Levodopa‐induced dyskinesia is a common complication in Parkinson disease. Pathogenic mechanisms include phasic stimulation of dopamine receptors, nonphysiological levodopa‐to‐dopamine conversion in ...serotonergic neurons, hyperactivity of corticostriatal glutamatergic transmission, and overstimulation of nicotinic acetylcholine receptors on dopamine‐releasing axons. Delay in initiating levodopa is no longer recommended, as dyskinesia development is a function of disease duration rather than cumulative levodopa exposure. We review current and in‐development treatments for peak‐dose dyskinesia but suggest that improvements in levodopa delivery alone may reduce its future prevalence. Ann Neurol 2018;84:797–811
Functional neurological disorders (FND) are common sources of disability in medicine. Patients have often been misdiagnosed, correctly diagnosed after lengthy delays, and/or subjected to poorly ...delivered diagnoses that prevent diagnostic understanding and lead to inappropriate treatments, iatrogenic harm, unnecessary and costly evaluations, and poor outcomes.
Functional Neurological Symptom Disorder/Conversion Disorder was adopted by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, replacing the term psychogenic with functional and removing the criterion of psychological stress as a prerequisite for FND. A diagnosis can now be made in an inclusionary manner by identifying neurological signs that are specific to FNDs without reliance on presence or absence of psychological stressors or suggestive historical clues. The new model highlights a wider range of past sensitizing events, such as physical trauma, medical illness, or physiological/psychophysiological events. In this model, strong ideas and expectations about these events correlate with abnormal predictions of sensory data and body-focused attention. Neurobiological abnormalities include hypoactivation of the supplementary motor area and relative disconnection with areas that select or inhibit movements and are associated with a sense of agency. Promising evidence has accumulated for the benefit of specific physical rehabilitation and psychological interventions alone or in combination, but clinical trial evidence remains limited.
Functional neurological disorders are a neglected but potentially reversible source of disability. Further research is needed to determine the dose and duration of various interventions, the value of combination treatments and multidisciplinary therapy, and the therapeutic modality best suited for each patient.
The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated α-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into ...plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation at autopsy reflects pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated α-synuclein in
gene multiplication or aggregated β-amyloid in
mutations), their near universality at postmortem in sporadic PD and AD suggests they may alternatively represent common outcomes from upstream mechanisms or compensatory responses to cellular stress in order to delay cell death. These 3 conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time. Whereas animal models, in which neither PD nor AD occur in natural states, consistently support a pathogenic role of protein aggregation, indirect evidence from human studies does not. We hypothesize that (1) current biomarkers of protein aggregates may be relevant to common pathology but not to subgroup pathogenesis and (2) disease-modifying treatments targeting oligomers or fibrils might be futile or deleterious because these proteins are epiphenomena or protective in the human brain under molecular stress. Future precision medicine efforts for molecular targeting of neurodegenerative diseases may require analyses not anchored on current clinicopathologic criteria but instead on biological signals generated from large deeply phenotyped aging populations or from smaller but well-defined genetic-molecular cohorts.
Animal studies have demonstrated that the pedunculopontine nucleus (PPN) is involved in the control of posture and gait, and that it is also a key structure in controlling basic non-motor functions ...such as sleep, attention and arousal. In this systematic review we aimed to evaluate all available studies assessing the role of PPN on cognition, nocturnal sleep and alertness in humans. Finally, we attempted to define a model in which PPN acts as an interface structure between motor control and behavior.
A systematic search of the computerized databases MEDLINE and PubMed was conducted to identify papers on PPN and cognitive functions, sleep and alertness. Key search terms included: ‘PPN’, ‘arousal’, ‘sleep’, ‘cognition’, ‘memory’, ‘language’, ‘attention’, ‘alertness’, ‘PPN-DBS’, ‘Parkinson's and PPN’, ‘Parkinson's and PPN-DBS’.
Twelve studies met our inclusion criteria and were included. All of them involved PD patients implanted with unilateral or bilateral PPN-DBS, most patients had concomitant DBS of another anatomical structure (subthalamic nucleus or Zona incerta). There is a lack of consistent evidences confirming the effect of PPN-DBS on specific cognitive functions, alertness or sleep in PD. There is heterogeneity between and within surgical centres of study protocols especially regarding DBS targeting, parameters of stimulation and experimental methods. Moreover, the available studies are limited by the small sample size and the short follow-up time. It has been suggested that low frequency stimulation (25 Hz) has a better effect compared to the high frequency one (60–80 Hz) on alertness, however this needs to be confirmed in further studies.
