AbobotulinumtoxinA provides flexibility for the treatment of cervical dystonia with 500 U/1 mL and 500 U/2 mL dilutions.

INTRODUCTION: Cervical dystonia (CD) is a neurologic movement disorder with potentially disabling effects and significant impact on quality of life of those affected. AbobotulinumtoxinA (aboBoNT-A) was initially approved for a dilution of 500 U/1 mL and subsequently for a dilution of 500 U/2 mL, providing flexibility for clinicians to treat CD. Here, we explore the safety and efficacy of the 500 U/2 mL dilution versus 500 U/1 mL dilution of aboBoNT-A in a retrospective analysis based on published clinical trial data. METHODS: The safety and efficacy of aboBoNT-A in patients with CD was evaluated in three multicenter, double-blind, randomized, placebo-controlled trials and open-label extensions. Trials 1 (NCT00257660) and 2 (NCT00288509) evaluated the 500 U/1 mL dilution in 80 and 116 patients, respectively; Trial 3 (NCT01753310) evaluated the 500 U/2 mL dilution in 125 patients. RESULTS: Comparison of the adjusted mean difference in TWSTRS total scores at Week 4 from baseline for aboBoNT-A in Trial 1 (-6.0; 95% CI, -10.8, -1.3), Trial 2 (-8.8; 95% CI, -12.9, -4.7), and Trial 3 (-8.7; 95% CI, -13.2, -4.2) showed similar, significant improvements. Dysphagia and muscle weakness patterns were comparable across the three trials, indicating that an increased dilution of aboBoNT-A does not result in an increased risk of diffusion-related adverse events. CONCLUSION: The results of these trials show that aboBoNT-A is similarly efficacious using either dilution, with similar safety and tolerability across trials. Having the 500 U/1 mL and 500 U/2 mL dilution volumes available provides further flexibility in administration, benefiting patient care.

SNCA-Rep1 polymorphism correlates with susceptibility and iron deficiency in restless legs syndrome.

BACKGROUND: Brain iron disequilibrium and dopaminergic dysfunction are key pathophysiological features of Restless Legs Syndrome (RLS). Rep1 polymorphism in the promotor region of SNCA is associated with risk of Parkinson's disease, however its association with RLS and iron status is unclear. OBJECTIVE: To investigate SNCA-Rep1 polymorphism in RLS and its phenotypes. METHODS: We recruited RLS patients as well as age and gender matched healthy controls. Demographic information and clinical features of RLS were recorded. Laboratory examinations were performed to exclude possible secondary causes. RESULTS: 215 RLS patients and 369 healthy controls were included. We found that the Rep1 allele 0 homozygosity significantly decreased RLS risk (OR: 0.345; P < 0.0001, and remained significant after the Bonferroni correction). Phenotypic analysis demonstrated that longer Rep1 alleles were associated with increased susceptibility to iron deficiency (53.0% vs 36.1%, P = 0.017), however had no phenotypic significant effects on age, gender, onset age, duration, RLS family history, severity, laterality, extra body involvement and seasonal fluctuation. Multivariate logistic regression analyses confirmed long Rep1 allele was associated with higher risk of iron deficiency in RLS after adjusting for potential confounding factors. In detail, Rep1 allele 2 homozygosity was prone to a higher risk of peripheral iron deficiency in RLS (OR: 4.550, P = 0.006, remained significant after the Bonferroni correction). CONCLUSION: The SNCA-Rep1 variability modified RLS risk and influenced peripheral iron deficiency in this group of Chinese RLS patients. Rep1 allele 0 homozygosity decreased the risk of RLS, while homozygous allele 2 increased the risk of nonanemic iron deficiency in RLS.

Correlates of Nonanemic Iron Deficiency in Restless Legs Syndrome.

