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ObjectiveTo investigate in a cross-sectional study the contributions of altered cerebellar resting-state functional connectivity (FC) to cognitive impairment in Parkinson disease (PD).MethodsWe conducted morphometric and resting-state FC-MRI analyses contrasting 81 participants with PD and 43 age-matched healthy controls using rigorous quality assurance measures. To investigate the relationship of cerebellar FC to cognitive status, we compared participants with PD without cognitive impairment (Clinical Dementia Rating [CDR] scale score 0, n = 47) to participants with PD with impaired cognition (CDR score ≥0.5, n = 34). Comprehensive measures of cognition across the 5 cognitive domains were assessed for behavioral correlations.ResultsThe participants with PD had significantly weaker FC between the vermis and peristriate visual association cortex compared to controls, and the strength of this FC correlated with visuospatial function and global cognition. In contrast, weaker FC between the vermis and dorsolateral prefrontal cortex was found in the cognitively impaired PD group compared to participants with PD without cognitive impairment. This effect correlated with deficits in attention, executive functions, and global cognition. No group differences in cerebellar lobular volumes or regional cortical thickness of the significant cortical clusters were observed.ConclusionThese results demonstrate a correlation between cerebellar vermal FC and cognitive impairment in PD. The absence of significant atrophy in cerebellum or relevant cortical areas suggests that this could be related to local pathophysiology such as neurotransmitter dysfunction.

ObjectiveTo evaluate resting-state functional connectivity as a potential prognostic biomarker of Parkinson disease (PD) progression. The study examined longitudinal changes in cortical resting-state functional connectivity networks in participants with PD compared to controls as well as in relation to baseline protein measures and longitudinal clinical progression.MethodsIndividuals with PD without dementia (n = 64) and control participants (n = 27) completed longitudinal resting-state MRI scans and clinical assessments including full neuropsychological testing after overnight withdrawal of PD medications (“off”). A total of 55 participants with PD and 20 control participants also completed baseline β-amyloid PET scans and lumbar punctures for CSF protein levels of α-synuclein, β-amyloid, and tau. Longitudinal analyses were conducted with multilevel growth curve modeling, a type of mixed-effects model.ResultsFunctional connectivity within the sensorimotor network and the interaction between the dorsal attention network with the frontoparietal control network decreased significantly over time in participants with PD compared to controls. Baseline CSF α-synuclein protein levels predicted decline in the sensorimotor network. The longitudinal decline in the dorsal attention–frontoparietal internetwork strength correlated with the decline in cognitive function.ConclusionsThese results indicate that α-synuclein levels may influence longitudinal declines in motor-related functional connectivity networks. Further, the interaction between cortical association networks declines over time in PD prior to dementia onset and may serve as a prognostic marker for the development of dementia.

Essential tremor is most prevalent and most disabling in older patients. Additional therapies are required for patients with an inadequate response or intolerable side effects. In small trials, topiramate appeared to be beneficial in essential tremor.In this multicenter, double-blind, placebo-controlled, parallel-design trial, patients with moderate to severe essential tremor of the upper limbs were randomized to 24 weeks of treatment with placebo or topiramate (target dose, 400 mg/day) as monotherapy or as an adjunct to one antitremor medication. The primary efficacy variable was the final visit tremor score based on the Fahn-Tolosa-Marin Tremor Rating Scale (TRS).The intent-to-treat population was 208 patients (topiramate, 108; placebo, 100). The final visit score (last observation carried forward) was lower in the topiramate group than with placebo (p0.001). Mean percentage improvement in overall TRS scores was 29% with topiramate at a mean final dose of 292 mg/day and 16% with placebo (p0.001). Topiramate was associated with greater improvement in function and disability (p = 0.001). A between-group difference (p0.001) was observed at the first on-treatment visit at 4 weeks when the target topiramate dose was 100 mg/day (mean achieved dose, 62 +/- 9 mg/day). The most common treatment-limiting adverse events in topiramate-treated patients were paresthesia (5%), nausea (3%), concentration/attention difficulty (3%), and somnolence (3%). Adverse events were treatment limiting in 31.9% of topiramate patients and 9.5% of placebo patients.Topiramate was effective in the treatment of moderate to severe essential tremor. Tremor reduction was accompanied by functional improvements, such as in motor tasks, writing, and speaking.

