Motor Worsening Research Articles

Progression of prodromal motor and non-motor symptoms in the premotor phase study - 2-year follow-up data.

The neuropathological process starts years before the diagnosis of Parkinson's disease (PD). Assessment of prodromal features in healthy individuals may help to define those with high risk for future PD. Our aim was to evaluate the presence and progression of prodromal markers in individuals with low risk [healthy controls (HC), n = 14] and high risk for PD (HR-PD, n = 34) and early PD (n = 14) patients. Several risk or prodromal markers were combined to define HR-PD. Other prodromal markers were followed in 6-month intervals for 2 years. As recommended by the Movement Disorder Society Task Force, likelihood ratios (LRs) of markers, motor scores and PD probability scores were calculated and compared. The baseline LR for non-motor prodromal markers was significantly higher in PD and HR-PD compared to HC. Within 2 years, changes in these LRs did not significantly differ between the groups. Motor worsening was significant only in the PD group (50% of the patients) against HR-PD (15%) and HC (7%). Change in the non-motor prodromal LR did not significantly correlate with motor worsening, but higher baseline non-motor LRs were associated with Unified Parkinson's Disease Rating Scale III values at 2 years of follow-up. Our study shows that the frequency of non-motor prodromal markers is higher in the HR-PD group but does not increase within 2 years. The progression of motor and non-motor markers seems to be independent, but higher baseline non-motor burden is associated with the motor status after 2 years. Moreover, our data argue for a high impact of motor markers in the risk estimation for future PD.

Clinical outcomes following corticosteroid administration in patients with delayed diagnosis of spinal arteriovenous fistulas

Background and purposeThere have been several previously reported cases of acute progression of myelopathic symptoms in patients with spinal arteriovenous fistula (SAVF) treated with intravenous methylprednisolone. This usually occurs during...

Parkinson disease psychosis – A case report

IntroductionPsychosis is one of the most prevalent non-motor complications in Parkinson's disease (PD). Risk factors for PD psychosis are advancing age, longer disease duration, severe motor symptoms, presence of dementia, sleep disorders, depression and autonomic dysfunction. Treatment is challenging in this setting because antipsychotic medications are known to worse motor symptoms.ObjectivesTo highlight the therapeutic difficulties in PD-related psychosis.MethodsCase description and literature review.ResultsWe report a case of a 74-year-old woman with a 9-year history of PD, who presented a complex psychotic disorder consisting in auditory, olfactory and visual (gulliverian and lilliputian) hallucinations, persecutory and sexual delusions. Additionally, the patient presented euthymic mood, without evidence of cognitive impairment or impulse-control disorder. These symptoms began after dopamine agonist therapy (ropinirole 4 mg/day). Other medical conditions that could justify these symptoms were excluded. Initially, ropinirole was removed, but without psychotic remission. Then, she was treated with antipsychotic medication (clozapine 25 mg/day) with full psychotic remission and without significant worsening of motor symptoms.ConclusionsClozapine treatment is frequently delayed, mainly for fear of its side effects, particularly agranulocytosis. However, this antipsychotic drug presents many benefits regarding the management of PD-related psychosis, namely few motor effects and even improvement of motor fluctuations.Disclosure of interestThe authors have not supplied their declaration of competing interest.

