistently reported, the effects of ageing on D1 receptors have been controversial. We used positron emission tomography (PET) with [11C]SCH 23390 to investigate dopamine D1 receptor binding in 21 normal volunteers aged 22-74 years. We also assessed their motor function with a Modified Columbia Score (MCS) and the Purdue Pegboard Test (PPBT). D1 binding potentials were derived using a graphical analysis with a cerebellar tissue input function. Standard linear regression techniques were used to determine the age-related rate of decline of D1 binding. We found an age-dependent decrease of D1 receptor binding in the caudate (6.9% per decade) and putamen (7.4% per decade). There was also a significant inverse correlation between [11C]SCH 23390 binding in the occipital cortex and age (8.6% decline per decade). PPBT score also decreased with age (P = 0.007). There was a direct correlation between PPBT score and D1 binding potential. We conclude that dopamine D1 receptor density declines with age and that the effects of physiological ageing may play a role in the expression of extrapyramidal disorders in the elderly.

Hereditary form of parkinsonism--dementia.

In four generations of a family, 13 members were afflicted with an autosomal dominant disorder characterized by young age at onset, early weight loss, and rapidly progressive dopa-responsive parkinsonism, followed later by dementia and, in some, by hypotension. Intellectual dysfunction began with subjective memory loss and objective visuospatial dysfunction and was followed later by decline of frontal lobe cognitive and memory functions. Neuropathological examination in 4 autopsied cases showed neuronal loss in the substantia nigra and locus ceruleus and widespread Lewy bodies, many of them in the cerebral cortex; those in the hypothalamus and locus ceruleus were often of bizarre shapes. Other findings were vacuolation of the temporal cortex, unusual neuronal loss and gliosis in the hippocampus (CA 2/3), and neuronal loss in the nucleus basalis. There were no neuritic plaques, neurofibrillary tangles, or amyloid deposits. Positron emission tomography in 3 patients showed decreased striatal uptake of fluorodopa. Neurochemical analysis of an autopsied brain showed a pronounced decrease in choline acetyltransferase activity in the frontal and temporal cortices and hippocampus and a severe depletion of striatal dopamine with a pattern not typical of classic Parkinson's disease.

Striatal D2 receptors in symptomatic and asymptomatic carriers of dopa-responsive dystonia measured with [11C]-raclopride and positron-emission tomography.

We tested the hypothesis that asymptomatic carriers of dopa-responsive dystonia (DRD) have increased dopamine D2 receptors in the striatum that protect them from the clinical manifestations of dopaminergic deficiency. We examined striatal D2-receptor binding in (1) symptomatic subjects (treated and untreated) and (2) asymptomatic gene carriers. Using [11C]-raclopride PET, we found elevated striatal D2-receptor binding in both groups. In one of our drug-naive symptomatic subjects, 7 months of treatment with levodopa/carbidopa did not affect the receptor binding as measured on a second scan. We conclude that increased D2-receptor binding in DRD may be a homeostatic response to the dopaminergic deficit in subjects carrying the DRD gene, but is not the sole factor determining the clinical state of these individuals.

Effect of age on caudate dopaminergic function in idiopathic Parkinsonism.

Aging has long been implicated in the pathogenesis of Idiopathic Parkinsonism (IP). However, postmortem studies have demonstrated that the pathological changes in aging and IP affect the dopaminergic function in putamen and caudate nuclei differently. This has been considered by some authors as evidence against the role of aging in IP. We performed fluorodopa (FD) positron emission tomography (PET) in 36 patients with IP and 25 normal controls to test the hypothesis that the effect of aging on the striatal dopaminergic function in IP differs from the effect of aging in normal controls. We found that the FD uptake constant (Ki) in the caudate nucleus of patients with IP declines with both age (p = 0.002) and duration (p = 0.05) of symptoms. This effect was over and above that of normal aging (p = 0.007). We did not find a similar superimposed effect of age in the putamen. We conclude that the effect of aging on the dopaminergic function in the caudate nucleus in IP differs from that in normal aging. Whether this abnormal aging precedes and even predisposes to IP or is triggered by pathogenetic factors in IP is unclear.

Fluorodopa and raclopride PET analysis of patients with Machado-Joseph disease.

We performed [18F]6-fluoro-L-dopa (6-FD) and [11C]raclopride (RAC) PET studies in six patients with Machado-Joseph disease (MJD) (age, 17 to 61 years; duration of illness, 3 to 10 years), normal controls (n = 10 in 6-FD-PET, n = 8 in RAC-PET), and patients with idiopathic parkinsonism (n = 15 in 6-FD-PET). The youngest patient with MJD had prominent dystonia and pyramidal features (type 1 MJD), whereas the remainder were prominently ataxic (types 2 and 3 MJD). Striatal RAC binding was normal in patients with MJD. Striatal 6-FD influx constants (Ki) were low in the range of idiopathic parkinsonism in two patients with MJD (youngest and oldest patients), whereas striatal Ki were normal in the remaining patients with MJD. The impairment of the nigrostriatal dopaminergic pathway did not correlate with the phenotype, CAG repeat length, disease duration, or age of onset of patients with MJD. Our results suggest that striatal D2 receptors are normal and the nigral damage is diverse in MJD.