Alzheimer disease (AD) is characterized by progressive cerebral atrophy that may be measured using MRI. Reported are MRI findings of a Phase IIa immunotherapy trial in AD prematurely terminated owing to meningoencephalitis in a subset of patients.To assess cerebral volume changes in patients immunized with AN1792 (beta-amyloid [Abeta] 1 to 42) who were antibody responders (anti-AN1792 IgG titer ofor =1:2,200) compared with placebo patients.This randomized, multicenter, placebo-controlled, double-blind trial of AN1792 225 mug plus QS-21 50 mug included 372 patients with probable AD. Patients received one to three injections of AN1792/QS-21 or saline and were assessed for 12 months. Volumetric MRI was performed pre dose and at month 12 or early termination. Brain, ventricular, and hippocampal volume changes were measured from registered scan pairs.Two hundred eighty-eight patients had paired scans (mean interval 10.9 months). Antibody responders (n = 45) had greater brain volume decrease (3.12 +/- 1.98 vs 2.04 +/- 1.74%; p = 0.007), greater ventricular enlargement as a percentage of baseline brain volume (1.10 +/- 0.75 vs 0.48 +/- 0.40%; p0.001), and a nonsignificant greater hippocampal volume decrease (3.78 +/- 2.63 vs 2.86 +/- 3.19%; p = 0.124) than placebo patients (n = 57). Increased losses in brain volume were not reflected in worsening cognitive performance; a composite z score across a Neuropsychological Test Battery showed differences favoring antibody responders over placebo (0.03 +/- 0.39 vs -0.24 +/- 0.45; p = 0.008).A dissociation between brain volume loss and cognitive function was observed in AN1792/QS-21 antibody responders. The reasons for this remain unclear but include the possibility that volume changes were due to amyloid removal and associated cerebral fluid shifts.

Background: Similarities between Alzheimer disease (AD) and Parkinson disease (PD) suggest a possible role for apolipoprotein E (APOE) in PD. Most previous studies seeking to establish such a link used case-control datasets and results have been inconsistent. Objective: To investigate APOE’s role in PD using family-based association analyses. Methods: APOE functional polymorphisms were genotyped for 658 PD affected families, including 282 multiplex and 376 singleton families. The pedigree disequilibrium test (PDT) and the genotype-PDT were used to test the risk effect of APOE. The Monks-Kaplan test was used to evaluate the effect of APOE on age at onset of PD. Results: APOE was significantly associated with risk of developing PD. Stratified analysis revealed that APOE was most strongly associated with families with a positive PD family history (global p = 0.003). Like AD, the APOE-4 allele increases disease risk while the APOE-3 allele decreases risk. We detected a positive association of APOE-3 ( p = 0.019) and a negative association of APOE-4 ( p = 0.015) with age at onset in PD. Conclusions: The APOE-4 allele increases risk and decreases age at onset of PD, an association that may not be dependent upon cognitive impairment.

This manuscript reviews apomorphine administration in formulations other than intermittent bolus injection, and comments on other potential uses for this unique compound. Continuous sc apomorphine therapy has been shown to alter peak-dose dyskinesia thresholds in advancing patients, and in some instances may replace all other anti-parkinson therapies. In general continuous infusion of sc apomorphine at a rate of 4 mg/h is well tolerated, and has been postulated to be equivalent to approximately 600 mg levodopa/day. This therapy is associated with skin complications, particularly nodule formation, and focal panniculitis is seen in more than 50% of subjects. Optimal dosages for intranasal apomorphine range from 2 to 5 mg per inhalation with benefit seen at 7.5 minutes and duration of effect of 45 to 55 minutes. Side effects included nasal irritation, vestibulitis, dyskinesias, yawning, and nausea. Comparison of 3 mg sc and 30 mg sublingual apomorphine in 9 Parkinson's disease subjects in a blinded cross-over trial found that the time to peak benefit was beyond 40 minutes with sl apomorphine, compared to 21 minutes in the sc preparation. Chronic use of the sublingual formulation was associated with severe stomatitis in half the subjects, and markedly limited the treatment. Rectal administration of apomorphine has been evaluated in limited, usually post-operative settings. Administration of a 200 mg apomorphine rectal suppository resulted in an average time to benefit of 32 minutes with an average duration of 195 minutes. Sedation, nausea and faintness were reported as side effects. Although the diagnostic confirmation potential of this agent has been questioned, the drug may have an important role in evaluating the potential for benefit in the deep brain stimulation surgical setting.