A New Perspective in the Treatment of Parkinson’s Disease Psychosis

Neuropsychiatric symptoms, such as psychosis, are well described in Parkinson’s disease (PD); most appear to be due to disease pathology with exacerbation caused by dopaminergic treatment. More than 50% of patients with PD develop psychosis at some point throughout their disease course. Clinicians need to routinely assess patients with PD for psychotic symptoms, particularly hallucinations. Treatment of psychotic symptoms in PD is an unmet need as there are currently no US Food and Drug Administration (FDA) approved medications specifically for PD psychosis (PDP). Current treatments for PDP have been adapted from dopamine antagonists used to treat psychosis in other conditions, such as schizophrenia. Typical antipsychotics, as well as some atypical antipsychotics, worsen PD motor symptoms due to blockade of dopamine D2 receptors. Quetiapine and clozapine have been studied in PDP and are the most commonly used treatments for PDP. Clozapine has been shown to be effective; however, regular bloodwork is required, while data for quetiapine are inconsistent. Pimavanserin, a highly selective serotonin (5HT2A subtype) receptor inverse agonist, is not associated with motor worsening in PDP patients due to the absence of dopamine blockade. In a double-blind, placebo-controlled study, pimavanserin showed significant improvement in moderate to severe psychosis compared to placebo, with good tolerability and without worsening of PD motor symptoms. These data suggest that pimavanserin is a safe and efficacious treatment for PDP psychosis and could be a potential new treatment option for PDP.

Risk factors for worsened muscle strength after the surgical treatment of arteriovenous malformations of the eloquent motor area.

OBJECT Case selection for the surgical treatment of arteriovenous malformations (AVMs) of the eloquent motor area remains challenging. The aim of this study was to determine the risk factors for worsened muscle strength after surgery in patients with this disorder. METHODS At their hospital the authors retrospectively studied 48 consecutive patients with AVMs involving motor cortex and/or the descending pathway. All patients had undergone preoperative functional MRI (fMRI) and diffusion tensor imaging (DTI), followed by resection. Both functional and angioarchitectural factors were analyzed with respect to the change in muscle strength. Functional factors included lesion-to-corticospinal tract distance (LCD) on DTI and lesion-to-activation area distance (LAD) and cortical reorganization on fMRI. Based on preoperative muscle strength, the changes in muscle strength at 1 week and 6 months after surgery were defined as short-term and long-term surgical outcomes, respectively. Statistical analysis was performed using the statistical package SPSS (version 20.0.0, IBM Corp.). RESULTS Twenty-one patients (43.8%) had worsened muscle strength 1 week after surgery. However, only 10 patients (20.8%) suffered from muscle strength worsening 6 months after surgery. The LCD was significantly correlated with short-term (p < 0.001) and long-term (p < 0.001) surgical outcomes. For long-term outcomes, patients in the 5 mm ≥ LCD > 0 mm (p = 0.009) and LCD > 5 mm (p < 0.001) categories were significantly associated with a lower risk of permanent motor worsening in comparison with patients in the LCD = 0 mm group. No significant difference was found between patients in the 5 mm ≥ LCD > 0 mm group and LCD > 5 mm group (p = 0.116). Nidus size was the other significant predictor of short-term (p = 0.021) and long-term (p = 0.016) outcomes. For long-term outcomes, the area under the ROC curve (AUC) was 0.728, and the cutoff point was 3.6 cm. Spetzler-Martin grade was not associated with short-term surgical outcomes (0.143), although it was correlated with long-term outcomes (0.038). CONCLUSIONS An AVM with a nidus in contact with tracked eloquent fibers (LCD = 0) and having a large size is more likely to be associated with worsened muscle strength after surgery in patients with eloquent motor area AVMs. Surgical treatment in these patients should be carefully considered. In patients with an LCD > 5 mm, radical resection may be considered to eliminate the risk of hemorrhage.

Differential spectral quantitative electroencephalography patterns between control and Parkinson's disease cohorts.