PPN-DBS is a promising but yet an experimental procedure. PD represents an encouraging pathological model for future studies aiming to shade light on the role of PPN in cognition, attention and alertness in humans.
Parkinson's disease (PD) patients have impairment of facial expressivity (hypomimia) and difficulties in interpreting the emotional facial expressions produced by others, especially for aversive ...emotions. We aimed to evaluate the ability to produce facial emotional expressions and to recognize facial emotional expressions produced by others in a group of PD patients and a group of healthy participants in order to explore the relationship between these two abilities and any differences between the two groups of participants.
Twenty non-demented, non-depressed PD patients and twenty healthy participants (HC) matched for demographic characteristics were studied. The ability of recognizing emotional facial expressions was assessed with the Ekman 60-faces test (Emotion recognition task). Participants were video-recorded while posing facial expressions of 6 primary emotions (happiness, sadness, surprise, disgust, fear and anger). The most expressive pictures for each emotion were derived from the videos. Ten healthy raters were asked to look at the pictures displayed on a computer-screen in pseudo-random fashion and to identify the emotional label in a six-forced-choice response format (Emotion expressivity task). Reaction time (RT) and accuracy of responses were recorded. At the end of each trial the participant was asked to rate his/her confidence in his/her perceived accuracy of response.
For emotion recognition, PD reported lower score than HC for Ekman total score (p<0.001), and for single emotions sub-scores happiness, fear, anger, sadness (p<0.01) and surprise (p = 0.02). In the facial emotion expressivity task, PD and HC significantly differed in the total score (p = 0.05) and in the sub-scores for happiness, sadness, anger (all p<0.001). RT and the level of confidence showed significant differences between PD and HC for the same emotions. There was a significant positive correlation between the emotion facial recognition and expressivity in both groups; the correlation was even stronger when ranking emotions from the best recognized to the worst (R = 0.75, p = 0.004).
PD patients showed difficulties in recognizing emotional facial expressions produced by others and in posing facial emotional expressions compared to healthy subjects. The linear correlation between recognition and expression in both experimental groups suggests that the two mechanisms share a common system, which could be deteriorated in patients with PD. These results open new clinical and rehabilitation perspectives.
Despite being introduced in clinical practice more than 20 years ago, selection criteria for deep brain stimulation (DBS) in Parkinson's disease (PD) rely on a document published in 1999 called 'Core ...Assessment Program for Surgical Interventional Therapies in Parkinson's Disease'. These criteria are useful in supporting the selection of candidates. However, they are both restrictive and out-of-date, because the knowledge on PD progression and phenotyping has massively evolved. Advances in understanding the heterogeneity of PD presentation, courses, phenotypes, and genotypes, render a better identification of good DBS outcome predictors a research priority. Additionally, DBS invasiveness, cost, and the possibility of serious adverse events make it mandatory to predict as accurately as possible the clinical outcome when informing the patients about their suitability for surgery. In this viewpoint, we analyzed the pre-surgical assessment according to the following topics: early versus delayed DBS; the evolution of the levodopa challenge test; and the relevance of axial symptoms; patient-centered outcome measures; non-motor symptoms; and genetics. Based on the literature, we encourage rethinking of the selection process for DBS in PD, which should move toward a broad clinical and instrumental assessment of non-motor symptoms, quantitative measurement of gait, posture, and balance, and in-depth genotypic and phenotypic characterization.
Evoked resonant neural activity (ERNA) is induced by subthalamic deep brain stimulation (DBS) and was recently suggested as a marker of lead placement and contact selection in Parkinson's disease. ...Yet, its underlying mechanisms and how it is modulated by stimulation parameters are unclear. Here, we recorded local field potentials from 27 Parkinson's disease patients, while leads were externalised to scrutinise the ERNA. First, we show that ERNA in the time series waveform and spectrogram likely represent the same activity, which was contested before. Second, our results show that the ERNA has fast and slow dynamics during stimulation, consistent with the synaptic failure hypothesis. Third, we show that ERNA parameters are modulated by different DBS frequencies, intensities, medication states and stimulation modes (continuous DBS vs. adaptive DBS). These results suggest the ERNA might prove useful as a predictor of the best DBS frequency and lowest effective intensity in addition to contact selection. Changes with levodopa and DBS mode suggest that the ERNA may indicate the state of the cortico-basal ganglia circuit making it a putative biomarker to track clinical state in adaptive DBS.