Background: Manganese is known to cause a parkinsonian syndrome similar clinically to Parkinson disease (PD). l-Dopa responsiveness is a hallmark of PD; however, l-dopa’s effect on manganese-induced parkinsonism is not well defined. Objective: To access the efficacy and safety of l-dopa therapy in a double-blind, randomized, placebo-controlled trial. Methods: Thirteen patients with manganese-induced parkinsonism were evaluated in a cross-over study with a modified Unified PD Rating Scale (UPDRS), timed walk test, tapping, and global clinical impression scores. Adverse reactions were assessed. Results: There was no significant difference between placebo and l-dopa for any measure: motor UPDRS, 27.4 vs 28.8; walk time, 16.6 seconds vs 17.7 seconds; tapping right hand, 69.5 vs 64.7; and tapping left hand, 66.8 vs 64.4. There were no differences in the global impression scores. Adverse reactions occurred similarly in the two groups, including headaches, drowsiness, and diarrhea. Conclusions: l-Dopa therapy is not effective for the management of parkinsonism in welders. l-dopa unresponsiveness may be useful to distinguish manganese-induced parkinsonism from Parkinson disease.

Levodopa, introduced in the late 1960s, was the first highly effective drug for the symptomatic treatment of Parkinson's disease (PD) and remains the mainstay of pharmacologic treatment. However, long-term treatment has important limitations. The disease continues to progress despite treatment with levodopa, and a neuroprotective therapy is urgently required. In addition, motor complications associated with chronic levodopa therapy are an important source of disability. Treatment of these complications forms a major focus of modern PD management, and it is in this area that recent advances in our knowledge offer the best opportunity for therapeutic gain. In the search for improved therapies, suitable outcome measures to better assess overall disability in PD and disease progression are essential.

The early treatment of Parkinson's disease (PD) consists of nonpharmacologic treatment, consideration of neuroprotective therapy, and initial symptomatic treatment. Education for the patient and family, access to support groups, regular exercise, and good nutrition are essential to the overall management of PD. Disease-modifying therapies, such as agents that provide neurorescue or neuroprotection, will provide a major advance in the treatment of PD. Intervention at the genetic/environmental level or that affects the cascade of pathophysiologic events, protein aggregation, or apoptosis could result in neuroprotection. Many agents are now being investigated for neuroprotective potential. A major paradigm shift has recently occurred because of the recent basic and clinical data indicating that dopamine agonists, rather than levodopa, should be the initial symptomatic therapy in PD. However, levodopa may be started first in some patients because of patient age, cognitive status, or cost of drugs.

Objective: The purpose of this study was to investigate the relationship between disruption of MRI-measured resting-state functional connectivity (rs-fcMRI) brain networks and CSF levels of potentially pathogenic proteins that reflect brain pathology in Parkinson disease (PD). Methods: PD participants without dementia (n = 43) and age-matched controls (n = 22) had lumbar punctures to measure CSF protein levels, Pittsburgh compound B (PiB)–PET imaging, and rs-fcMRI while off medication. Imaging analyses focused on 5 major resting-state networks as well as the striatum. Results: Participants with PD had significantly reduced sensorimotor functional connectivity, which correlated with reduced CSF levels of α-synuclein. The PD group also had significantly stronger default mode network functional connectivity that did not correlate with CSF β-amyloid (Aβ) 42 or PiB uptake. In contrast, default mode network functional connectivity in the control group did correlate with CSF Aβ 42 levels. Functional connectivity was similar between groups in the dorsal attention, control, and salience networks. Conclusion: These results suggest that abnormal α-synuclein accumulation, but not Aβ, contributes to the disruption of motor-related functional connectivity in PD. Furthermore, correlating CSF protein measures with the strength of resting-state networks provides a direct link between abnormal α-synuclein metabolism and disrupted brain function in PD.

Objective: To evaluate the safety and efficacy of botulinum toxin type A injection in essential tremor of the hand. Background: Botulinum toxin type A is an effective treatment for dystonia, spasticity, and other movement disorders and has been found to be useful in open-label studies and one double-masked study of essential hand tremor. Methods: One hundred thirty-three patients with essential tremor were randomized to low-dose (50 U) or high-dose (100 U) botulinum toxin type A (Botox) or vehicle placebo treatment. Injections were made into the wrist flexors and extensors. Patients were followed for 16 weeks. The effect of treatment was assessed by clinical rating scales, measures of motor tasks and functional disability, and global assessment of treatment. Hand strength was evaluated by clinical rating and by a dynamometer. Results: Both doses of botulinum toxin type A significantly reduced postural tremor on the clinical rating scales after 4 to 16 weeks. However, kinetic tremor was significantly reduced only at the 6-week examination. Measures of motor tasks and functional disability were not consistently improved with botulinum toxin type A treatment. Grip strength was reduced for the low- and high-dose botulinum toxin type A groups as compared with the placebo group. Adverse reactions consisted mainly of dose-dependent hand weakness. Conclusion: Botulinum toxin type A injections for essential tremor of the hands resulted in significant improvement of postural, but not kinetic, hand tremors and resulted in limited functional efficacy. Hand weakness is a dose-dependent significant side effect of treatment at the doses used in this study.