It is believed that progressive Lewy-type synucleinopathy (LTS) is primarily responsible for the worsening of motor and non-motor Parkinson's disease (PD) signs and symptoms. Characterization of quantitative electroencephalography (QEEG) abnormalities across the spectrum of LTS to PD dementia (PD-D) may provide insight into the pathophysiology of PD cortical dysfunction. Here our enlarged EEG database was leveraged to characterize spectral QEEG abnormalities in asymptomatic autopsy-defined groups of control participants and incidental Lewy body disease (ILBD) and three clinically defined groups of participants with PD (cognitively normal PD, mild cognitive impairment PD, and PD-D). The PD cohort was studied as part of the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). AZSAND utilizes its Brain and Body Donation Program to perform prospective, standardized, regular longitudinal pre-mortem assessments until death. Resting EEG from subjects was analyzed for spectral domain QEEG measures of background rhythm frequency and global relative power in delta, theta, alpha and beta bands. The various spectral QEEG measures showed differential changes specific to the groups compared. Important findings were background rhythm frequency showing the most pairwise differences across the groups, and this also was the only significant difference between control and ILBD. An increase in delta bandpower was characteristic of worsening cognitive deficits. Different patterns of change amongst QEEG measures across LTS and PD cognitive states suggest that they correlate with heterogeneous pathophysiologies of cortical dysfunction within the PD clinical spectrum. In addition, the biomarker application of a specific spectral QEEG measure needs to be selectively suited to its study purpose.

Pramipexole Induced Complete Heart Block: A Case Report

Pramipexole is a dopamine agonist of non-ergoline class which is mainly used in the treatment of Parkinson's disease and restless leg syndrome. Fibromyalgia and depression are other off labelled indications. Adverse events like orthostatic hypotension, worsening of motor and psychiatric symptoms, confusion ,and drowsiness are often stated. Pramipexole induced cardiac events are often less likely, especially in those who doesn't had any underlying heart failure or renal impairment. We report a rare case of Pramipexole induced complete heart block which was observed in a 68 year old female who was admitted to the emergency department with syncope, generalised tiredness, and one episode of giddiness with blurring of vision. She had a history of depression but no history of any cardiac and renal disease. She was on a trial of pramipexole on suspicion of Parkinson's disease after which she developed complete heart block with intermittent atrioventricular block which was evident in the electrocardiogram (ECG). All alternative causes of AV block were ruled out. ECG returned to normal 24 hours after the withdrawal of pramipexole. A total of 7 reports have been found regarding Pramipexole induced cardiac failure. Among these, two reports from New Zealand are noted to have a causality score as 'unlikely'. Since Pramipexole causing AV block remains a blurred adverse effect, and the relative unawareness of this syndrome among the physicians, makes it a prudent topic to be reported. This case report gives emphasis on the importance of close monitoring, early detection and management of this adverse drug reaction based on current standard guidelines.

Influence of depression in mild Parkinson's disease on longitudinal motor and cognitive function.

Studies have suggested a relationship between non-motor symptoms with motor fluctuations in patients with Parkinson's disease (PD). We studied the influence of depression on longitudinal motor and cognitive function among mild PD patients. A 1.5 years longitudinal study of 102 patients with mild idiopathic PD. Patients were assessed with a standardized clinical assessment battery including motor and non-motor scales. Patients also underwent serial neurocognitive testing that assessed global cognition, memory, attention, language, visuospatial and executive function. 81 patients with mean age of 64.9(SD = 7.9) years and mean Hoehn & Yahr of 1.9(SD = 0.4) completed baseline and follow-up visits. 22 patients had clinically significant depression at baseline with mean Geriatric Depression Scale of 6.9(SD = 2.4). These patients presented with concomitant apathy and anxiety and were more likely to be females with longer duration of PD. At baseline, patients with depression had poorer performance on global cognition and all cognitive domains although not significantly different from patients without depression. At follow-up, there was no statistically significant difference on cognitive performance between those with and without baseline depression. Patients with baseline depression demonstrated worsening of motor function after 18 months (UPDRS Motor Score Change: +5.0[7.0]vs.+0.2[7.3]; p = 0.015). On multivariate analysis Baseline Motor Score (B = -0.229,CI = -0.445 to-0.013,p = 0.038), Baseline GDS (B = 0.622,CI = 0.078 to 1.166,p = 0.026) and PD duration (B = 0.520,CI = 0.105 to 0.935,p = 0.015) independently predicted increase in UPDRS Motor Score. The findings suggest a relationship between early depression with motor worsening and cognition decline in PD patients. Further biomarker-supported studies investigating the role of depression on motor and cognitive function are needed.