Objective: Iron deficiency anemia (IDA) is a well-known cause of secondary restless legs syndrome (RLS). Iron deficiency without anemia (IDNA) is insidious, and its association with RLS is less evaluated. We investigate prevalence and features of IDNA in a consecutive cohort of patients with RLS. Methods: We included sequential primary RLS patients and RLS patients with IDA. We also recruited age- and gender-matched healthy controls. RLS mimics and other comorbidities were carefully excluded. Results: One-hundred and ninety-six RLS patients without anemia, 26 RLS patients with IDA, and 63 controls were included. 42.3% of RLS patients without anemia had iron deficiency. Women were much more susceptible for IDNA with a relative risk of 5.51 (p < 0.0001). Women with IDNA and RLS had younger age both at interview and at RLS onset compared to women with RLS without iron deficiency (NID) (P < 0.01). IDNA RLS patients showed a tendency to higher risk of severe/very severe tiredness or sleepiness during the day as compared to NID RLS patients. Furthermore, IDNA RLS patients had longer duration of RLS (P < 0.01 in men, P < 0.05 in women) and younger age at onset (only in men, P < 0.05) compared to IDA RLS patients. Conclusion: IDNA is frequent in RLS and iron deficiency may be severe despite a normal hemoglobin level. Women are at much higher risk for IDNA, and IDNA in women presents some specific clinical features. Features of IDNA RLS are different from IDA RLS. Regular screening of peripheral iron parameters even in patients with normal blood counts is recommended for timely optimal management.

Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: an IRLSSG task force report.

BACKGROUND: Brain iron deficiency has been implicated in the pathophysiology of RLS, and current RLS treatment guidelines recommend iron treatment when peripheral iron levels are low. In order to assess the evidence on the oral and intravenous (IV) iron treatment of RLS and periodic limb movement disorder (PLMD) in adults and children, the International Restless Legs Syndrome Study Group (IRLSSG) formed a task force to review these studies and provide evidence-based and consensus guidelines for the iron treatment of RLS in adults, and RLS and PLMD in children. METHODS: A literature search was performed to identify papers appearing in MEDLINE from its inception to July 2016. The following inclusion criteria were used: human research on the treatment of RLS or periodic limb movements (PLM) with iron, sample size of at least five, and published in English. Two task force members independently evaluated each paper and classified the quality of evidence provided. RESULTS: A total of 299 papers were identified, of these 31 papers met the inclusion criteria. Four studies in adults were given a Class I rating (one for IV iron sucrose, and three for IV ferric carboxymaltose); only Class IV studies have evaluated iron treatment in children. Ferric carboxymaltose (1000 mg) is effective for treating moderate to severe RLS in those with serum ferritin <300 µg/l and could be used as first-line treatment for RLS in adults. Oral iron (65 mg elemental iron) is possibly effective for treating RLS in those with serum ferritin ≤75 µg/l. There is insufficient evidence to make conclusions on the efficacy of oral iron or IV iron in children. CONCLUSIONS: Consensus recommendations based on clinical practice are presented, including when to use oral iron or IV iron, and recommendations on repeated iron treatments. New iron treatment algorithms, based on evidence and consensus opinion have been developed.

A 500 U/2 mL dilution of abobotulinumtoxinA vs. placebo: randomized study in cervical dystonia.

