Opinions and clinical practices related to diagnosing and managing functional (psychogenic) movement disorders: changes in the last decade.

BACKGROUND AND PURPOSE: There is large variability in the diagnostic approach and clinical management in functional movement disorders (FMD). This study aimed to examine whether opinions and clinical practices related to FMD have changed over the past decade. METHODS: Adapted from a 2008 version, we repeated the survey to members of the International Parkinson and Movement Disorder Society (MDS). RESULTS: In all, 864/7689 responses (denominator includes non-neurologists) were received from 92 countries. Respondents were more often male (55%), younger than 45 (65%) and from academic practices (85%). Although the likelihood of ordering neurological investigations prior to delivering a diagnosis of FMD was nearly as high as in 2008 (47% vs. 51%), the percentage of respondents communicating the diagnosis without requesting additional tests increased (27% vs. 19%; P = 0.003), with most envisioning their role as providing a diagnosis and coordinating management (57% vs. 40%; P < 0.001). Compared to patients with other disorders, 64% of respondents were more concerned about missing a diagnosis of another neurological disorder. Avoiding iatrogenic harm (58%) and educating patients about the diagnosis (53%) were again rated as the most effective therapeutic options. Frequent treatment barriers included lack of physician knowledge and training (32%), lack of treatment guidelines (39%), limited availability of referral services (48%) and cultural beliefs about psychological illnesses (50%). The preferred term for communication favored 'functional' over 'psychogenic' (P < 0.001). CONCLUSIONS: Attitudes and management of FMDs have changed over the past decade. Important gaps remain in access to treatment and in the education of neurologists about the inclusionary approach to FMD diagnosis.

Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy.

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

Targeted delivery of an ADP-ribosylating bacterial toxin into cancer cells.

The actin cytoskeleton is an attractive target for bacterial toxins. The ADP-ribosyltransferase TccC3 from the insect bacterial pathogen Photorhabdus luminescence modifies actin to force its aggregation. We intended to transport the catalytic part of this toxin preferentially into cancer cells using a toxin transporter (Protective antigen, PA) which was redirected to Epidermal Growth Factor Receptors (EGFR) or to human EGF receptors 2 (HER2), which are overexpressed in several cancer cells. Protective antigen of anthrax toxin forms a pore through which the two catalytic parts (lethal factor and edema factor) or other proteins can be transported into mammalian cells. Here, we used PA as a double mutant (N682A, D683A; mPA) which cannot bind to the two natural anthrax receptors. Each mutated monomer is fused either to EGF or to an affibody directed against the human EGF receptor 2 (HER2). We established a cellular model system composed of two cell lines representing HER2 overexpressing esophageal adenocarcinomas (EACs) and EGFR overexpressing esophageal squamous cell carcinomas (ESCCs). We studied the specificity and efficiency of the re-directed anthrax pore for transport of TccC3 toxin and established Photorhabdus luminescence TccC3 as a toxin suitable for the development of a targeted toxin selectively killing cancer cells.

Neurologic diagnostic criteria for functional neurologic disorders.

The diagnosis of functional neurologic disorders can be challenging. In this chapter we review the diagnostic criteria and rating scales reported for functional/psychogenic sensorimotor disturbances, psychogenic nonepileptic seizures (PNES) and functional movement disorders (FMD). A recently published scale for sensorimotor signs has some limitations, but may help in the diagnosis, and four motor and two sensory signs have been reported as highly reliable. There is good evidence using eight specific signs for the differentiation of PNES from seizures. Recently, diagnostic criteria were developed for PNES; their sensitivity and specificity need to be evaluated. The definitive diagnosis of PNES can be made by recording typical positive features during the spells, and in a low proportion of cases, where the distinction with an organic etiology cannot easily be done, a normal electroencephalogram suggests the diagnosis. FMD diagnosis relies on diagnostic criteria, which have been refined over time and may be supplemented by laboratory tests in some phenotypes. Rating scales for PNES and FMD could be useful for severity measures, but several limitations remain to be addressed.