Lack of exacerbation of neurodegeneration in a double transgenic mouse model of mutant LRRK2 and tau.

LRRK2 (leucine-rich repeat kinase) mutations constitute the most common cause of familial Parkinson's disease (PD). Microtubule-associated protein tau mutations cause a group of neurodegenerative diseases termed tauopathies. Genome-wide association studies show that, after α-synuclein, polymorphisms in the tau gene have the second strongest genetic association with PD. In a proportion of PD patients with LRRK2 mutations, and in several transgenic animal models of LRRK2, tau hyperphosphorylation and aggregation, rather than α-synuclein aggregation, are the most prominent neuropathologic findings. To further examine the relationship between LRRK2 and tau, we crossed LRRK2 R1441G BAC transgenic mice (Mus musculus) with tau P301S mutant transgenic mice and characterized their behavioral, neuropathological and biochemical phenotypes. We found that the combination of the two mutations does not increase tau hyperphosphorylation or aggregation nor does it exacerbate the behavioral and pathological deficits previously described in the tau P301S mice. The double-mutant mice had no shortening of lifespan and no worsening of motor or memory deficits. There was no increase in the aggregation of tau or α-synuclein. Dopaminergic neuron cell counts and striatal levels of dopamine and its metabolites were unaltered. There was no exacerbation of cell loss, microgliosis or astrogliosis in multiple brain regions. These results suggest that LRRK2 and tau do not interact to exacerbate behavioral, biochemical or pathological abnormalities in neurodegeneration and that LRRK2 and tau exert their pathogenic effects through independent mechanisms.

Long-term effects of contralesional rTMS in severe stroke: safety, cortical excitability, and relationship with transcallosal motor fibers.

Contralesional hemispheric repetitive transcranial magnetic stimulation (rTMS) may improve motor function in mild to moderate stroke and effects are considered to be mediated through transcallosal motor fibers. This study aimed to investigate the safety of contralesional rTMS in a selected group of severe chronic stroke patients. Ten sessions of 1 Hz rTMS were applied to contralesional primary motor cortex (M1) using neuronavigated stimulation and changes in motor impairment were evaluated before, during and after rTMS applications and at 4-weeks follow-up. Neurophysiological response to stimulation was assessed through cortical excitability evaluations. The relationship between functional and neurophysiological response to rTMS and microstructural integrity of transcallosal motor fibers were searched using diffusion tensor imaging (DTI) based fractional anisotropy (FA). rTMS was well-tolerated with high compliance and no dropouts; no seizures or motor worsening occurred. Transcallosal FA values revealed a positive linear relationship with the mild motor improvement detected after rTMS while higher FA values were observed in subjects with better motor outcome. Cortical excitability showed a significant change in contralesional short-interval intracortical inhibition indicating altered plasticity following rTMS. Our results suggest that noninvasive neuromodulation of the contralesional hemisphere may present a possibility to assist adaptive neuroplastic changes in severe chronic stroke. Implementation of DTI-derived measures of transcallosal microstructural integrity may allow for individually-tailored interventions to guide processes of interhemispheric neuroplasticity. Further research is warranted to establish the clinical value of these findings in neurorehabilitation settings for subjects with chronic severe stroke.

Non-motor symptoms in an Indian cohort of Parkinson's disease patients and correlation of progression of non-motor symptoms with motor worsening.

To document the frequency and prevalence of non-motor symptoms (NMS) in an Indian cohort of Parkinson's disease (PD) patients. To validate the non-motor score scale (NMSS) in an Indian cohort of PD patients for recording NMS of the disease, to study the prevalence and frequency of NMS in Indian PD patients using the NMSS, and to compare the progression of NMS with motor worsening. Conclusion and Results: This was a cross-sectional, single-center, open-label, one point in time evaluation study conducted from 2009 to 2011. It validated the NMSS scale in an Indian population. The study has profiled the prevalence and pattern of NMS in an Indian cohort of PD patients. Comparison of NMS scale scores with the Unified PD Rating Scale motor scores demonstrated a correlation between non-motor and motor symptoms in the disease progression, particularly of manifestations related to the cognitive decline, memory disturbances, urinary incontinence and smell.