Graphical analysis of 6-fluoro-L-dopa trapping: effect of inhibition of catechol-O-methyltransferase.

UNLABELLED: Graphical methods to analyze tracer time-course data allow reliable quantitation of the rate of incorporation of tracer from plasma into a "trapped" kinetic component, even when the details of the kinetic model are unknown. Applications of the method over long time periods often expose the slow reversibility of the trapping process. In the extended graphical method, both trapping rate and a presumed first-order loss rate constant are estimated simultaneously from the time-course data. METHODS: We applied the extended graphical method to 6-fluoro-L-dopa (6-FD), simultaneously estimating the rate of uptake (Ki) and the rate constant for loss from the trapped component (K(loss)) in a single fitting procedure. We applied this approach to study the effects of two catechol-O-methyl-transferase inhibitors on the kinetics of 6-FD in cynomolgus monkeys. RESULTS: Inhibition of peripheral O-methylation with either inhibitor, confirmed by high-performance liquid chromatography analysis of labeled compounds in arterial plasma, had no significant effect on Ki, in agreement with previously reported studies. In contrast, tolcapone, a catechol-O-methyl-transferase inhibitor, having central effects in addition to peripheral effects at the dosage used, decreased K(loss) by 40% from control values (p < 0.002), whereas nitecapone, which has no known central activity, had no significant effect. CONCLUSION: This method provides insight into the neurochemical basis for the kinetic behavior of 6-FD in both health and disease and may be used to define the action of centrally active drugs that influence the metabolism of dopamine.

Efficacy, stability and predictors of outcome of pallidotomy for Parkinson's disease. Six-month follow-up with additional 1-year observations.

We tested the efficacy, stability and predictors of outcome of unilateral pallidotomy used to treat patients with Parkinson's disease inadequately controlled with pharmacotherapy (IP). The surgical procedure was as simple as possible; we used CT rather than MRI, and we omitted microelectrode recording. We studied 24 patients with IP; 22 of these patients had drug-induced dyskinesias. There was a significant and stable improvement in all the major parkinsonian motor signs in the OFF (medication) state on the contralateral side. In the ON (medication) state peak-dose dyskinesias were alleviated on the contralateral side. The only significant and stable change on the ipsilateral side was improvement in dyskinesias less marked than on the contralateral side. The improvement in Unified Parkinson's Disease Rating Scale motor scores in the OFF state increased with age. The improvement in total dyskinesia scores occurred irrespective of age, but increased with duration of disease, duration of dyskinesias and baseline severity of dyskinesias. Five patients had transient neurological complications while facial paresis was permanent in one subject. Our results are similar to those obtained by others who used the time consuming microelectrode recording technique for localization. By simplifying the procedure in the way that we describe, the operation could become available to a greater number of patients.

Presynaptic and postsynaptic striatal dopaminergic function in patients with manganese intoxication: a positron emission tomography study.

We performed PET on four patients with chronic industrial Mn intoxication; presynaptic and postsynaptic dopaminergic function were measured with [18F]6-fluoro-L-dopa (6FD) and [11C]raclopride (RAC). All patients had a rigid-akinetic syndrome; they had no sustained benefit from L-dopa. Influx constants (Ki) of 6FD were normal in the caudate and putamen. RAC binding was mildly reduced in the caudate and normal in the putamen. We conclude that nigrostriatal dopaminergic dysfunction is not responsible for the parkinsonism caused by chronic Mn intoxication. The pathology is likely to be downstream of the dopaminergic projection.

Which clinical sign of Parkinson's disease best reflects the nigrostriatal lesion?

Clinical scales, based on the major signs of Parkinson's disease (PD), are commonly used to assess the effect of symptomatic treatment of PD. With the appearance of therapy aiming to rescue or protect the nigrostriatal neurons in PD, it becomes essential to define which of these signs best reflects the underlying neuronal deficit. Fluorodopa positron emission tomography has been shown to correlate with postmortem nigral cell counts. We correlated the major signs of PD with positron emission tomography results in 35 PD patients. We found that in the "practically defined off" state, (1) Purdue pegboard scores correlated best with the nigrostriatal dopaminergic deficit; (2) of the subscales of the modified Columbia score, the bradykinesia subscale correlated best; (3) rigidity and postural disturbance correlated less highly than bradykinesia, and their inclusion in a multiple regression did not improve the correlation of pegboard or bradykinesia scores alone; and (4) tremor did not correlate with the nigrostriatal dopaminergic deficit. We conclude that pegboard and bradykinesia scores represent the best clinical measures for studying the effect of treatment on the evolution of the nigrostriatal lesion of PD. Inclusion of other clinical signs provides additional information only for the study of functional impairments.

