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.

Plasma glucose and insulin responses to traditional Pima Indian meals.

The in vivo glycemic and insulin responses and in vitro starch digestibility were determined for six staple foods (corn, lima beans, white and yellow teparies, mesquite, and acorns) traditionally consumed by Pima Indians. Equivalent carbohydrate portions (25 g) of the foods were fed to eight healthy Caucasian volunteers. The calculated glycemic indices (GIs) (mean +/- SEM with glucose as the standard) were all low, ranging from 16 +/- 2 for acorns to 40 +/- 5 for corn. Insulin responses and in vitro starch digestibilities correlated with the GI. These results provide further support for the hypothesis that the slow digestion and absorption of starch in traditional foods was a factor that helped protect susceptible populations from developing diabetes.

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.

Positron emission tomography in progressive supranuclear palsy.

Positron emission tomography with 6-[18F]fluoro-L-dopa (6-FD) provides in vivo information on the function of nigrostriatal dopaminergic neurons. We used 6-FD and positron emission tomography to investigate the integrity of the nigrostriatal system in seven patients with progressive supranuclear palsy. All patients had axial hypertonia, vertical gaze palsy, and parkinsonian features. Dementia, pyramidal signs, and ataxia were seen in varying proportions. We analyzed the scans with a graphic method to calculate a steady-state 6-FD uptake rate constant for the whole striatum. Results were compared with those obtained in seven age-matched controls. As a group, the patients with progressive supranuclear palsy had reduced 6-FD uptake constants. The 6-FD uptake constant correlated inversely with the duration of the disease. Normal positron emission tographic findings in one patient with the shortest duration of symptoms suggests that in early progressive supranuclear palsy, parkinsonism may relate to dysfunction distal to the dopaminergic neurons.

Positron emission tomographic scanning demonstrates a presynaptic dopaminergic lesion in Lytico-Bodig. The amyotrophic lateral sclerosis-parkinsonism-dementia complex of Guam.

We performed positron emission tomography using 18F-6-fluorodopa on four Guamanians with an amyotrophic lateral sclerosis syndrome, eight Guamanians with parkinsonism, and seven clinically normal Guamanians; the results were compared with those of nine Vancouver control subjects. The Guamanian subjects had all been exposed to similar Chamorro lifestyles. The scans were analyzed using a graphic method that calculates a constant for whole striatal 18F-6-fluorodopa uptake. The parkinsonian subjects all had significantly reduced striatal 18F-6-fluorodopa uptake. The group with amyotrophic lateral sclerosis had significantly reduced uptake that was intermediate between that of the control group and the parkinsonian group. Two Guamanian normal subjects had reduced striatal 18F-6-fluorodopa uptake. The nigrostriatal dopaminergic lesion in Guamanian parkinsonism is similar to that found in idiopathic parkinsonism. The nigrostriatal lesions in the subjects with amyotrophic lateral sclerosis and the Guamanian normal subjects are examples of subclinical neuronal damage demonstrable in living subjects with positron emission tomography.

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.

Phenotypic expression of X-linked dystonia-parkinsonism (lubag) in two women.

Lubag (X-linked dystonia-parkinsonism) has been considered a sex-linked recessive trait and has been mapped to the pericentromeric region of the X chromosome. We studied a 54-year-old man with lubag and two of his female first cousins. Genetic typing was carried out using X chromosome markers. Fluorodopa PET was performed on the man and one of the women. The man had moderately severe parkinsonism and dystonia. A 61-year-old female first cousin had mild left-sided dystonia and her 54-year-old sister had mild generalized chorea. Genetic typing data revealed that all three inherited an X chromosome with marker alleles strongly associated with lubag. Cytologic analysis did not reveal evidence of X chromosomal deletion. Fluorodopa PET in both the man and one affected cousin revealed reduced striatal uptake rate constants consistent with nigrostriatal involvement. These observations suggest that lubag may be a codominant disorder and that it is possible for women to be affected.

The effect of entacapone (OR-611) on brain [18F]-6-L-fluorodopa metabolism: implications for levodopa therapy of Parkinson's disease.