Purpose/aim: AbobotulinumtoxinA (Dysport®, Ipsen Biopharmaceuticals, Inc., Basking Ridge, NJ, USA) is an acetylcholine release inhibitor and a neuromuscular blocking agent. The United States prescribing information for abobotulinumtoxinA previously indicated only one dilution for cervical dystonia: 500 U/1 mL. Clinical trial data supporting a larger volume with a 500 U/2 mL dilution would offer clinicians flexibility with injection volume to better meet patient needs. MATERIALS AND METHODS: We conducted a 12-week, phase 3b, multicenter, randomized, double-blind, placebo-controlled trial (NCT01753310). Adult subjects with a primary diagnosis of cervical dystonia were randomized (2:1) to receive a single injection of either abobotulinumtoxinA, 500 U/2 mL dilution, or placebo. The primary efficacy endpoint was changed from baseline in Toronto Western Spasmodic Torticollis Rating Scale total score at Week 4. RESULTS: A total of 134 subjects (abobotulinumtoxinA, n = 89; placebo, n = 45) were randomized (intent-to-treat population) and 129 (abobotulinumtoxinA, n = 84; placebo, n = 45) completed the Week 4 primary endpoint evaluation (modified intent-to-treat population). In the modified intent-to-treat population, subjects receiving abobotulinumtoxinA experienced significantly greater changes from baseline versus placebo on the primary endpoint (weighted overall treatment difference -8.3, P < 0.001). The most common treatment-emergent adverse events (TEAEs) were dysphagia, muscle weakness, neck pain and headache. Overall, TEAEs were consistent with those reported in the abobotulinumtoxinA prescribing information (1 mL dilution) for cervical dystonia patients. CONCLUSIONS: This trial provides evidence that a 500 U/2 mL dilution is an effective treatment for cervical dystonia and exhibits a safety profile consistent with the known safety profile of abobotulinumtoxinA.

Clinical features of Parkinson's disease with and without rapid eye movement sleep behavior disorder.

BACKGROUND: Rapid eye movement sleep behavior disorder (RBD) and Parkinson's disease (PD) are two distinct clinical diseases but they share some common pathological and anatomical characteristics. This study aims to confirm the clinical features of RBD in Chinese PD patients. METHODS: One hundred fifty PD patients were enrolled from the Parkinson`s disease and Movement Disorders Center in  Department of Neurology, Shanghai General Hospital from January 2013 to August 2014. This study examined PD patients with or without RBD as determined by the REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), assessed motor subtype by Unified PD Rating Scale (UPDRS) III at "on" state, and compared the sub-scale scores representing tremor, rigidity, appendicular and axial. Investigators also assessed the Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Parkinson's disease Sleep Scale (PDSS). RESULTS: One hundred fourty one PD patients entered the final study. 30 (21.28%) PD patients had probable RBD (pRBD) diagnosed with a RBDSQ score of 6 or above. There were no significant differences for age, including age of PD onset and PD duration, gender, smoking status, alcohol or coffee use, presence of anosmia or freezing, UPDRS III, and H-Y stages between the pRBD+ and pRBD- groups. pRBD+ group had lower MMSE scores, higher PDSS scores, and pRBD+ PD patients had more prominent proportion in anxiety, depression, constipation, hallucination and a greater prevalence of orthostatic hypotension. CONCLUSION: pRBD+ PD patients exhibited greater changes in non-motor symptoms. However, there was no increase in motor deficits.

Effects of deep brain stimulation in relatively young-onset multiple system atrophy Parkinsonism.

OBJECTIVE: The aim of this study was to analyze outcomes after 1 year of bilateral STN deep brain stimulation (DBS) in relatively young-onset patients with multiple system atrophy-Parkinsonism (MSA-P). BACKGROUND: The efficacy of DBS has been demonstrated in idiopathic Parkinson's disease. However, the experience with DBS in relatively young-onset MSA-P is limited and controversial. METHODS: Information about the demographic and clinical data from five MSA patients treated with STN DBS was entered into a database and analyzed. RESULTS: Five patients with relatively young-onset MSA (mean age at onset 42.2±2.2 years, 3 women, 2 men) have been treated with bilateral STN stimulators, the mean duration between DBS surgery and disease onset was 7.0±3.5 years. All of the patients had dyskinesia and postural instability, and subjective benefit from levodopa. During the 6 months after surgery, the clinical status of three patients improved with a decrease of dyskinesia. However, by 1 year, the symptoms reappeared and progressed in all patients. Overall, the mean "off" medication UPDRS-III score worsened 23.5±15.3 1 year after surgery and the levodopa dosage was not reduced. CONCLUSIONS: This data does not support the use of STN DBS for relatively young-onset MSA-P.

