Prefrontal dopamine signaling and cognitive symptoms of Parkinson's disease.

Cognitive dysfunction is a common symptom of Parkinson's disease (PD) that causes significant morbidity and mortality. The severity of these symptoms ranges from minor executive symptoms to frank dementia involving multiple domains. In the present review, we will concentrate on the aspects of cognitive impairment associated with prefrontal dopaminergic dysfunction, seen in non-demented patients with PD. These symptoms include executive dysfunction and disorders of thought, such as hallucinations and psychosis. Such symptoms may go on to predict dementia related to PD, which involves amnestic dysfunction and is typically seen later in the disease. Cognitive symptoms are associated with dysfunction in cholinergic circuits, in addition to the abnormalities in the prefrontal dopaminergic system. These circuits can be carefully studied and evaluated in PD, and could be leveraged to treat difficult clinical problems related to cognitive symptoms of PD.

Upcoming treatments in Parkinson's disease, including gene therapy.

Progress is being made in the development of three categories of therapy for Parkinson's disease: (1) Symptomatic, (2) Neuroprotective, (3) Neurorestorative. Evolving approaches to symptomatic therapy, already in clinical trials, include the use of adenosine 2(A) antagonists, novel glutamate antagonists, and serotonin receptor antagonists, the latter for the therapy of Parkinson's psychosis and/or levodopa-induced dyskinesias. Examples of promising neuroprotective therapies under evaluation include the administration of creatine, urate-inducing compounds, calcium channel blockers, and pioglitazone, a peroxisome proliferator-activated receptor agonist. Cell-based restorative therapies are not the subject of this presentation, but various forms of gene therapy have shown promise in human Parkinson's disease trials. These protocols typically involve gene transfer into the CNS through the use of viral vectors. Currently, the most advanced studies of this technique involve delivery of an adeno-associated viral vector encoding glutamic acid decarboxylase into the subthalamic nucleus. This treatment has shown modest benefit in early clinical trials. Other gene therapies, in various stages of human clinical trials, include gene transfer for the production of trophic factors, for aromatic amino acid decarboxylase alone, and most recently, a lentiviral vector transfer of an enzymatic dopamine "factory" consisting of three essential enzymes required for production for this neurotransmitter.

Secondary dystonia in a botulinum toxin clinic: clinical characteristics, neuroanatomical substrate and comparison with idiopathic dystonia.

The analysis of patients with secondary dystonia has been valuable to explore the anatomical, pharmacological and physiological bases of this disorder. The goal of this study is to compare the clinical characteristics of patients with primary and secondary dystonia and analyze the neuroanatomical bases of a subgroup of patients with lesion-induced dystonia. We identified patients evaluated in our Botulinum Toxin Clinic from 1/2000 to 7/2009 with an ICD code for "dystonia". Medical records of all subjects were reviewed, recording demographic, clinical, therapeutic and neuroimaging data. A total of 230 patients were included in the study. Idiopathic/primary dystonia was diagnosed in 162 and secondary dystonia in 58, while in 10 the etiology was uncertain. We found a female predominance (2.4:1 and 1.9:1 for primary and secondary dystonia, respectively). The cervical region was most commonly affected in primary dystonia and the limbs in secondary cases. The age at presentation was higher in primary (54.4 ± 14.1) than secondary (49 ± 17.9) dystonia. Among patients with secondary dystonia, a focal lesion was the presumed etiology in 32, with localizing diagnostic studies available in 16. The most common lesions were strokes involving the corticospinal pathway. All of those patients exhibited limb dystonia, except one with cervical dystonia following a thalamic infarct. In conclusion, primary and secondary dystonias are more prevalent in women, suggesting a sex-related predisposition to the development of this movement disorder. Lesion-induced dystonia most frequently involves the limbs and is caused by lesions in the cerebral cortex and subcortical white matter.

Juvenile parkinsonism: epidemiology, diagnosis and treatment.

Juvenile parkinsonism, with onset prior to age 21 years, is a relatively rare syndrome. It is caused by a group of heterogeneous entities that can present with a clinical picture similar to idiopathic Parkinson's disease or manifest parkinsonism as part of a spectrum of other signs. Diagnostic testing is guided by the presenting symptoms and aimed at uncovering potentially reversible and/or treatable causes. If an underlying condition is found, treatment is tailored accordingly. Otherwise, treatment is symptomatic and relies on medications commonly employed to treat idiopathic Parkinson's disease. Juvenile parkinsonism patients tend to be plagued by treatment-induced complications, so caution must be employed.