Protocol of a randomised delayed-start double-blind placebo-controlled multi-centre trial for Levodopa in EArly Parkinson's disease: the LEAP-study.

BACKGROUND: The aim of this study is to investigate if early treatment with levodopa has a beneficial disease modifying effect on Parkinson's disease (PD) symptoms and functional health, improves the ability to (maintain) work, and reduces the use of (informal) care, caregiver burden, and costs. Additionally, cost-effectiveness and cost-utility of early levodopa treatment will be assessed. METHODS: To differentiate between the direct symptomatic effects and possible disease modifying effects of levodopa, we use a randomised delayed-start double-blind placebo-controlled multi-centre trial design. Patients with early stage PD whose functional health does not yet necessitate initiation of PD-medication will be randomised to either 40 weeks of treatment with levodopa/carbidopa 100/25 mg TID including 2 weeks of dose escalation or to 40 weeks placebo TID. Subsequently, all patients receive levodopa/carbidopa 100/25 mg TID for 40 weeks. There are 8 assessments: at baseline and at 4, 22, 40, 44, 56, 68, and 80 weeks. The primary outcome measure is the difference in the mean total Unified Parkinson's Disease Rating Scale scores between the early- and delayed-start groups at 80 weeks. Secondary outcome measures are rate of progression, the AMC Linear Disability Score, side effects, perceived quality of life with the Parkinson's Disease Questionnaire-39, the European Quality of Life-5 Dimensions (EQ-5D), ability to (maintain) work, the use of (informal) care, caregiver burden, and costs. 446 newly diagnosed PD patients without impaired functional health need to be recruited in order to detect a minimal clinical relevant difference of 4 points on the total UPDRS at 80 weeks. DISCUSSION: The LEAP-study will provide insights into the possible disease modifying effects of early levodopa. TRIAL REGISTRATION: ISRCTN30518857, EudraCT number 2011-000678-72.

Post-mortem assessment of the short and long-term effects of the trophic factor neurturin in patients with α-synucleinopathies.

Substantial interest persists for developing neurotrophic factors to treat neurodegenerative diseases. At the same time, significant progress has been made in implementing gene therapy as a means to provide long-term expression of bioactive neurotrophic factors to targeted sites in the brain. Nonetheless, to date, no double-blind clinical trial has achieved positive results on its primary endpoint despite robust benefits achieved in animal models. A major issue with advancing the field is the paucity of information regarding the expression and effects of neurotrophic factors in human neurodegenerative brain, relative to the well-characterized responses in animal models. To help fill this information void, we examined post-mortem brain tissue from four patients with nigrostriatal degeneration who had participated in clinical trials testing gene delivery of neurturin to the putamen of patients. Each had died of unrelated causes ranging from 1.5-to-3-months (2 Parkinson's disease patients), to 4+-years (1 Parkinson's disease and 1 multiple-system atrophy-parkinsonian type patient) following gene therapy. Quantitative and immunohistochemical evaluation of neurturin, alpha-synuclein, tyrosine hydroxylase (TH) and an oligodendroglia marker (Olig 2) were performed in each brain. Comparable volumes-of-expression of neurturin were seen in the putamen in all cases (~15-22%; mean=18.5%). TH-signal in the putamen was extremely sparse in the shorter-term cases. A 6-fold increase was seen in longer-term cases, but was far less than achieved in animal models of nigrostriatal degeneration with similar or even far less NRTN exposure. Less than 1% of substantia nigra (SN) neurons stained for neurturin in the shorter-term cases. A 15-fold increase was seen in the longer-term cases, but neurturin was still only detected in ~5% of nigral cells. These data provide unique insight into the functional status of advanced, chronic nigrostriatal degeneration in human brain and the response of these neurons to neurotrophic factor stimulation. They demonstrate mild but persistent expression of gene-mediated neurturin over 4-years, with an apparent, time-related amplification of its transport and biological effects, albeit quite weak, and provide unique information to help plan and design future trials.