Orthostatic tremor: a review of 45 cases.

OBJECTIVE: To evaluate the clinical characteristics, associated features, and treatment response of a large orthostatic tremor series seen over a 26-year period. METHODS: We reviewed the medical records of 45 patients seen between 1987 and 2013 who fulfilled the diagnostic criteria for orthostatic tremor. RESULTS: The mean age at onset was 59.5 years and 23/45 (51%) were men. A family history of any tremor was noted in 23/45 (51%) patients. A family history of orthostatic tremor was reported in 3/45 (7%) patients. 40/45 (89%) had primary orthostatic tremor with (n = 30) or without (n = 10) an associated postural arm tremor. We found that 5/45 (11%) had orthostatic tremor plus additional neurological features. One patient was diagnosed with dementia with Lewy bodies preceded by orthostatic tremor for 20 years. Prospective follow-up data was available for 30/45 patients and averaged 54.4 months. Treatment response to medications was modest and inconsistent. In 11/30 cases, orthostatic tremor worsened over the follow-up period. One patient with primary orthostatic tremor underwent thalamic deep brain stimulation surgery. CONCLUSIONS: In our population of orthostatic tremor patients, mild postural hand tremor was a frequent finding. Over half of our patients had a family history of tremor, but a family history of orthostatic tremor was uncommon. Additional neurological features were seen in the minority of patients and we report possibly the first case of dementia with Lewy bodies associated with orthostatic tremor. Our series is the largest series of orthostatic tremor reported in the literature and contributes to understanding the clinical characteristics of this rare disease.

Association studies of variants in MEIS1, BTBD9, and MAP2K5/SKOR1 with restless legs syndrome in a US population.

BACKGROUND: A genome-wide association study (GWAS) identified significant association between variants in MEIS1, BTBD9, and MAP2K5/SKOR1 and restless legs syndrome (RLS). However, many independent replication studies are needed to unequivocally establish a valid genotype-phenotype association across various populations. To further validate the GWAS findings, we investigated three variants, rs2300478 in MEIS1, rs9357271 in BTBD9, and rs1026732 in MAP2K5/SKOR1 in 38 RLS families and 189 RLS patients/560 controls from the US for their association with RLS. METHOD: Both family-based and population-based case-control association studies were carried out. RESULTS: The family-based study showed that SNP rs1026732 in MAP2K5/SKOR1 was significantly associated with RLS (P=0.01). Case-control association studies showed significant association between all three variants and RLS (P=0.0001/OR=1.65, P=0.0021/OR=1.59, and P=0.0011/OR=1.55 for rs2300478, rs9357271, and rs1026732, respectively). CONCLUSION: Variants in MEIS1, BTBD9, and MAP2K5/SKOR1 confer a significant risk of RLS in a US population.

Intrastriatal transplantation of microcarrier-bound human retinal pigment epithelial cells versus sham surgery in patients with advanced Parkinson's disease: a double-blind, randomised, controlled trial.

BACKGROUND: Human retinal pigment epithelial (RPE) cells produce levodopa and their transplantation into the striatum might improve continuity of administration compared with that achieved with oral levodopa. We aimed to assess the safety, tolerability, and efficacy of transplantation of microcarrier-bound human RPE cells versus a sham surgery control in patients with advanced Parkinson's disease. METHODS: In this randomised, double-blind study eligible patients were aged 36-70 years, had been symptomatic for at least 5 years, were in Hoehn and Yahr stage 3-4 and had unified Parkinson's disease rating scale (UPDRS) motor scores of 38-70 when off medication (off state), and had symptoms that responded to oral levodopa but were insufficiently controlled by optimised pharmacotherapy. Randomisation was done in a 1:1 ratio. Only the neurosurgical team was aware of treatment assignments. During stereotactic transplantation around 325,000 cells per side were injected into the postcommissural putamen; sham surgery patients received partial burr holes. The primary efficacy endpoint was change in UPDRS off-state motor score at 12 months. This study is registered with ClinicalTrials.gov, number NCT00206687. FINDINGS: Of 71 enrolled patients, 35 underwent cell transplantation and 36 sham surgery. Change in mean motor scores did not differ significantly between groups (-10.5 [SD 10.26] for transplantation vs -10.1 [SD 12.26] for sham surgery, p=0.9). The overall rate of adverse events was similar in the two study groups, although the number attributable to surgery or RPE cells (mostly neurological or psychiatric) was higher in transplant recipients. Two and seven patients died in the sham surgery and transplantation group, respectively; one death in the latter group was possibly related to surgery or RPE cells. INTERPRETATION: Transplantation of human RPE cells provided no antiparkinsonian benefits compared with sham surgery. FUNDING: Bayer HealthCare AG.