Clinical characteristics related to worsening of motor function assessed by the Unified Parkinson's Disease Rating Scale in the elderly population.

There is evidence that nigrostriatal pathology may at least partly underlie mild Parkinsonian signs. We evaluated whether an increase in the Unified Parkinson's Disease Rating Scale part III (UPDRS-III) could be predicted by the presence of risk and prodromal markers for neurodegenerative diseases in elderly individuals without those diseases. Therefore, we analyzed the UPDRS-III score and various risk and prodromal markers known to antecede neurodegenerative diseases in a population-based cohort comprising 807 individuals free of neurodegenerative diseases at baseline. After 5 years, eight persons (1.0 %) were diagnosed with Parkinson's Disease (PD). Of those, seven (87.5 %) had motor worsening ≥3 points on the UPDRS-III from baseline to follow-up, one had two points increase. Of the 788 people without PD, 568 (72.1 %) showed no increase in the UPDRS-III scale, 220 (27.9 %) had ≥1 point increase and out of these 104 (13.2 %) had an increase of ≥3 points in the UPDRS-III score after 5 years. We identified an age >60 years (relative risk, RR = 1.7; confidence interval, CI 1.3-2.1) and the occurrence of ≥2 risk factors (RR = 1.5; CI 1.2-1.9) as possible predictors of motor progression. After 5 years, individuals with an increase in the UPDRS-III score had more often a one-sided reduced arm swing (p < 0.001) and identified less odors in the Sniffin' sticks test (p < 0.041) than persons with stable motor performance. Our data support the assumption that progression of Parkinsonian signs assessed by the UPDRS-III parallels the development of prodromal markers for neurodegenerative diseases in the elderly population.

Medical and surgical treatment of primary divergent strabismus

PurposeTo evaluate the long-term effectiveness of different therapies applied in the past 30 years, both medical and surgical, and results, with the ultimate aim of determining which are the most appropriate criteria to indicate when and how to perform medical and surgical treatment in these patients. MethodA retrospective randomized study was conducted on 198 patients with primary divergent strabismus first seen in our clinic (IOC) in the last 36 years (1976–2012), with a mean follow-up of 8.38 years. Demographic and clinical characteristics, as well as the various treatments performed, and motor and sensory outcome were collected. They were finally divided into 3 groups of 70, 71 and 56 patients, respectively, according to their first visit, in order to compare the therapies applied. ResultsHalf (50%) of our patients debuted before 2 years of age (P50=24 months), and 26.3% had optimal binocular vision at the beginning of the study. Medical treatment was used as exclusive therapy in 29.3% of cases (occlusion therapy, applying negative lenses, botulinum toxin), and 70.7% required surgery (61.2% by double retro-insertion of lateral rectus, and 38.8% monolateral retro-resection). There was a recurrence in 26.7% of patients, and 40 re-interventions were performed (70% due to recurrence of divergent strabismus, 12.5% due to surgical over-correction, and 17.5% for other reasons). In the end, 61.1% of patients had perfect binocular vision (TNO=60″), and the proportion was higher in patients who showed proper control of their strabismus at the beginning (p=0.003). However, no differences were found in the other variables studied. When the patients were divided into 3 groups (which are demographically comparable), an increased number of patients in Group 3 were found to be treated using negative lenses and botulinum toxin (p<0.001 and p=0.003). This group was found to have had a higher proportion of bilateral surgery (p=0.032), seeking greater immediate postoperative over-correction, thus reducing the number of re-interventions from 40.5 to 19%, although it did not reach statistical significance (p=0.093). It was also found that there was a significantly increased number of injections of botulinum toxin in the middle rectum for treatment of excessive postoperative overcorrection (p=0.028). No other differences in final binocular vision were found between the 3 groups (p=0.703). ConclusionsIn cases of clear ocular dominance, occlusion therapy must be applied twice daily on the dominating eye, in order to encourage divergent strabismus control and improve sensoriality. An attempt should be made to wait until patients reach four years of age before indicating surgical treatment, except in cases of a significant worsening of motor or sensory component. Bilateral surgery on both lateral rectus should be attempted, provided that patient characteristics allow this. A slight post-surgical overcorrection should be looked for in the immediate postoperative period, as this, in our experience, reduces the total amount of re-operations. When working on the middle rectus, remember that the elasticity of this muscle is the key factor for obtaining a proper post-surgical outcome, but a reliable measurement of this still cannot be made. In cases of excessive post-surgical over-correction, an injection of botulinum toxin should be applied to these poor elasticity muscles, in order to reduce the number of re-operations.