Impaired navigation in drivers with Parkinson's disease.

Navigating a new route during automobile driving uses the driver's cognitive resources and has the potential to impair driving ability in people with Parkinson's disease (PD). Our aim was to assess navigation and safety errors during a route following task (RFT) in drivers with the illness. Seventy-seven subjects with mild-moderate PD (median Hoehn-Yahr stage = 2.0) and 152 neurologically normal elderly adults, all active and licensed drivers, were tested with a battery of visual, cognitive and motor tests of abilities. Each driver also performed a RFT administered on the road in an instrumented vehicle. Main outcome variables included: number of incorrect turns, times lost and at-fault safety errors. All group comparisons were adjusted for age, gender, education and familiarity with the region. Drivers with PD performed significantly worse on cognitive, visual and motor tests compared to controls, and took longer to finish the RFT. Higher proportions of these drivers made incorrect turns {53.9% in PD versus 21.1% in controls, Odds Ratio (OR) [95% Confidence Interval (CI)] = 2.8 [1.4, 5.7], P = 0.006}, got lost (15.8% versus 2.0%, OR [95%CI] = 4.7 [1.1, 20.0], P = 0.037), or committed at-fault safety errors (84.2% versus 46.7%, OR [95%CI] = 7.5 [3.3, 17.0], P < 0.001). Within the patient group, the navigational and safety errors were predicted by poor performances on cognitive and visual tests, but not by the severity of motor dysfunction. Drivers with PD made more navigation and safety errors than neurologically normal drivers on a RFT that placed demands on driver memory, attention, executive functions and visual perception. The PD group driver safety was degraded possibly due to an increase in the cognitive load in patients with limited reserves. Navigational errors and lower driver safety were associated more with impairments in cognitive and visual function than the motor severity of their disease in drivers with PD.

Impaired visual search in drivers with Parkinson's disease.

OBJECTIVE: To assess the ability for visual search and recognition of roadside targets and safety errors during a landmark and traffic sign identification task in drivers with Parkinson's disease (PD). METHODS: Seventy-nine drivers with PD and 151 neurologically normal older adults underwent a battery of visual, cognitive, and motor tests. The drivers were asked to report sightings of specific landmarks and traffic signs along a four-lane commercial strip during an experimental drive in an instrumented vehicle. RESULTS: The drivers with PD identified significantly fewer landmarks and traffic signs, and they committed more at-fault safety errors during the task than control subjects, even after adjusting for baseline errors. Within the PD group, the most important predictors of landmark and traffic sign identification rate were performances on Useful Field of View (visual speed of processing and attention) and Complex Figure Test-Copy (visuospatial abilities). Trail Making Test (B-A), a measure of cognitive flexibility independent of motor function, was the only independent predictor of at-fault safety errors in drivers with PD. INTERPRETATION: The cognitive and visual deficits associated with PD resulted in impaired visual search while driving, and the increased cognitive load during this task worsened their driving safety.

Isolated high-frequency jaw tremor relieved by botulinum toxin injections.

Jaw tremor can be seen as a component of various neurological disorders such as essential tremor, Parkinson's disease, dystonia, branchial myoclonus, hereditary geniospasm, task-specific tremor, and Whipple's disease, as well as in normal situations such as shivering, and subclinical physiological jaw tremor. In most of these conditions, the jaw tremor is usually associated with tremor or other abnormal involuntary movements affecting additional body parts, and its frequency is lower than 12 Hz. Schrag and colleagues reported a patient with a high-frequency idiopathic jaw tremor, and they speculated it could be related to orthostatic tremor affecting the masseter muscles. We encountered a similar patient with intermittent rapid focal jaw tremor that was successfully treated with botulinum toxin injections to the masseters.

Predictors of weight loss in Parkinson's disease.