Repetitive transcranial magnetic stimulation plus standardized suggestion of benefit for functional movement disorders: an open label case series.

BACKGROUND: We studied suggestion of benefit combined with motor cortex and premotor cortex repetitive transcranial magnetic stimulation (rTMS) in chronic (>2 years) FMDs. METHODS: Patients were identified from our patient records who had clinically definite FMDs and had undergone neuropsychiatric evaluation. Those with chronic FMDs were offered open-label rTMS over the dominant motor cortex. If they failed to improve they received dominant premotor cortex rTMS. The primary outcome was change from baseline to post-rTMS in quality of life measured by the World Health Organization Quality of Life Brief (WHOQOL-BREF) scale. Secondary outcomes were subject and investigator global impression of change (GIC), blinded Rush psychogenic movements rating scale, Barbers suggestibility scale, baseline expectation of benefit scale, and adverse effects. RESULTS: Six subjects were enrolled. For the primary outcome, there was significant improvement in the physical domain scores but significant reduction in psychological domain scores after premotor cortex rTMS compared to baseline and after motor cortex rTMS. There was no significant change between baseline and motor cortex rTMS or in any other domain after premotor cortex rTMS. Secondary outcome measures showed no meaningful change. Transient headache and worsening of FMD symptoms were the most common adverse effects observed. CONCLUSION: rTMS combined with strong suggestion of benefit provided dissonant results after premotor cortex rTMS with improvement in physical quality of life but reduction in psychological quality of life. These results serve to underscore the complex nature of FMDs where the overt physical manifestation is but one part of a comprehensive neuropsychological syndrome.

Neuronal degeneration, synaptic defects, and behavioral abnormalities in tau45₋230 transgenic mice.

The complement of mechanisms underlying tau pathology in neurodegenerative disorders has yet to be elucidated. Among these mechanisms, abnormal tau phosphorylation has received the most attention because neurofibrillary tangles present in Alzheimer's disease (AD) and related disorders known as tauopathies are composed of hyperphosphorylated forms of this microtubule-associated protein. More recently, we showed that calpain-mediated cleavage leading to the generation of the 17kDa tau45₋230 fragment is a conserved mechanism in these diseases. To obtain insights into the role of this fragment in neurodegeneration, we generated transgenic mice that express tau45₋230 and characterized their phenotype. Our results showed a significant increase in cell death in the hippocampal pyramidal cell layer of transgenic tau45₋230 mice when compared to wild-type controls. In addition, significant synapse loss was detected as early as six months after birth in transgenic hippocampal neurons. These synaptic changes were accompanied by alterations in the expression of the N-methyl-d-aspartate glutamate (NMDA) receptor subunits. Furthermore, functional abnormalities were detected in the transgenic mice using Morris Water Maze and fear conditioning tests. These results suggest that the accumulation of tau45₋230 is responsible, at least in part, for neuronal degeneration and some behavioral changes in AD and other tauopathies. Collectively, these data provide the first direct evidence of the toxic effects of a tau fragment biologically produced in the context of these diseases in vertebrate neurons that develop in situ.

Tremor retrainment as therapeutic strategy in psychogenic (functional) tremor.

BACKGROUND: Entrainment, the change or elimination of tremor as patients perform a voluntary rhythmical movement by the unaffected limb, is a key diagnostic hallmark of psychogenic tremor. OBJECTIVE: To evaluate the feasibility of using entrainment as a bedside therapeutic strategy ('retrainment') in patients with psychogenic tremor. METHODS: Ten patients with psychogenic tremor (5 women, mean age, 53.6 ± 12.8 years; mean disease duration 4.3 ± 2.7 years) were asked to participate in a pilot proof-of-concept study aimed at "retraining" their tremor frequency. Retrainment was facilitated by tactile and auditory external cueing and real-time visual feedback on a computer screen. The primary outcome measure was the Tremor subscale of the Rating Scale for Psychogenic Movement Disorders. RESULTS: Tremor improved from 22.2 ± 13.39 to 4.3 ± 5.51 (p = 0.0019) at the end of retrainment. The benefits were maintained for at least 1 week and up to 6 months in 6 patients, with relapses occurring in 4 patients between 2 weeks and 6 months. Three subjects achieved tremor freedom. CONCLUSIONS: Tremor retrainment may be an effective short-term treatment strategy in psychogenic tremor. Although blinded evaluations are not feasible, future studies should examine the long-term benefits of tremor retrainment as adjunctive to psychotherapy or specialized physical therapy.