Tratamiento médico y quirúrgico del estrabismo divergente primario

PurposeTo evaluate the long-term effectiveness of different therapies applied in the past 30 years, both medical and surgical, and results, with the ultimate aim of determining which are the most appropriate criteria to indicate when and how to perform medical and surgical treatment in these patients. MethodA retrospective randomized study was conducted on 198 patients with primary divergent strabismus first seen in our clinic (IOC) in the last 36 years (1976-2012), with a mean follow-up of 8.38 years. Demographic and clinical characteristics, as well as the various treatments performed, and motor and sensory outcome were collected. They were finally divided into 3 groups of 70, 71 and 56 patients, respectively, according to their first visit, in order to compare the therapies applied. ResultsHalf (50%) of our patients debuted before 2 years of age (P50=24 months), and 26.3% had optimal binocular vision at the beginning of the study. Medical treatment was used as exclusive therapy in 29.3% of cases (occlusion therapy, applying negative lenses, botulinum toxin), and 70.7% required surgery (61.2% by double retro-insertion of lateral rectus, and 38.8% monolateral retro-resection). There was a recurrence in 26.7% of patients, and 40 re-interventions were performed (70% due to recurrence of divergent strabismus, 12.5% due to surgical over-correction, and 17.5% for other reasons). In the end, 61.1% of patients had perfect binocular vision (TNO=60”), and the proportion was higher in patients who showed proper control of their strabismus at the beginning (P=.003). However, no differences were found in the other variables studied. When the patients were divided into 3 groups (which are demographically comparable), an increased number of patients in Group 3 were found to be treated using negative lenses and botulinum toxin (P<.001 and P=.003). This group was found to have had a higher proportion of bilateral surgery (P=.032), seeking greater immediate postoperative over-correction, thus reducing the number of re-interventions from 40.5 to 19%, although it did not reach statistical significance (P=.093). It was also found that there was a significantly increased number of injections of botulinum toxin in the middle rectum for treatment of excessive postoperative overcorrection (P=.028). No other differences in final binocular vision was found between the 3 groups (P=.703). ConclusionsIn cases of clear ocular dominance, occlusion therapy must be applied twice daily on the dominating eye, in order to encourage divergent strabismus control and improve sensoriality. An attempt should be made to wait until patients reach four years of age before indicating surgical treatment, except in cases of a significant worsening of motor or sensory component. Bilateral surgery on both lateral rectus should be attempted, provided that patient characteristics allow this. A slight post-surgical overcorrection should be looked for in the immediate postoperative period, as this, in our experience, reduces the total amount of re-operations. When working on the middle rectus, remember that the elasticity of this muscle is the key factor for obtaining a proper post-surgical outcome, but a reliable measurement of this still cannot be made. In cases of excessive post-surgical over-correction, an injection of botulinum toxin should be applied to these poor elasticity muscles, in order to reduce the number of re-operations.