Positron emission tomography (PET) measurements of striatal D(2) receptors in untreated Parkinson's disease patients with follow-up after 6 and 12 months' treatment with SINEMET((R)) or SINEMET((R)) CR.

Untreated Parkinson's disease (FD) patients typically demonstrate an upregulation in striatal D(2) receptor binding. Reduced D(2) binding is found in levodopa-treated patients with a fluctuating response to this drug. Using PET and (11)C-raclopride, we determined striatal:background uptake ratios to provide a measure of D(2) receptor binding in 10 untreated, newly diagnosed PD patients who were treated subsequently with levodopa for 1 yr. At baseline, we found increased striatal D(2) receptor uptake ratios in patients (3.89) in comparison to normal controls (3.22; p < 0.02). Furthermore, the ratio between caudate and putamen D(2) uptake was significantly reduced in patients (0.86 vs. 0.98 in normals, p < 0.01). Patients were subsequently randomized to treatment with either SINEMET((R)) (300 mg of levodopa/d) or SINEMET((R)) CR (400 mg of levodopa/d). Patients in both groups received similar symptomatic benefit following treatment, and none developed motor fluctuations. All patients were rescanned after 6 months of treatment. There were no significant differences in striatal (or caudate and putamen considered singly) raclopride binding between the first and 6 month post-treatment scans. Similarly, there were no significant differences between pre- and 6 month post-treatment scans on the basis of levodopa preparations. Patients were subsequently treated with the other Sinemet preparation for another 6 month period before rescanning. Again, no differences in raclopride binding were found compared to pre-treatment or between type of levodopa preparation. We conclude that there is no evidence for downregulation of D(2) receptor binding after 1 yr of low-dose levodopa therapy in patients who receive symptomatic benefit without motor fluctuations, regardless of type of preparation. Follow-up of such individuals may permit determination of when and in what context D(2) receptor downregulation occurs.

Presynaptic nigrostriatal function in genetically tested asymptomatic relatives from the pallido-ponto-nigral degeneration family.

Pallido-ponto-nigral degeneration (PPND) is a dominantly inherited disorder with parkinsonism. We performed PET with [18F]fluorodopa (FD) and, later, gene testing in 12 asymptomatic relatives at risk from a family with PPND and compared the striatal FD uptake constant (Ki) in them with 4 symptomatic individuals and 10 normal control subjects. Four relatives with positive linkage had a significantly reduced Ki from the normal control subjects but to a lesser degree than the symptomatic patients. The mean Ki in the relatives with negative linkage (n = 8) did not differ from normal control subjects. In conclusion, we identified reduced dopaminergic function in asymptomatic relatives with positive genetic linkage from the PPND family. Most of the reduction in this disorder occurs in the fifth decade, when the disease manifests clinically.

The presymptomatic period in a patient with idiopathic parkinsonism.

A 68-year-old, normal female volunteer was scanned by positron emission tomography (PET) with [(18)F]6-L-fluorodopa (FD). Striatal FD uptake was in the high normal range. Subsequently, she developed parkinsonism 3.7 years after the scan. A repeat FD PET scan revealed a significant reduction of FD uptake by 20% over the 5.2 year interval. Our observations suggest a relatively short presymptomatic period with fast initial losses of nigral neurons in idiopathic parkinsonism.

Drug management of Parkinson's disease.

Levodopa remains the cornerstone for managing Parkinson's disease. Physician's preference usually determines the dopamine agonist chosen for the early phases of treatment. The concept of neuro-protection, however, remains unproven. A better understanding of the cause of the disease and treatment-related complications could make managing Parkinson's disease more rewarding.

Reproducibility and discriminating ability of fluorine-18-6-fluoro-L-Dopa PET in Parkinson's disease.

UNLABELLED: Fluorine-18-fluorodopa (F-Dopa) PET assesses the integrity of the nigrostriatal dopaminergic neurons in Parkinson's disease. It has been used in longitudinal studies to measure the progression of Parkinson's disease and the effects of medications and intracerebral transplants. The significance of changes in PET indices in such studies depends largely on the reproducibility of the F-Dopa PET measurements. METHODS: We performed repeated F-Dopa PET scans in 12 subjects with Parkinson's disease (between Hoehn and Yahr stages I and III) to measure scan-to-scan variations. Data were analyzed using five methods comprising two sets of regions of interest (ROIs) (total striatum and substriatal), the striatum-to-cortex ratio and two graphical methods (one using plasma radioactivity, the other using cortical radioactivity as the input function). We also studied the effectiveness of each method in discriminating between patients with Parkinson's disease and normal subjects using data obtained from a similar study in 10 normal subjects. RESULTS: We found reliability coefficients between 66% and 93%; the scan-to-scan intrasubject standard deviation ranged from 2% to 16% of the mean value depending on the method of analysis and the size of the ROIs. All methods discriminated significantly between patients with Parkinson's disease and normal subjects. The ability to discriminate, as reflected by the intergroup/intragroup ratio of variance, ranged from 2 to 18. CONCLUSION: These results permit selection of the best method of analysis for studies of nigrostriatal dopaminergic function.