Palliative care for advanced Parkinson disease: an interdisciplinary clinic and new scale, the ESAS-PD.

UNLABELLED: Palliative care provides a holistic approach to symptom relief using a multidisciplinary team approach to enhance quality of life throughout the entire course of a particular illness. The care team consists of movement disorders neurologist, a palliative care physician, a wound care nurse, a spiritual counselor and a care coordinator. Palliative care concepts were applied to a group of advanced Parkinson disease (PD) patients in a dedicated Palliative Care Clinic. METHODS: A modified Edmonton Symptom Assessment System Scale for PD (ESAS-PD) was developed and applied to 65 PD patients at their initial consultation and following recommended interventions. Scores were compared to those of metastatic cancer patients reported in the palliative care literature. RESULTS: The ESAS-PD scores significantly improved after the interventions (56 and 40 respectively, p = 0.0001). The most improved items were constipation, dysphagia, anxiety, pain and drowsiness. ESAS-PD scores were not significantly different from metastatic cancer patients' ESAS scores. CONCLUSIONS: ESAS-PD is a quick, effective scale for assessment of late stage PD symptoms. Scores are sensitive to intervention, and therefore have potential clinical utility for physicians and other healthcare providers. Advanced PD patients have a similar degree of symptoms as metastatic cancer patients, respond to treatment in a similar way, and therefore should have access to palliative care services.

Associated movement disorders in orthostatic tremor.

INTRODUCTION: Orthostatic tremor is a rare tremor syndrome triggered exclusively by standing, with pathognomonic neurophysiological features. More recently, it has been suggested that orthostatic tremor can present either in isolation (pure orthostatic tremor) or associated with other movement disorders (orthostatic tremor-plus). The present study aims at expanding the knowledge concerning orthostatic tremor associated with other movement disorders. METHODS: A retrospective case review of the clinical and neurophysiological data of patients diagnosed with orthostatic tremor. RESULTS: Median age of onset was 61 years with a median diagnostic delay of 4.5 years. Orthostatic tremor-plus accounted for eight cases (30.8%). The associated movement disorders were Parkinson's disease (n=1), parkinsonism (n=1), progressive supranuclear palsy (n=1), restless leg syndrome (n=1), multifocal action tremor (n=2), pathological proven dementia with Lewy bodies (n=1) and focal dystonia of the arm (n=1). There were no significant differences between primary orthostatic tremor and orthostatic tremor-plus in demographics, clinical presentation of orthostatic tremor, findings in neurophysiological studies and response to treatment. In the majority of cases (n=18, 72%), there was a progressive and disabling course with refractoriness to medical therapy without significant differences between pure orthostatic tremor and orthostatic tremor-plus. CONCLUSION: One of the largest series on orthostatic tremor is presented and the second only focused on additional movement disorders. A progressive course was found, with increasing disability associated with orthostatic tremor. Dementia with Lewy bodies and task specific arm dystonia are reported for the first time as associated movement disorders.

How does parkinsonism start? Prodromal parkinsonism motor changes in idiopathic REM sleep behaviour disorder.