Parkinson’s disease (PD) is named in honor of James Parkinson, whose classic monograph, “An Essay on the Shaking Palsy,” written in 1817, has provided an enduring description of the clinical features of this disorder.1 PD is an age-related neurodegenerative disorder with an average age at onset of 60 years. An estimated 1 million persons in the United States suffer from PD,2 and there are approximately 60,000 new cases each year. United States Census Bureau projections indicate that there will be a substantial increase in the number of at-risk individuals 60 years of age and older, and therefore the prevalence of PD is likely to increase in the coming decades. The introduction of levodopa in the late 1960s represented a major therapeutic advance in the management of PD,3 providing clinical benefit to virtually all patients and reduced mortality. However, it soon became apparent that long-term treatment with levodopa is complicated by the development of adverse events that include motor fluctuations, dyskinesias, and neuropsychiatric complications.4-6⇓⇓ In addition, with disease progression, patients develop features that do not respond well to levodopa therapy, such as freezing episodes, autonomic dysfunction, falling, and dementia. As a consequence, despite levodopa treatment, most PD patients eventually suffer disabilities that cannot be satisfactorily controlled with existing medical therapies. Therefore, there has been an intensive effort to develop new treatments that reverse disabilities in patients with advanced disease, that provide enhanced clinical benefits with a reduced risk for adverse events, and that slow the rate of disease progression. This has led to an explosion of new laboratory and clinical information and to a variety of new treatment strategies for the management of PD. Physicians who treat PD patients must now assimilate a considerable body of data to optimally manage patients with this complex disorder. …

As the substantia nigra degenerates in Parkinson's disease (PD), the nigrostriatal pathway is disrupted, reducing striatal dopamine and producing PD symptoms. Although dopamine does not readily cross the blood-brain barrier, its precursor, levodopa, does. Levodopa is absorbed in the small bowel and is rapidly catabolized by aromatic-L-amino-acid decarboxylase (AADC) and catechol-O-methyltransferase (COMT). Because gastric AADC and COMT degrade levodopa, the drug is given with inhibitors of AADC (carbidopa or benserazide), and inhibitors of COMT will also enter clinical use. Although the exact site of decarboxylation of exogenous levodopa to dopamine in the brain is unknown, most striatal AADC is located in nigrostriatal dopaminergic nerve terminals. Newly synthesized dopamine is stored in the terminals and then released, stimulating postsynaptic dopamine receptors and mediating the antiparkinsonian action of levodopa. Dopamine agonists act directly on postsynaptic dopamine receptors, thus obviating the need for metabolic conversion, storage, and release. How the actions of dopaminergic drugs produce side effects and how these side effects should be managed are discussed.

Unilateral pallidotomy is thought to have a low risk for cognitive morbidity. Nonetheless, recent research suggests that some patients experience declines in memory and language and that pallidal stimulation might be a safer treatment for Parkinson's disease (PD). We investigated the neurobehavioral effects of unilateral pallidal stimulation. Nine consecutive PD patients undergoing unilateral deep brain-stimulating electrode implantation in the globus pallidus interna were evaluated with a neuropsychological test battery approximately 1 month before and 3 months after surgery. Patients reported significantly fewer symptoms of anxiety and greater vigor after surgery. There was a trend toward fewer depressive symptoms. Semantic verbal fluency and visuoconstructional test scores declined significantly after surgery. However, among five patients showing declines in semantic verbal fluency, only one patient's score declined by more than 2 SD. No patient showed significant decline or improvement in the overall level of cognitive functioning. This study supports the relative safety, in terms of cognitive function, of unilateral pallidal stimulation in PD.

We enrolled and treated 122 patients with idiopathic cervical dystonia in a double-blind, placebo-controlled safety and efficacy study of botulinum toxin type B (BotB). Both A-responsive and A-resistant patients were enrolled. Patients received intramuscular injections of either BotB (2,500 U, 5,000 U, or 10,000 U) or placebo. The primary outcome measure of efficacy was the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at 4 weeks following study drug administration. Secondary measures of efficacy were TWSTRS-Severity, -Disability, and -Pain subscale scores, and Analog Pain Assessment, Investigator Global Assessment, Patient Global Assessment, and Sickness Impact Profile scores. Duration of effect was estimated with an intent-to-treat analysis of responders. Safety measures included clinical parameters, laboratory tests, and adverse events. The primary and most of the secondary analyses indicated a statistically significant treatment effect and a dose response. BotB is safe, well tolerated, and efficacious in the treatment of cervical dystonia at the doses tested.