We used PET and [18F]-6-L-fluorodopa ([18F]dopa) to measure the effect of a peripheral COMT inhibitor, entacapone, on the extracerebral metabolism and subsequent striatal uptake of [18F]dopa. Four parkinsonian patients and six age-matched normal controls were each scanned twice, once after carbidopa (150 mg) plus placebo and once after carbidopa (150 mg) plus entacapone (400 mg or 800 mg). Without entacapone premedication, by 90 minutes from injection, only 22% of the [18F] signal in plasma represented unmetabolized [18F]dopa (the balance being 3-O-methyl[18F]dopa). After entacapone medication, this fraction increased to 56% of the [18F] signal (p < 0.0001). We did not find any significant differences between the changes observed in patients versus controls or between those subjects who received 400 mg entacapone versus 800 mg in either this or any of the other reported measures. PET image contrast increased in all cases, reflecting an increase in the specific striatal signal ([striatum-occipital]:occipital ratio increased 38% [p < 0.0001]). Entacapone did not alter the rate of striatal uptake and decarboxylation of [18F]dopa as estimated using a graphic approach with metabolite-corrected plasma as input function to calculate the influx constant, Ki(p) (p = NS). This confirms that such an analytic approach adequately corrects for the effect of extracerebral [18F]dopa methylation. In contrast, the influx constant Ki(o) (calculated using occipital counts as the input function) increased 45% after entacapone (p < 0.0001). This demonstrates the sensitivity of this analytic approach to the presence of peripheral 3-O-methyl[18F]dopa and provides an estimate of the percentage increase in brain free [18F]dopa resulting from entacapone premedication.

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.

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.

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.

Manganese intoxication in the rhesus monkey: a clinical, imaging, pathologic, and biochemical study.

We gave three adult rhesus monkeys seven IV injections of manganese chloride at approximately 1-week intervals. We evaluated neurologic status by serial clinical examinations and performed a levodopa test if the animal developed features of basal ganglia dysfunction. After the animals were killed, we performed neuropathologic, neurochemical, and laser microprobe mass analysis (LAMMA) studies. Two of three animals developed a parkinsonian syndrome characterized by bradykinesia, rigidity, and facial grimacing suggestive of dystonia but not tremor. Neither animal responded to levodopa. Autopsy demonstrated gliosis primarily confined to the globus pallidus (GP) and the substantia nigra pars reticularis (SNr). We detected focal mineral deposits throughout the GP and SNr, particularly in a perivascular distribution. LAMMA studies noted that mineral deposits were primarily comprised of iron and aluminum. The severity of pathologic change correlated with the degree of clinical dysfunction. These studies demonstrate that, in contrast to Parkinson's disease (PD) and MPTP-induced parkinsonism, manganese primarily damages the GP and SNr and relatively spares the nigrostriatal dopaminergic system. Further, the results suggest that Mn-induced parkinsonism can be differentiated from PD and MPTP-induced parkinsonism by the clinical syndrome and response to levodopa. The accumulation of iron and aluminum suggests that iron/aluminum-induced oxidant stress may contribute to the damage associated with Mn toxicity.

MRI and PET studies of manganese-intoxicated monkeys.

Using MRI and PET, we investigated the consequences of manganese intoxication in a primate model of parkinsonism and dystonia. Three rhesus monkeys were injected intravenously with doses of 10 to 14 mg/kg of MnCl2 on seven occasions, each a week apart. Two animals became hypoactive with abnormal extended posturing in the hind limbs. These motor disturbances did not improve with administration of levodopa. In all three monkeys, T1-weighted MRI demonstrated high signal intensities in the regions of the striatum, globus pallidus, and substantia nigra. No significant changes were found on [18F]6-fluoro-L-dopa, [11C]raclopride, or [18F]fluorodeoxyglucose PET. These results are consistent with the pathologic findings, which were primarily confined to the globus pallidus, and indicate that manganese intoxication is associated with preservation of the nigrostriatal dopaminergic pathway, despite clinical evidence of parkinsonian deficits. Chronic manganese intoxication may cause parkinsonism by damaging output pathways downstream to the nigrostriatal dopaminergic pathway. This is consistent with the demonstrated lack of therapeutic response to levodopa.