Parkinsonism, as a gradually progressive disorder, has a prodromal interval during which neurodegeneration has begun but cardinal manifestations have not fully developed. A systematic direct assessment of this interval has never been performed. Since patients with idiopathic REM sleep behaviour disorder are at very high risk of parkinsonism, they provide a unique opportunity to observe directly the development of parkinsonism. Patients with idiopathic REM sleep behaviour disorder in an ongoing cohort study were evaluated annually with several quantitative motor measures, including the Unified Parkinson's Disease Rating Scale, Purdue Pegboard, alternate-tap test and timed up-and-go. Patients who developed parkinsonism were identified from this cohort and matched according to age to normal controls. Their results on motor testing from the preceding years were plotted, and then assessed with regression analysis, to determine when markers first deviated from normal values. Sensitivity and specificity of quantitative motor markers for diagnosing prodromal parkinsonism were assessed. Of 78 patients, 20 developed parkinsonism. On regression analysis, the Unified Parkinson's Disease Rating Scale first intersected normal values at an estimated 4.5 years before diagnosis. Voice and face akinesia intersected earliest (estimated prodromal interval = 9.8 years), followed by rigidity (4.4 years), gait abnormalities (4.4 years) and limb bradykinesia (4.2 years). Quantitative motor tests intersected normal values at longer prodromal intervals than subjective examination (Purdue Pegboard = 8.6 years, alternate-tap = 8.2, timed up-and-go = 6.3). Using Purdue Pegboard and the alternate-tap test, parkinsonism could be detected with 71-82% sensitivity and specificity 3 years before diagnosis, whereas a Unified Parkinson's Disease Rating Scale score >4 identified prodromal parkinsonism with 88% sensitivity and 94% specificity 2 years before diagnosis. Removal of action tremor scores improved sensitivity to 94% and specificity to 97% at 2 years before diagnosis (cut-off >3). Although distinction between conditions was often difficult, prodromal dementia with Lewy bodies appeared to have a slower progression than Parkinson's disease (prodromal interval = 6.0 versus 3.8 years). Using a cut-off of Unified Parkinson's Disease Rating Scale >3 (excluding action tremor), 25% of patients with 'still-idiopathic' REM sleep behaviour disorder demonstrated evidence of possible prodromal parkinsonism. Therefore, using direct assessment of motor examination before parkinsonism in a REM sleep behaviour disorder, we have estimated a prodromal interval of ∼4.5 years on the Unified Parkinson's Disease Rating Scale; other quantitative markers may detect parkinsonism earlier. Simple quantitative motor measures may be capable of reliably detecting parkinsonism, even before a clinical diagnosis can be made by experienced movement disorders neurologists.

Pardoprunox as adjunct therapy to levodopa in patients with Parkinson's disease experiencing motor fluctuations: results of a double-blind, randomized, placebo-controlled, trial.

AIMS: To determine the efficacy and safety of pardoprunox in levodopa-treated patients with Parkinson's disease (PD) experiencing motor fluctuations. METHODS: Patients were randomized to pardoprunox (up to 42 mg/day, n = 150) or placebo (n = 144). Pardoprunox was titrated to an optimal dose over 7 weeks, followed by a 12-week stable dose period. The primary efficacy variable was the change from baseline to study endpoint in total daily OFF time, based on patient diaries. Secondary analyses included the change in ON time without troublesome dyskinesias, UPDRS-ADL + Motor ON, UPDRS-ADL OFF and PDQ-39. Subgroup analyses explored the impact of pardoprunox on dyskinesias (UPDRS items 32 + 33), depression (Hospital Anxiety Depression Scale) and pain (Visual Analogue Scale). RESULTS: Pardoprunox significantly reduced OFF time versus placebo (-1.62 h/day versus -0.92 h/day, respectively, p = 0.0215). Compared to placebo, pardoprunox improved ON time without troublesome dyskinesias (p = 0.0386), UPDRS-ADL + Motor ON (p = 0.0003), and UPDRS-ADL OFF (p < 0.0001), while no significant difference was observed on PDQ-39. A high drop-out rate due to adverse events (AEs) (pardoprunox, 37%; placebo, 12%) suggested that the selected dose range may have been too high, and/or titration was too rapid. CONCLUSIONS: Pardoprunox decreased OFF time and increased ON time without troublesome dyskinesias in levodopa-treated PD patients. The high drop-out rate at the selected doses justifies the investigation of lower doses. The impact of pardoprunox on dyskinesias and non-motor symptoms deserves further investigation.