•Waveform and spectrogram-based ERNA reflect the same activity.•ERNA has slow and fast dynamics that may be explained by synaptic depletion.•ERNA parameters are modulated by increasing DBS frequencies and intensities.•ERNA parameters change with levodopa and differ during continuous and adaptive DBS.•ERNA may be generated within the STN-GPe loop and may be of clinical relevance.
Treatment Recommendations for Tardive Dyskinesia Ricciardi, Lucia; Pringsheim, Tamara; Barnes, Thomas R.E. ...
Canadian journal of psychiatry,
06/2019, Letnik:
64, Številka:
6
Book Review, Journal Article
Recenzirano
Odprti dostop
Background:
Tardive dyskinesia is a movement disorder characterised by irregular, stereotyped, and choreiform movements associated with the use of antipsychotic medication. We aim to provide ...recommendations on the treatment of tardive dyskinesia.
Methods:
We performed a systematic review of studies of the treatment of tardive dyskinesia. Studies were rated for methodological quality using the American Academy of Neurology Risk of Bias Classification system. Overall level of evidence classifications and grades of recommendation were made using the Scottish Intercollegiate Guidelines Network framework.
Results:
Preventing tardive dyskinesia is of primary importance, and clinicians should follow best practice for prescribing antipsychotic medication, including limiting the prescription for specific indications, using the minimum effective dose, and minimising the duration of therapy. The first-line management of tardive dyskinesia is the withdrawal of antipsychotic medication if clinically feasible. Yet, for many patients with serious mental illness, the discontinuation of antipsychotics is not possible due to disease relapse. Switching from a first-generation to a second-generation antipsychotic with a lower D2 affinity, such as clozapine or quetiapine, may be effective in reducing tardive dyskinesia symptoms. The strongest evidence for a suitable co-intervention to treat tardive dyskinesia comes from tests with the new VMAT inhibitors, deutetrabenazine and valbenazine. These medications have not been approved for use in Canada.
Conclusion:
Data on tardive dyskinesia treatment are limited, and the best management strategy remains prevention. More long-term safety and efficacy data are needed for deutetrabenazine and valbenazine, and their routine availability to patients outside of the USA remains in question.
Gait is a core motor function and is impaired in numerous neurological diseases, including Parkinson's disease (PD). Treatment changes in PD are frequently driven by gait assessments in the clinic, ...commonly rated as part of the Movement Disorder Society (MDS) Unified PD Rating Scale (UPDRS) assessment (item 3.10). We proposed and evaluated a novel approach for estimating severity of gait impairment in Parkinson's disease using a computer vision-based methodology. The system we developed can be used to obtain an estimate for a rating to catch potential errors, or to gain an initial rating in the absence of a trained clinician-for example, during remote home assessments. Videos (n=729) were collected as part of routine MDS-UPDRS gait assessments of Parkinson's patients, and a deep learning library was used to extract body key-point coordinates for each frame. Data were recorded at five clinical sites using commercially available mobile phones or tablets, and had an associated severity rating from a trained clinician. Six features were calculated from time-series signals of the extracted key-points. These features characterized key aspects of the movement including speed (step frequency, estimated using a novel Gamma-Poisson Bayesian model), arm swing, postural control and smoothness (or roughness) of movement. An ordinal random forest classification model (with one class for each of the possible ratings) was trained and evaluated using 10-fold cross validation. Step frequency point estimates from the Bayesian model were highly correlated with manually labelled step frequencies of 606 video clips showing patients walking towards or away from the camera (Pearson's r=0.80, p<0.001). Our classifier achieved a balanced accuracy of 50% (chance = 25%). Estimated UPDRS ratings were within one of the clinicians' ratings in 95% of cases. There was a significant correlation between clinician labels and model estimates (Spearman's ρ=0.52, p<0.001). We show how the interpretability of the feature values could be used by clinicians to support their decision-making and provide insight into the model's objective UPDRS rating estimation. The severity of gait impairment in Parkinson's disease can be estimated using a single patient video, recorded using a consumer mobile device and within standard clinical settings; i.e., videos were recorded in various hospital hallways and offices rather than gait laboratories. This approach can support clinicians during routine assessments by providing an objective rating (or second opinion), and has the potential to be used for remote home assessments, which would allow for more frequent monitoring.
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