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.

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.

The reproducibility of striatal uptake data obtained with positron emission tomography and fluorine-18-L-6-fluorodopa tracer in non-human primates.

Cynomolgus and rhesus monkeys have been studied via PET with [18F]-L-6 fluorodopa tracer. Striatal fluorodopa uptake rate constants have been derived by graphical analysis of transaxial slice images centered on the striata. The differences between pairs of values of the rate constant, obtained from two scans on the same monkey separated by two weeks or more, exhibited a relative standard deviation of 34.4%. If the two scans were conducted one immediately after the other, with the position of the monkey undisturbed, the standard deviation was reduced to 14.0%. The utility of this technique was demonstrated by comparing the effects on the scans of halothane and pentobarbital anesthesia and by the administration of NSD 1015, a peripheral and central inhibitor of L-aromatic amino-acid decarboxylase, between back-to-back scans. With NSD 1015, the fluorodopa uptake constant was reduced by an average of 76.0%.

Reproducibility of fluorine-18-6-fluorodopa positron emission tomography in normal human subjects.

UNLABELLED: Fluorine-18-6-fluorodopa (FD) positron emission tomography (PET) is established for measuring nigrostriatal dopaminergic function. This is despite the absence of data on the reproducibility of results. METHODS: With an ECAT 953B/31 tomograph, we performed two or three repeated FD PET scans in 10 normal subjects to measure the scan-to-scan variation in the total striatal uptake rate constant (Ki). RESULTS: We found a scan-to-scan standard deviation (s.d.) of 8.7% of the mean. The between-subject s.d. was 26% of the mean, resulting in a reliability coefficient of 90%. Analysis of the variation in the components contributing to Ki showed a reliability varying from 77% to 86% (depending on the different time points analyzed) for emission data measured by the PET camera. The reliability of the blood radioactivity time course, as reflected by the stretch time, varied from 43% to 81%. The overall reliability for the correction of the blood time course for metabolites of FD was 71%. Variation in the blood radioactivity contributed to the variability of Ki by 50% more than the metabolite correction and by 200% more than the emission data. CONCLUSION: The striatal Ki is a reliable measurement; it has a 95% chance of lying within +/- 18% of its value for an individual normal subject.

Recovery of the human striatal signal in a slice oriented positron emission tomograph.

The human striatum is small enough for partial volume effects to be important when imaged in positron tomographs with slice widths 10 mm or greater. The combination of interslice distance and slice width in such tomographs results in an axial undersampling of the striatal activity which introduces the additional problem of variation of axial recovery as a function of position of the striatum along the tomograph axis. Using striatal phantoms, we have developed a method that corrects the recovered striatal signal to a maximum value equivalent to that measured when the object is centered with respect to a slice. This makes the recovery independent of the axial position of the striatum. The method also provides an estimate of the total striatal activity by integrating the axial image intensity distribution along the tomograph axis. The method is able to detect and correct for relative axial tilt of the left and right striatum. We applied it to 26 human [18F]-6-L-fluorodopa scans and obtained an average uptake rate constant k value of 0.25 +/- 0.05 ml/min/striatum and a left to right k value percentage asymmetry of 0.1% +/- 6.3%.

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.

The relationship of eyelid movement to the blink reflex.

Although the blink reflex is a standard neurophysiological investigation its relationship with eyelid movement has not been clearly established. We studied normal subjects and patients with unilateral facial paralysis to define the pattern of eyelid movement following glabellar tap, supraorbital nerve stimulation, facial nerve stimulation and direct corneal stimulation. We found that eyelid closure did not necessarily occur in a single movement. Following glabellar tap the first component of a two-stage movement was initiated by levator palpebrae relaxation while with supraorbital nerve stimulation orbicularis oculi contraction produced the first movement. The compound muscle action potential following direct facial nerve stimulation produced only minimal eyelid movement, the major closure being associated with a longer latency orbicularis oculi reflex. Corneal stimulation elicited a single component eyelid movement. Thus, the pattern of eyelid movement differed for each stimulus reflecting variations in orbicularis oculi contraction and levator palpebrae inhibition.