The clinical diagnosis of Parkinson's disease (PD) is most difficult early in the disease when the signs and symptoms are most subtle. The differential diagnosis of PD includes a number of movement disorders with similar symptomatology (e.g., essential tremor, multiple system atrophy, vascular parkinsonism). In most published studies of PD, the disease is diagnosed simply by the presence of two of the three cardinal motor signs-tremor, rigidity, and bradykinesia-or by the presence of three of the four motor signs: tremor, rigidity, bradykinesia, and postural instability. However, there is an obvious need for better diagnostic criteria. Until discrete biologic markers are developed, the use of exclusion criteria may improve the accuracy of the presumptive diagnosis of PD.

Objective: To determine the relative contribution of genetics and environment to essential tremor using a twin study method. Methods: Twins with postural or kinetic tremor were identified by movement disorders specialists during the conduct of a study investigating PD in members of the National Academy of Sciences and National Research Council World War II Veteran Twins Registry. The diagnosis of essential tremor was made by consensus using established diagnostic criteria. Results: A total of 196 twins had postural or kinetic tremor on examination. Of these, 137 had PD or had a twin with PD and were excluded from this study. Thirty-three others were excluded because of incomplete data for their twin. Sixteen twin pairs were identified in which at least one twin had essential tremor. Pairwise concordance in monozygotic twins was approximately two times that in dizygotic twins (0.60 monozygotic, 0.27 dizygotic). Conclusion: This pattern is consistent with a genetic cause of essential tremor. Because monozygotic concordance is not 100%, environmental factors may also play a role in the cause of the disease.

In this review, we attempt to evaluate the evidence that a long pre-symptomatic period occurs in PD. Much of this discussion is speculative, but we hope important in setting the context for the specific works that follow in this monograph

Background: AN1792 (beta-amyloid [Aβ]1–42) immunization reduces Aβ plaque burden and preserves cognitive function in APP transgenic mice. The authors report the results of a phase IIa immunotherapy trial of AN1792(QS-21) in patients with mild to moderate Alzheimer disease (AD) that was interrupted because of meningoencephalitis in 6% of immunized patients. Methods: This randomized, multicenter, placebo-controlled, double-blind trial of IM AN1792 225 μg plus the adjuvant QS-21 50 μg (300 patients) and saline (72 patients) included patients aged 50 to 85 years with probable AD, Mini-Mental State Examination (MMSE) 15 to 26. Injections were planned for months 0, 1, 3, 6, 9, and 12. Safety and tolerability were evaluated, and pilot efficacy (AD Assessment Scale–Cognitive Subscale [ADAS–Cog], MRI, neuropsychological test battery [NTB], CSF tau, and Aβ42) was assessed in anti-AN1792 antibody responder patients (immunoglobulin G titer ≥ 1:2,200). Results: Following reports of meningoencephalitis (overall 18/300 [6%]), immunization was stopped after one (2 patients), two (274 patients), or three (24 patients) injections. Of the 300 AN1792(QS-21)-treated patients, 59 (19.7%) developed the predetermined antibody response. Double-blind assessments were maintained for 12 months. No significant differences were found between antibody responder and placebo groups for ADAS–Cog, Disability Assessment for Dementia, Clinical Dementia Rating, MMSE, or Clinical Global Impression of Change, but analyses of the z-score composite across the NTB revealed differences favoring antibody responders (0.03 ± 0.37 vs -0.20 ± 0.45; p = 0.020). In the small subset of subjects who had CSF examinations, CSF tau was decreased in antibody responders (n = 11) vs placebo subjects (n = 10; p Conclusion: Although interrupted, this trial provides an indication that Aβ immunotherapy may be useful in Alzheimer disease.