P214: Study of sympathetic skin response in diabetic patients with soft tissue rheumatism of the hand

P214: Study of sympathetic skin response in diabetic patients with soft tissue rheumatism of the hand

Behavioral and anatomical consequences of repetitive mild thoracic spinal cord contusion injury in the rat

Moderate and severe spinal cord contusion injuries have been extensively studied, yet much less is known about mild injuries. Mild contusions result in transient functional deficits, proceeding to near-complete recovery, but they may render the spinal cord vulnerable to future injuries. However, to date there have been no appropriate models to study the behavioral consequences, anatomical changes, and susceptibility of a mild contusion to repeated injuries, which may occur in children as well as adults during competitive sport activities. We have developed a novel mild spinal cord contusion injury model characterized by a sequence of transient functional deficits after the first injury and restoration to near-complete motor and sensory function, which is then followed up by a second injury. This model can serve not only to study the effects of repeated injuries on behavioral and anatomical changes, but also to examine the relationship between successive tissue damage and recovery of function. In the present study, we confirmed that mild thoracic spinal cord contusion, utilizing the NYU impactor device, resulted in localized tissue damage, characterized by a cystic cavity and peripheral rim of spared white matter at the injury epicenter, and rapid functional recovery to near-normal levels utilizing several behavioral tests. Repeated injury after 3weeks, when functional recovery has been completed, resulted in worsening of both motor and sensory function, which did not recover to prior levels. Anatomical analyses showed no differences in the volumes of spared white matter, lesion, or cyst, but revealed modest extension of lesion area rostral to the injury epicenter as well as an increase in inflammation and apoptosis. These studies demonstrate that a mild injury model can be used to test efficacy of treatments for repeated injuries and may serve to assist in the formulation of policies and clinical practice regarding mild SCI injury and spinal concussion.

Can fall of blood pressure prevent falls in Parkinson disease?

Idiopathic Parkinson disease (PD) is an α-synucleinopathy, one of several proteinopathies characterized by intracellular and extracellular accumulation of abnormal filament proteins.1 Relentless progression of neuropathologic changes, consisting of α-synuclein-positive Lewy bodies and Lewy neurites, and widespread neuronal loss closely correlate with clinical worsening of motor and nonmotor PD symptoms. Typically, unilateral onset of tremor, rigidity, or bradykinesia, the cardinal motor features, is followed by contralateral spread of disease signs. The presence of midline problems, such as gait disorder and balance impairment, generally represents a more advanced phase of the disease, used as the central criteria in Hoehn & Yahr staging.

US Pilot Study of Lumbar to Sacral Nerve Rerouting to Restore Voiding and Bowel Function in Spina Bifida: 3-Year Experience.

Objective. To report our experience with creating a skin-central nervous system-bladder reflex arc with intradural lumbar to sacral motor root microanastomosis to restore bladder/bowel function in spina bifida patients. Methods. Urinary/bowel changes from baseline to three years were evaluated with questionnaires, voiding diaries, urodynamics (UDS), and renal function studies. Treatment response was defined as CIC ≤ once/day with stable renal function, voiding efficiency > 50%, and no worsening of motor function. Results. Of 13 subjects (9 female, median age 8 years), 3 voided small amounts at baseline, one voided 200 cc (voiding efficiency 32%), 4/13 reported normal bowels, and 2/13 were continent of stool. Postoperatively, all had transient lower extremity weakness; one developed permanent foot drop. Over three years, renal function remained stable and mean maximum cystometric capacity (MCC) increased (P = 0.0135). In the 10 that returned at 3 years, 7 were treatment responders and 9 had discontinued antimuscarinics, but most still leaked urine. Only 2/8 with baseline neurogenic detrusor overactivity (NDO) still had NDO, all 3 with compliance <10 mL/cm H2O had normalized, 7/10 considered their bowels normal, 5/10 were continent of stool, and 8/10 would undergo the procedure again. Conclusion. Lumbar to sacral nerve rerouting can improve elimination in spina bifida patients. This trial is registered with ClinicalTrials.gov NCT00378664.

Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial

Parkinson's disease psychosis, which includes hallucinations and delusions, is frequent and debilitating in people with Parkinson's disease. We aimed to assess safety and efficacy of pimavanserin, a selective serotonin 5-HT2A inverse agonist, in this population. In our 6 week, randomised, double-blind, placebo-controlled study, we enrolled adults (aged ≥40 years) with Parkinson's disease psychosis. Antipsychotic treatments were not permitted during the study, but controlled antiparkinsonian medication or deep brain stimulation was allowed. Eligible participants entered a 2 week non-pharmacological lead-in phase to limit the placebo response, after which they were randomly allocated (1:1) to receive pimavanserin 40 mg per day or matched placebo. The primary outcome was antipsychotic benefit as assessed by central, independent raters with the Parkinson's disease-adapted scale for assessment of positive symptoms (SAPS-PD) in all patients who received at least one dose of study drug and had a SAPS assessment at baseline and at least one follow-up. We assessed safety and tolerability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01174004. Between Aug 11, 2010, and Aug 29, 2012, we randomly allocated 199 patients to treatment groups. For 90 recipients of placebo and 95 recipients of pimavanserin included in the primary analysis, pimavanserin was associated with a -5·79 decrease in SAPS-PD scores compared with -2·73 for placebo (difference -3·06, 95% CI -4·91 to -1·20; p=0·001; Cohen's d 0·50). Ten patients in the pimavanserin group discontinued because of an adverse event (four due to psychotic disorder or hallucination within 10 days of start of the study drug) compared with two in the placebo group. Overall, pimavanserin was well tolerated with no significant safety concerns or worsening of motor function. Pimavanserin may benefit patients with Parkinson's disease psychosis for whom few other treatment options exist. The trial design used in this study to manage placebo response could have applicability to other studies in neuropsychiatric disease. ACADIA Pharmaceuticals.

A fixed-dose randomized controlled trial of olanzapine for psychosis in Parkinson disease

Background: Psychosis is a common and debilitating side effect of long-term dopaminergic treatment of Parkinson disease (PD). While clozapine is an effective treatment, the need for blood monitoring has limited its first-line use. Objective: Since olanzapine shows similar receptor affinity to clozapine, we hypothesized that it might be an effective alternative to clozapine for treatment of drug-induced psychosis (DIP) in PD, and that lower doses than usual might make it tolerable. Methods: In 1998-2003 we conducted a four-week, double-blind, placebo-controlled, parallel group, fixed-dose trial of olanzapine (0, 2.5mg, or 5mg) in 23 PD patients with DIP while allowing for clinically realistic dose adjustments of dopaminomimetic mid-study. The primary outcome measures were Brief Psychiatric Rating Scale (BPRS) ratings scored from videotaped interviews after study termination by an observer blinded to dose assignment and to interview timing, and CGI (Clinical Global Impression). The Unified Parkinson’s Disease Rating Scale motor subscale (UPDRS) was the primary measure of tolerability. Results: Intention-to-treat analysis found no significant differences among treatment groups in study completion or serious adverse events. However, a disproportionate number of olanzapine vs. placebo subjects reported mild side effects (p<0.04), many citing motor worsening. Fourteen patients completed the study (seven on placebo, two on 2.5mg olanzapine, five on 5mg olanzapine). In study completers, analysis by repeated measures ANOVA revealed no significant difference between olanzapine and placebo groups in BPRS psychosis reduction (p=0.536), parkinsonism (p=0.608), or any other measured parameters (CGI, MMSE, Beck Depression Inventory, Hamilton Depression score, PDQ‑39, Schwab-England ADL assessment, and sleep scores). Conclusion: This study adds to other evidence that olanzapine is ineffective in treating medication-induced psychosis in Parkinson disease.