Phenotype in parkinsonian and nonparkinsonian LRRK2 G2019S mutation carriers.

OBJECTIVES: Using a family study design, we describe the motor and nonmotor phenotype in probands with LRRK2 G2019S mutations and family members and compare these individuals to patients with idiopathic Parkinson disease (iPD) and unrelated controls. METHODS: Probands with G2019S mutations and their first-degree relatives, subjects with iPD, and unrelated control subjects were identified from 4 movement disorders centers. All underwent neurologic examinations and tests of olfaction, color vision, anxiety, and depression inventories. RESULTS: Tremor was more often a presenting feature among 25 individuals with LRRK2-associated PD than among 84 individuals with iPD. Subjects with LRRK2-PD had better olfactory identification compared with subjects with iPD, higher Beck Depression Inventory scores, and higher error scores on Farnsworth-Munsell 100-Hue test of color discrimination. Postural or action tremor was more common among 29 nonmanifesting mutation carriers compared with 53 noncarriers within the families. Nonparkinsonian family members had higher Unified Parkinson's Disease Rating Scale motor scores, more constipation, and worse color discrimination than controls, regardless of mutation status. CONCLUSIONS: Although tremor is a more common presenting feature of LRRK2-PD than iPD and some nonmotor features differed in degree, the phenotype is largely overlapping. Postural or action tremor may represent an early sign. Longitudinal evaluation of a large sample of nonmanifesting carriers will be required to describe any premotor phenotype that may allow early diagnosis.

Clinical vignettes in Parkinson's disease: a collection of unusual medication-induced hallucinations, delusions, and compulsive behaviours.

Hallucinations, delusions, and compulsive behaviors are frequent iatrogenic complications of the treatment of motor dysfunction in Parkinson's disease (PD). Although these have been studied, and the phenomenology described, there are few detailed descriptions of the various psychiatric problems our treated PD patients live with that allow physicians who do not have a great deal of experience with PD patients to appreciate the extent of their altered lives. This report is a compilation of vignettes describing these behavioral problems that the treating neurologist or psychiatrist attributed to the medications used for treating PD.

Drug-induced deactivation of inhibitory networks predicts pathological gambling in PD.

OBJECTIVE: Some patients with Parkinson disease (PD) develop pathological gambling when treated with dopamine agonists (DAs). However, little is known about DA-induced changes in neuronal networks that may underpin this drug-induced change in behavior in vulnerable individuals. In this case-control study, we aimed to investigate DA-induced changes in brain activity that may differentiate patients with PD with DA-induced pathological gambling (gamblers) from patients with PD without such a history (controls). METHODS: Following overnight withdrawal of antiparkinsonian medication, patients were studied with H2(15)O PET before and after administration of DA (3 mg apomorphine) to measure changes in regional cerebral blood flow as an index of regional brain activity during a card selection game with probabilistic feedback. RESULTS: We observed that the direction of DA-related activity change in brain areas that are implicated in impulse control and response inhibition (lateral orbitofrontal cortex, rostral cingulate zone, amygdala, external pallidum) distinguished gamblers from controls. DA significantly increased activity in these areas in controls, while gamblers showed a significant DA-induced reduction of activity. CONCLUSIONS: We propose that in vulnerable patients with PD, DAs produce an abnormal neuronal pattern that resembles those found in nonparkinsonian pathological gambling and drug addiction. DA-induced disruption of inhibitory key functions--outcome monitoring (rostral cingulate zone), acquisition and retention of negative action-outcome associations (amygdala and lateral orbitofrontal cortex)--together with restricted access of those areas to executive control (external pallidum)--may well explain loss of impulse control and response inhibition in vulnerable patients with PD, thereby fostering the development of pathological gambling.