Intravenous iron dextran for severe refractory restless legs syndrome.

Reduced brain iron is strongly associated with restless legs syndrome (RLS). Oral iron supplements are commonly recommended for RLS but are largely ineffective due to poor absorption and poor tolerability at required doses. Intravenous iron dextran has been shown to increase brain iron content. Surprisingly only a few reports have ever presented data on the clinical effect of high dose intravenous iron for RLS. We retrospectively identified 25 subjects (age 53.2+/-11.9, 7 male) that received intravenous iron for RLS refractory to conventional treatments. We infused 1g of high molecular weight iron dextran over five hours. The age of RLS onset was 32.6+/-13.0 years and 15 subjects had a positive family history of RLS. Patients attempted 7.5+/-2.7 medications for RLS prior to iron therapy. Baseline ferritins ranged from 5 to 248 ng/ml (mean 43.5+/-58.0) and 20/25 had ferritins of less than 50. Two subjects did not complete their entire infusion due to anaphylactic type symptoms but are included. Overall, 2 subjects reported complete amelioration of all RLS symptoms, 11 reported marked improvement, 2 moderate improvement, 3 mild improvement, and 6 reported no improvement. For those with improvement, the duration of effect was highly variable (mean 15.8+/-17.7 weeks, range 1-60 weeks). Twelve subjects had multiple infusions. Iron dextran can dramatically improve refractory RLS but results are inconsistent and not predicted by patient demographics. Although burdened by a higher rate of anaphylactic reactions, iron dextran may be superior to other IV iron preparations.

Increased melanoma risk in Parkinson disease: a prospective clinicopathological study.

OBJECTIVE: To evaluate the possible association of Parkinson disease (PD) and melanoma in North America. DESIGN, SETTING, AND PATIENTS: Thirty-one centers enrolled patients with idiopathic PD. At visit 1, a neurologist obtained a medical history. At visit 2, a dermatologist recorded melanoma risk factors, performed a whole-body examination, and performed a biopsy of lesions suggestive of melanoma for evaluation by a central dermatopathology laboratory. We compared overall prevalence of melanoma with prevalence calculated from the US Surveillance Epidemiology and End Results (SEER) cancer database and the American Academy of Dermatology skin cancer screening programs. RESULTS: A total of 2106 patients (mean [SD] age, 68.6 [10.6] years; duration of PD, 7.1 [5.7] years) completed the study. Most (84.8%) had received levodopa. Dermatology examinations revealed 346 pigmented lesions; dermatopathological findings confirmed 20 in situ melanomas (0.9%) and 4 invasive melanomas (0.2%). In addition, histories revealed 68 prior melanomas (3.2%). Prevalence (5-year limited duration) of invasive malignant melanoma in the US cohort of patients with PD (n = 1692) was 2.24-fold higher (95% confidence interval, 1.21-4.17) than expected in age- and sex-matched populations in the US SEER database. Age- or sex-adjusted relative risk of any melanoma for US patients was more than 7 times that expected from confirmed cases in American Academy of Dermatology skin cancer screening programs. CONCLUSIONS: Melanoma prevalence appears to be higher in patients with PD than in the general population. Despite difficulties in comparing other databases with this study population, the study supports increased melanoma screening in patients with PD.