In the early 1960s, when levodopa was undergoing initial clinical trials in Europe and North America as treatment for Parkinson’s disease (PD), nonselective monoamine oxidase (MAO) inhibitors were used in an attempt to potentiate the effect of levodopa.1,2⇓ However, life-threatening fluctuations in blood pressure prompted early termination of these trials.3 In 1965, Knoll et al.4 developed an irreversible inhibitor of MAO with relative specificity for the B form of the enzyme.5 This new drug, isopropyl-methyl-propargylamine (E-250, Eldepryl®, deprenyl, selegiline), provided for the first time an MAO inhibitor that avoided the so-called “cheese effect” (tyramine-induced sympathomimetic side effects such as hypertension and tachycardia) and allowed its use along with levodopa in the treatment of PD without the need for dietary restrictions. At daily doses of 10 mg, selegiline was shown to inhibit 90% of brain MAO-B, whereas at daily doses above 20 mg the drug was shown to lose selectivity.6,7⇓ Therefore, in most studies, daily oral doses have ranged from 5 to 10 mg. Based on evidence that selegiline was a selective inhibitor of MAO-B, avoided the cheese effect, and could be used safely with levodopa, clinical trials were initiated in the early 1970s, assessing the drug’s benefit as adjunctive therapy in patients with PD.8–13⇓⇓⇓⇓⇓ These studies clearly demonstrated that selegiline was safe and significantly improved “on” time in PD patients experiencing end-of-dose “wearing off.” However, certain levodopa-related side effects, such as nausea, psychosis, orthostatic hypotension, and dyskinesia, prompted reduction of levodopa, thus negating some of the levodopa-potentiating effects of the drug. Whereas most of these studies assessed relatively short-term effects of selegiline, Birkmayer et al.15 conducted a retrospective evaluation of patients treated long-term with selegiline and levodopa compared to those treated with levodopa alone. From this …

We examined in a double-blind, placebo-controlled study the effects of botulinum toxin in 10 patients with essential head tremor. Each subject received two treatments approximately 3 months apart, one with botulinum toxin injections and another with normal saline injections into the sternocleidomastoid and splenius capitis muscles. The subjects were assessed before each treatment and at 2, 4, and 8 weeks after injections. There was moderate to marked improvement in clinical ratings in five subjects after botulinum toxin injections and in one subject after placebo. There was moderate to marked subjective improvement in five patients with botulinum toxin as compared with three subjects with placebo. Side effects were mild and transient. We conclude that botulinum toxin may be useful for patients with essential head tremor who have failed to benefit from oral medications.

Background: The vast majority of the parkin mutations previously identified have been found in individuals with juvenile or early onset PD. Previous screening of later onset PD cohorts has not identified substantial numbers of parkin mutations. Methods: Families with at least two siblings with PD were ascertained to identify genes contributing to PD susceptibility. Screening of the parkin gene, by both quantitative PCR and exon sequencing, was performed in those families with either early onset PD (age onset ≤50 years) or positive lod score with a marker in intron 7 of the parkin gene. Results: A total of 25 different mutations in the parkin gene were identified in 103 individuals from 47 families. Mutations were found in both parkin alleles in 41 of the individuals, whereas a single mutation in only one of the two parkin alleles was observed in 62 individuals. Thirty-five of the subjects (34%) with a parkin mutation had an age at onset of 60 years or above with 30 of these 35 (86%) having a detectable mutation on only one parkin allele. Few significant clinical differences were observed among the individuals with two, one, or no mutated copies of the parkin gene. Conclusion: Mutations in the parkin gene occur among individuals with PD with an older age at onset (≥60 years) who have a positive family history of the disease. In addition, the clinical findings of parkin -positive individuals are remarkably similar to those without mutations.

Background: Electrical stimulation of the thalamus dramatically reduces essential tremor (ET). It has been hypothesized that the cerebellum and inferior olive are involved in the generation of ET, and thalamic stimulation is presumed to dampen ET through interactions with cerebellar output to the thalamus. Evidence suggests that abnormal timing of agonist and antagonist muscle responses contribute to cerebellar tremor (CbT); however, this relationship has not been investigated for ET. The mechanisms of the tremor and improvement are unknown. Objective: To measure the effect of ventral intermediate thalamic stimulation in controlling the ET response to sudden stretch of an agonist muscle and to determine whether, in ET, the timing relationships between the initial agonist and antagonist electromyography (EMG) responses show abnormalities similar to those seen in CbT. Methods: The authors studied ET subjects (with implanted thalamic stimulators turned off and on) and normal controls as they responded to mechanical torque pulses given at the wrist joint. The wrist joint angle, wrist agonist, and antagonist EMG were recorded. Results: Like CbT, patients with ET showed delayed onsets of antagonist EMG and excessive rebound. Thalamic stimulation reduced the tremor but did not alter the antagonist delay or the rebound. Conclusions: In ET, antagonist muscle responses to a torque pulse are similar to that in CbT. However, benefit from thalamic stimulation did not alter these EMG responses; therefore, suppression of tremor must be caused by mechanisms other than the re-establishment of normal agonist–antagonist timing.