The objective of this study was to examine the change of body weight (BW) among Parkinson's disease (PD) patients and controls over years and determine the predictors of weight loss among PD patients. Studies on weight loss in PD studies are cross-sectional, have a short follow-up, or lack in clinical detail. We examined the percentage of BW change over years among 49 PD patients and 78 controls. The controls were from another study on longitudinal evolution of BW and body composition in the elderly. We determined the BW, Hoehn and Yahr (HY) stage, and dyskinesia status of 49 consecutive nondemented PD patients with symptom duration of 6.1 +/- 0.7 years (mean +/- SEM) and ascertained their BW at the time of diagnosis and 2.4 +/- 0.2 years before the diagnosis from medical records. We collected data again 7.2 +/- 0.5 years after the first visit. The PD group lost 7.7% +/- 1.5% of BW over the entire symptomatic period (13.1 +/- 0.8 years), while the control group lost only 0.2% +/- 0.7% of BW over 9.9 +/- 0.1 years; weight loss was clinically significant (>5%) in 55.6% of PD patients vs. 20.5% of the controls (both P values < 0.001, adjusted for sex, baseline age, and observation period duration). PD patients lost weight in both the early and advanced phases. While worsening of parkinsonism was the most important factor, age at diagnosis, emergence of visual hallucinations, and possibly dementia were also associated with weight loss. We demonstrated significant weight loss in PD patients compared to controls over approximately 1 decade. Neurodegeneration involving both motor and nonmotor systems may be associated with weight loss in PD.

Efficacy and safety of botulinum type A toxin (Dysport) in cervical dystonia: results of the first US randomized, double-blind, placebo-controlled study.

Botulinum toxin type A (Dysport) has been shown in European studies to be a safe and effective treatment for cervical dystonia. This multicenter, double-blind, randomized, controlled trial assessed the safety and efficacy of Dysport in cervical dystonia patients in the United States. Eighty patients were randomly assigned to receive one treatment with Dysport (500 units) or placebo. Participants were followed up for 4 to 20 weeks, until they needed further treatment. They were assessed at baseline and weeks 2, 4, 8, 12, 16, and 20 after treatment. Dysport was significantly more efficacious than placebo at weeks 4, 8, and 12 as assessed by the Toronto Western Spasmodic Torticollis Rating Scale (10-point vs. 3.8-point reduction in total score, respectively, at week 4; P < or = 0.013). Of participants in the Dysport group, 38% showed positive treatment response, compared to 16% in the placebo group (95% confidence interval, 0.02-0.41). The median duration of response to Dysport was 18.5 weeks. Side effects were generally similar in the two treatment groups; only blurred vision and weakness occurred significantly more often with Dysport. No participants in the Dysport group converted from negative to positive antibodies after treatment. These results confirm previous reports that Dysport (500 units) is safe, effective, and well-tolerated in patients with cervical dystonia.

Drug-induced movement disorders in children and adolescents.

The use of psychotropic medication among children and adolescents is increasing with a concomitant increase in the incidence of drug-related movement disorders. This class of adverse reactions to medications can be divided into those that are acute in onset, others that are continuous as long as the offending drug is administered, and a final category consisting of symptoms that are persistent, even after the causative agent has been discontinued. Within these three categories, this review discusses the epidemiology, risk factors, clinical features and treatment of acute dystonic reactions, drug-induced parkinsonism, neuroleptic malignant syndrome, serotonin syndrome, acute akathisia, and the tardive syndromes. In addition, drugs that commonly cause tremor, chorea, or myoclonus are included.

Moyamoya-induced paroxysmal dyskinesia.

Moyamoya disease (MMD) is an uncommon intracranial vasculopathy that typically presents with ischemic or hemorrhagic stroke. Persistent choreoathetosis has been identified as a rare early manifestation of MMD. We present 2 patients with paroxysmal dyskinesia as the initial symptom of MMD, one resembling paroxysmal kinesigenic dyskinesia (PKD) and the other paroxysmal non-kinesigenic dyskinesia (PNKD). We also review the cases of moyamoya-induced chorea reported previously, none of which resembled PKD or PNKD. We hypothesize that both hormonal and ischemic factors may be implicated in the pathogenesis of these abnormal involuntary movements. These cases suggest that MMD should be included in the differential diagnosis of PKD and PNKD.

Albuterol improves response to levodopa and increases skeletal muscle mass in patients with fluctuating Parkinson disease.