Selegiline orally disintegrating tablets in patients with Parkinson disease and "wearing off" symptoms.

BACKGROUND: Selegiline orally disintegrating tablet (ODT; Zelapar) is a selective monoamine oxidase B inhibitor developed as an adjunct to levodopa (LD) for Parkinson disease. Most patients on long-term LD therapy eventually experience deterioration at the end of the LD dosing interval, with predictable "wearing off" and "on-off" fluctuations. METHODS: We conducted a 12-week, double-blind, placebo-controlled, parallel-design trial of selegiline ODT. The primary efficacy point was reduction in the percentage of average daily "off" time. Secondary measures included reductions in daily off hours and total daily off time, Clinical Global Impressions-Improvement (CGI-I), and Patient Global Impression-Improvement (PGI-I). Patients on LD received selegiline ODT (1.25 mg/d for 6 weeks, then 2.5 mg/d for 6 weeks) or placebo. Safety and tolerability were measured. RESULTS: The intent-to-treat population included 98 patients receiving selegiline ODT and 50 patients receiving placebo. Combined efficacy results for weeks 10 and 12 revealed an 11.6% reduction in percentage of daily off time for selegiline ODT versus a 9.8% reduction for placebo (NS). PGI-I detected a statistically significant difference between treatment groups in favor of selegiline ODT (P = 0.02), whereas CGI-I detected a strong trend toward improvement (P = 0.06). Selegiline ODT was safe and well tolerated. CONCLUSIONS: This study showed no significant difference in improvement in percentage of off time with selegiline ODT versus placebo. Some clinical impressions (e.g., PGI-I, CGI-I) improved. This result contrasts with an identically designed study that showed a significant improvement in off time with selegiline ODT. A combined analysis of both studies suggested overall efficacy.

Locomotion is increased in a11-lesioned mice with iron deprivation: a possible animal model for restless legs syndrome.

Restless legs syndrome (RLS) is a common neurologic condition involving iron and dopamine systems. We sought to create an animal model consistent with RLS based on current understanding of human pathology. We performed bilateral 6-hydroxydopamine (6-OHDA) lesioning in the A11 nucleus of C57BL/6 mice and deprived a subset of mice from dietary iron to observe whether these manipulations can increase motor activity. Iron levels in serum, brain, and especially spinal cord were significantly decreased after iron deprivation. Interestingly, 6-OHDA lesioning appeared to further reduce CNS iron stores. Pathologic examination demonstrated a 94% reduction in A11 tyrosine hydroxylase staining cells in mice injected with 6-OHDA but minimal effects on other areas. Locomotor activities were significantly increased in both the mice that were iron deprived and the A11-lesioned mice compared with controls. The combination of iron deprivation and A11 lesions further significantly augmented activity. Additionally, the mice in the combined iron-deprived and lesioned group were more aggressive. The increased activity in A11-lesioned mice with or without iron deprivation was normalized after treatment with the D2/D3 agonist ropinirole, as is seen in human RLS but was worsened by the D1 agonist SKF38393. This model could be consistent with human RLS, attention deficit hyperactivity disorder, or akathisia.

Short-term and long-term safety of deep brain stimulation in the treatment of movement disorders.