The surgical treatment of tremor has evolved considerably in the past few years. Of the several conditions associated with severe tremor, the most common are Parkinson's disease (PD) and essential tremor (ET). Levodopa therapy reduced drastically the number of patients with PD who require surgery because of inadequate control. However, there remains a small number of "tremor dominant" PD patients for whom surgical treatment is often the best option. The ventralis intermediate nucleus (Vim) of the thalamus has been the preferred surgical target for the treatment of parkinsonian tremor for many years, but this is now challenged by the subthalamic nucleus (STN). Deep brain stimulation (DBS) of either target possesses high therapeutic efficacy against tremor in PD. ET may be difficult to treat pharmacologically. Thalamotomy is an effective surgical procedure for ameliorating ET but may be associated with persistent neurologic deficits. DBS of the thalamus is also a highly effective means of reducing ET. DBS appears to be safer than thalamotomy and is now the recommended surgical procedure.

Essential tremor (ET) is a common movement disorder that often causes functional disability, potentially leading to physical and emotional difficulties. The paucity of data available regarding the underlying pathophysiologic mechanism of ET hinders the development of innovative approaches to pharmacotherapeutic treatments. Options for drug therapy include the use of primidone, beta-adrenergic blockers, such as propranolol, alcohol, and other drugs, such as benzodiazepines, gabapentin, carbonic anhydrase inhibitors, clozapine, flunarizine, clonidine, and the methylxanthine derivative theophylline. Chemodenervation with botulinum toxin type A may be a therapeutic option for selected patients with ET. Each drug is classified as to the quality of evidence for efficacy and the suggested strength of therapeutic recommendation. In general clinical practice, primidone and propranolol have proven efficacy in ET.

Surgical treatment for essential tremor (ET) has been used since the early 1950s. Initially, different areas were targeted for tremor control. However, the optimal target was eventually determined to be the ventralis intermedius (VIM) nucleus of the thalamus. Thalamotomy improves contralateral tremor in more than 90% of patients. Long-term studies of thalamotomy indicate that the benefits continue in most patients. Persistent morbidity associated with thalamotomy, which occurs in less than 10% of patients, includes dysarthria, dysequilibrium, weakness, and cognitive impairment. Bilateral thalamotomy is associated with substantial morbidity and is usually avoided. Studies demonstrate that chronic stimulation of the VIM is safe and effective for tremor. Adverse effects of chronic stimulation include paresthesia, dysarthria, dysequilibrium, and localized pain. In many patients, bilateral thalamic stimulation is performed without a substantial increase in morbidity. ET patients with disabling medication-resistant tremor are reasonable candidates for these stereotactic procedures.

Objective: To evaluate short-term effects of unilateral thalamic deep brain stimulation (DBS) on cognition, mood state, and quality of life in patients with essential tremor (ET). Background: Unilateral thalamotomy and thalamic DBS are effective in alleviating refractory tremor contralateral to the side of surgery. Thalamotomy can lead to cognitive morbidity, and DBS might be a preferable surgical intervention given potential avoidance or reversibility of such morbidity. Although unilateral thalamic DBS is cognitively safe and leads to quality of life improvement in PD, its neurobehavioral effects in ET are unknown. Methods: Forty patients with ET were administered a broad neuropsychological test battery, measures of mood state, and generic and disease-specific quality of life measures approximately 1 month before and 3 months after surgery (left hemisphere, 38 patients). Results: Unilateral thalamic DBS was associated with significant improvements in tremor and dominant-hand fine visuomotor coordination. Statistically significant but clinically modest gains were observed on tasks of visuoperceptual and constructional ability, visual attention, delayed word list recognition, and prose recall. Only lexical verbal fluency declined significantly after surgery. Patients rated themselves as less anxious after surgery, and they perceived their quality of life as improved significantly. In particular, patients reported improved quality of life with respect to activities of daily living, stigma, emotional well-being, and communication. Conclusions: Unilateral thalamic DBS for ET is cognitively safe and associated with improvements in anxiety and quality of life in the near term and in the absence of operative complications. Patients were better able to carry out activities of daily living after surgery, and they reported improvement in several psychosocial domains of quality of life.