Animal studies indicate that beta(2)-adrenergic receptor agonists enhance transport of levodopa across the blood-brain barrier. Preliminary studies showed improved response to levodopa in patients with Parkinson disease (PD) who were given albuterol as adjunctive therapy. Beta(2)-adrenergic agonists may offer additional benefits to PD patients via their skeletal muscle anabolic effects, particularly those who experience decreased muscle strength and weight loss. Nondemented, fluctuating PD patients receiving levodopa but not experiencing severe dyskinesias underwent the following tests at baseline and 14 weeks after treatment with albuterol sulfate (4 mg four times a day, orally): Unified Parkinson's Disease Rating Scale motor, tapping, and stand-walk-sit tests every 30 minutes between 8 am and 5 pm; body composition analyses using whole-body plethysmography and computed tomography of the thigh; muscle strength tests; and the Parkinson's Disease Questionnaire (PDQ-39). Results were analyzed using paired t-tests (2 tailed), repeated-measures analysis of variance, and the Wilcoxon signed-rank test. Seven of 8 enrolled patients completed the study; 1 patient withdrew because of headache and anxiety. The area under the curve for all-day UPDRS motor scores improved by 9.8 +/- 9.1% (mean +/- standard deviation; P < 0.05) and tapping improved by 7.6 +/- 8.1% (P < 0.05). The effect was more pronounced when only the response to the first levodopa dose (area under the curve, 8-11 am) was analyzed: 13.0 +/- 9.8% and 9.8 +/- 9.6% respectively. Thigh muscle cross-sectional area increased significantly as measured by computed tomography (5.3 +/- 3.2%, P < 0.01), as did fat-free mass by whole-body plethysmography combined with total-body water determination (9.5 +/- 2.9%, P < 0.05). There was no significant improvement in the stand-walk-sit test, muscle strength tests, other UPDRS sections, daily OFF time, or PDQ-39. Four patients were rated as having a mild global improvement (+1 point) on a -3 to +3-point scale, and 3 of them chose to continue albuterol beyond the termination of the study. The mean heart rate increased from 78.3 +/- 9.3 beats/minute to 85.6 +/- 8.7 beats/minute (P < 0.05). No laboratory abnormalities or electrocardiographic changes were induced by albuterol in any subject. This open-label pilot study suggests that albuterol increases muscle mass and improves the therapeutic response to levodopa in patients with fluctuating PD. A double-blind, placebo-controlled study is needed to confirm the effects and safety profile of beta(2)-agonists in PD.

Tremor in children.

Tremor in childhood, beginning in the neonatal period, is more common than generally appreciated. Although some tremor disorders in children (eg, essential tremor) also affect adults, others (eg, shuddering, jitteriness, spasmus nutans, and vitamin B12-deficiency tremor) are seen exclusively in children. This review covers the etiology, clinical features, and treatment of the major tremor syndromes in children, and when appropriate, makes comparisons with similar disorders in adults.

Childhood dystonia.

Childhood dystonias are a heterogeneous group of disorders with strong inherited basis. This review describes the clinical characteristics, classification, genetic basis, pathophysiology, biochemistry, pathology, and treatment of dystonias, including the primary dystonias, the dystonia-plus syndromes, secondary dystonias, and heredodegenerative disorders. Conditions discussed in detail include idiopathic torsion dystonia, dopa-responsive dystonia, Wilson's disease, myoclonus dystonia, rapid-onset dystonia parkinsonism, neurodegeneration with brain iron accumulation (Hallervorden-Spatz syndrome), mitochondrial dystonias, Niemann-Pick type C, and neuroacanthocytosis.

Juvenile parkinsonism.

Juvenile parkinsonism (JP) is a clinically and etiologically heterogeneous entity. Unlike in the adult form, secondary causes, hereditary and metabolic conditions, are the predominant causes of JP. Idiopathic Parkinson's disease is very rare in this age group. In most cases of JP, parkinsonism is accompanied by other neurologic features, such as dystonia, cognitive impairment, seizures, oculomotor and visual dysfunction, and ataxia. Systemic findings, such as liver dysfunction or hepatosplenomegaly, may be present depending on the cause. This review article describes the clinical characteristics, classification, genetic basis, pathophysiology, biochemistry, pathology, and treatment of JP.

Drug-induced movement disorders in children.

The increased use of stimulants, antipsychotic agents, and antidepressant drugs in children by primary care physicians, psychiatrists, and neurologists has inevitably led to increased numbers of pediatric patients manifesting the side effects of these agents, many of which are movement disorders. Unlike the isolated abnormal involuntary movements associated with drugs prescribed for epilepsy or asthma, movement syndromes (eg, acute dystonic reaction, neuroleptic malignant syndrome, serotonin syndrome, tardive dyskinesia) associated with psychotropic drugs are complex, difficult to recognize, and potentially seriously disabling. Accurate clinical identification of these drug-induced syndromes is critical to engaging the proper therapeutic intervention for them.