OBJECT: The object of this study was to assess the long-term safety of deep brain stimulation (DBS) in a large population of patients with a variety of movement disorders. METHODS: All patients treated with DBS at the authors' center between 1995 and 2005 were assessed for intraoperative, perioperative, and long-term adverse events (AEs). A total of 319 patients underwent DBS device implantation. Of these 319, 182 suffered from medically refractory Parkinson disease; the other patients had essential tremor (112 patients), dystonia (19 patients), and other hyperkinetic movement disorders (six patients). Intraoperative AEs were rare and included vasovagal response in eight patients (2.5%), syncope in four (1.2%), severe cough in three (0.9%), transient ischemic attack in one (0.3%), arrhythmia in one (0.3%), and confusion in one (0.3%). Perioperative AEs included headache in 48 patients (15.0%), confusion in 16 (5.0%), and hallucinations in nine (2.8%). Serious intraoperative/perioperative AEs included isolated seizure in four patients (1.2%), intracerebral hemorrhage in two patients (0.6%), intraventricular hemorrhage in two patients (0.6%), and a large subdural hematoma in one patient (0.3%). Persistent long-term complications of DBS surgery included dysarthria (4.0%), worsening gait (3.8%), cognitive dysfunction (4.0%), and infection (4.4%). Revisions were completed in 25 patients (7.8%) for the following reasons: loss of effect, lack of efficacy, infection, lead fracture, and lead migration. Hardware-related complications included 12 lead fractures and 10 lead migrations. CONCLUSIONS: The authors conclude that in their 10-year experience, DBS has proven to be safe for the treatment of medically refractory movement disorders.

Spinal cord dopamine receptor expression and function in mice with 6-OHDA lesion of the A11 nucleus and dietary iron deprivation.

It is suggested that dysfunction of the diencephalospinal dopaminergic (DAergic) pathway may cause restless legs syndrome. We examined the mRNA and protein levels as well as DA receptor subtypes function within the lumbar spinal cord of an RLS animal model. C57BL/6 male mice with or without iron deprivation were lesioned with 6-hydroxydopamine (6-OHDA) in the bilateral A11 nuclei. Locomotor behaviors were observed. DA concentration, mRNA, and protein levels of D1, D2, and D3 receptors in the lumbar spinal cords were analyzed, and the specific binding of D1, D2, and D3 receptors was determined using [(3)H]SCH23390, [(3)H]Spiperone, and [(3)H]PD128907 radioligands respectively. The behavioral tests showed that the locomotor activities were increased significantly in the mice treated with iron-deficiency (ID) diet and 6-OHDA lesions, which were reversed by the D2/D3 agonist ropinirole. DA in the spinal cord was decreased significantly by 6-OHDA lesioning in A11. D2/D3 mRNA and protein levels as well as their binding capacity in the spinal cord were decreased significantly by 6-OHDA lesions. ID with 6-OHDA lesions produced a synergistic greater decrease of D2 binding. Although ID increased D1 mRNA and protein expression in the spinal cord, it did not significantly change D1 receptor binding. The present study suggests that ID and 6-OHDA lesions in A11 nuclei differentially altered the D1, D2, and D3 receptors expression and binding capacity in the lumbar spinal cord of RLS animal model, which was accompanied by changes in locomotor activities.

Deep brain stimulation: preoperative issues.

Numerous factors need to be taken into account in deciding whether a patient with Parkinson's disease (PD) is a candidate for deep brain stimulation. Patient-related personal factors including age and the presence of other comorbid disorders need to be considered. Neuropsychological and neuropsychiatric concerns relate both to the presurgical status of the patient and to the potential for surgery to result in new problems postoperatively. A number of factors related to the underlying PD need to be considered, including the specific parkinsonian motor indications (e.g., tremor, bradykinesia, gait dysfunction), previous medical therapies, including benefit from current therapy and adverse effects, and past surgical treatments. Definable causes of Parkinsonism, particularly atypical Parkinsonisms, should be considered. Finally, methods of evaluating outcomes should be defined and formalized. This is a report from the Consensus on Deep Brain Stimulation for Parkinson's Disease, a project commissioned by the Congress of Neurological Surgeons and the Movement Disorder Society (MDS). The report has been endorsed by the Scientific Issues Committee of the MDS and the American Society of Stereotactic and Functional Neurosurgery. It outlines answers to a series of questions developed to address all aspects of deep brain stimulation preoperative decision-making.

Essential tremor: treatment options.