To determine the safety and efficacy of botulinum toxin type B (BoNT/B) in patients with cervical dystonia (CD).BoNT/B is a form of chemodenervation therapy for the treatment of patients with CD.The authors performed a 16-week, randomized, multicenter, double-blind, placebo-controlled trial of BoNT/B in patients with CD who continue to respond to botulinum toxin type A. Placebo, or 5,000 U or 10,000 U of BoNT/B was administered in two to four muscles involved clinically in CD. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at week 4 was the primary efficacy measure. Clinical assessments and adverse events were recorded for treatment day 1 and at weeks 2, 4, 8, 12, and 16.A total of 109 patients were enrolled randomly across all three treatment groups. The mean improvement in the TWSTRS-Total scores in each group at week 4 was 4.3 (placebo), 9.3 (5,000 U), and 11.7 (10,000 U). For the prospectively defined primary contrast (10,000 U versus placebo), highly significant differences were noted for the primary (TWSTRS-Total, baseline to week 4, p = 0.0004) and supportive secondary (Patient Global Assessment, baseline to week 4, p = 0.0001) outcome measures. Improvement in pain, disability, and severity of CD occurred for patients who were treated with BoNT/B when compared with placebo-treated patients. Overall, improvements associated with BoNT/B treatment were greatest for patients who received the 10,000-U dose. The duration of treatment effect for BoNT/B was 12 to 16 weeks for both doses.Botulinum toxin type B (NeuroBloc) is safe and efficacious at 5,000 U and 10,000 U for the management of patients with cervical dystonia.

To determine the safety and efficacy of botulinum toxin type B (BoNT/B) in patients with type A-resistant cervical dystonia (CD).Local intramuscular injections of BoNT are an effective therapy for CD. After repeated use, some patients become resistant to therapy. BoNT/B, effective in type A toxin-responsive patients, is proposed as an alternative therapy for type A-resistant patients.The authors performed a 16-week, double-blind, placebo-controlled trial of BoNT/B in type A-resistant patients with CD. After resistance to therapy was confirmed with the frontalis-type A test, placebo or 10,000 U BoNT/B was administered in a single session into two to four clinically involved muscles. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) was the primary efficacy measurement. TWSTRS-Total, three visual analog scales (Patient Global Assessment of Change, Principal Investigator Global Assessment of Change, Patient Analog Pain Assessment), and adverse events were assessed at baseline and weeks 2, 4, 8, 12, and 16.A total of 77 patients participated (38 placebo, 39 active). Improvements in severity, disability, and pain were documented in the BoNT/B-treated group. TWSTRS-Total scores were improved in the BoNT/B-treated group at weeks 4 (p = 0.0001), 8 (p = 0.0002), and 12 (p = 0.0129). All three visual analog scales demonstrated improvements at week 4 (p0.0001, 0.0001, and 0.001). A Kaplan-Meier analysis supported a duration of effect of 12 to 16 weeks in the active group. Dry mouth and dysphagia were self-limited adverse effects, reported more commonly in the BoNT/B group.Botulinum toxin type B (BoNT/B) (NeuroBloc) is safe and efficacious for the management of patients with type A-resistant cervical dystonia with an estimated duration of treatment effect of 12 to 16 weeks.

To compare effects of immediate-release (IR) and sustained-release (CR) carbidopa/levodopa in levodopa-naive PD patients.It was hypothesized that the long-acting preparation would be associated with fewer long-term complications.A total of 618 patients were studied in 36 centers worldwide in a blinded, randomized parallel study. Measures of efficacy and adverse reactions were recorded at 3-month intervals for 5 years. Motor fluctuations and dyskinesias were evaluated by a patient diary and a physician-recorded questionnaire. The Nottingham Health Profile (NHP) was used to evaluate quality of life.Approximately 60% of patients completed the trial. After 5 years, the mean dose of IR was 426 mg/day, and the bioavailable dose of CR was 510 mg/day (mean dose, 736 mg/day). After 5 years, 20.6% of the IR group and 21.8% of the CR group had motor fluctuations or dyskinesia. Sixteen percent of both groups had changes in motor response by the questionnaire's definition. There was no significant difference between the two treatment groups. Disability scores and the motor score of the Unified Parkinson Disease Rating Scale (UPDRS) were highest at baseline, improved with therapy, and thereafter worsened over time to reach baseline scoring at the end of 5 years. The CR group was superior to IR for the Activities of Daily Living subsection of the UPDRS for all 5 years and for emotional reactivity and social isolation on the NHP; however, this may have resulted from higher doses of CR that were used.Despite the progressive nature of PD, both the immediate-release and sustained-release carbidopa/levodopa formulations maintained a similar level of control in PD after 5 years compared with baseline. Additionally, the low incidence of motor fluctuations or dyskinesia was not significantly different between the treatment groups and may be partly attributed to the relatively low doses of levodopa used throughout the 5-year study.