The treatment of essential tremor depends on the tremor severity, location, and risk benefit ratios. Mild to moderate tremor usually will respond to oral agents such as noncardiac selective beta-blockers or primidone. Other agents including ethanol, topiramate, benzodiazepines, gabapentin, levetiracetam, and zonisamide may be effective. There are very little data comparing different oral agents, but there is support for polypharmacy in some cases. Botulinum toxin injections are effective in some tremor patterns, especially wrist flexion/extension and head tremor. For severe tremor, surgical lesioning or deep brain stimulation of the thalamus is justified and often dramatically improves function.

Benefits and risks of pharmacological treatments for essential tremor.

Essential tremor can cause significant functional disability in some patients. The arms are the most common body part affected and cause the most functional disability. The treatment of essential tremor includes medications, surgical options and other forms of therapy. Presently there is no cure for essential tremor nor are there any medications that can slow the progression of tremor. Treatment for essential tremor is recommended if the tremor causes functional disability. If the tremor is disabling only during periods of stress and anxiety, propranolol and benzodiazepines can be used during those periods when the tremor causes functional disability. The currently available medications can improve tremor in approximately 50% of the patients. If the tremor is disabling, treatment should be initiated with either primidone or propranolol. If either primidone or propranolol do not provide adequate control of the tremor, then the medications can be used in combination. If patients experience adverse effects with propranolol, occasionally other beta-adrenoceptor antagonists (such as atenolol or metoprolol) can be used. If primidone and propranolol do not provide adequate control of tremor, occasionally the use of benzodiazepines (such as clonazepam) can provide benefit. Other medications that may be helpful include gabapentin or topiramate. If a patient has disabling head or voice tremor, botulinum toxin injections into the muscles may provide relief from the tremor. Botulinum toxin in the hand muscles for hand tremor can result in bothersome hand weakness and is not widely used. There are other medications that have been tried in essential tremor and have questionable efficacy. These drugs include carbonic anhydrase inhibitors (e.g. methazolamide), phenobarbital, calcium channel antagonists (e.g. nimodipine), isoniazid, clonidine, clozapine and mirtazapine. If the patient still has disabling tremor after medication trials, surgical options are usually considered. Surgical options include thalamotomy and deep brain stimulation of the thalamus. These surgical options provide adequate tremor control in approximately 90% of the patients. Surgical morbidity and mortality for these procedures is low. Deep brain stimulation and thalamotomy have been shown to have comparable efficacy but fewer complications have been reported with deep brain stimulation. In patients undergoing bilateral procedures deep brain stimulation of the thalamus is the procedure of choice to avoid adverse effects seen with bilateral ablative procedures. The use of medication and/or surgery can provide adequate tremor control in the majority of the patients.

Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease.

Mitochondrial (mt) impairment, particularly within complex I of the electron transport system, has been implicated in the pathogenesis of Parkinson disease (PD). More than half of mitochondrially encoded polypeptides form part of the reduced nicotinamide adenine dinucleotide dehydrogenase (NADH) complex I enzyme. To test the hypothesis that mtDNA variation contributes to PD expression, we genotyped 10 single-nucleotide polymorphisms (SNPs) that define the European mtDNA haplogroups in 609 white patients with PD and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.34-0.91; P=.02) or K (OR 0.52; 95% CI 0.30-0.90; P=.02) demonstrated a significant decrease in risk of PD versus individuals carrying the most common haplogroup, H. Furthermore, a specific SNP that defines these two haplogroups, 10398G, is strongly associated with this protective effect (OR 0.53; 95% CI 0.39-0.73; P=.0001). SNP 10398G causes a nonconservative amino acid change from threonine to alanine within the NADH dehydrogenase 3 (ND3) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men (OR 0.43; 95% CI 0.27-0.71; P=.0009). In addition, SNP 9055A of ATP6 demonstrated a protective effect for women (OR 0.45; 95% CI 0.22-0.93; P=.03). Our results suggest that ND3 is an important factor in PD susceptibility among white individuals and could help explain the role of complex I in PD expression.