BK Channelopathies and KCNMA1-Linked Disease Models.

Novel KCNMA1 variants, encoding the BK K+ channel, are associated with a debilitating dyskinesia and epilepsy syndrome. Neurodevelopmental delay, cognitive disability, and brain and structural malformations are also diagnosed at lower incidence. More than half of affected individuals present with a rare negative episodic motor disorder, paroxysmal nonkinesigenic dyskinesia (PNKD3). The mechanistic relationship of PNKD3 to epilepsy and the broader spectrum of KCNMA1-associated symptomology is unknown. This review summarizes patient-associated KCNMA1 variants within the BK channel structure, functional classifications, genotype-phenotype associations, disease models, and treatment. Patient and transgenic animal data suggest delineation of gain-of-function (GOF) and loss-of-function KCNMA1 neurogenetic disease, validating two heterozygous alleles encoding GOF BK channels (D434G and N999S) as causing seizure and PNKD3. This discovery led to a variant-defined therapeutic approach for PNKD3, providing initial insight into the neurological basis. A comprehensive clinical definition of monogenic KCNMA1-linked disease and the neuronal mechanisms currently remain priorities for continued investigation.

Sodium nitroprusside enhances stepping test performance and increases medium spiny neurons responsiveness to cortical inputs in a rat model of Levodopa-induced dyskinesias.

Levodopa (L-DOPA) is the classical gold standard treatment for Parkinson's disease. However, its chronic administration can lead to the development of L-DOPA-induced dyskinesias (LIDs). Dysregulation of the nitric oxide-cyclic guanosine monophosphate pathway in striatal networks has been linked to deficits in corticostriatal transmission in LIDs. This study investigated the effects of the nitric oxide (NO) donor sodium nitroprusside (SNP) on behavioural and electrophysiological outcomes in sham-operated and 6-hydroxydopamine-lesioned rats chronically treated with vehicle or L-DOPA, respectively. In sham-operated animals, systemic administration of SNP increased the spike probability of putative striatal medium spiny neurons (MSNs) in response to electrical stimulation of the primary motor cortex. In 6-hydroxydopamine-lesioned animals, SNP improved the stepping test performance without exacerbating abnormal involuntary movements. Additionally, SNP significantly increased the responsiveness of putative striatal MSNs in the dyskinetic striatum. These findings highlight the critical role of the NO signalling pathway in facilitating the responsiveness of striatal MSNs in both the intact and dyskinetic striata. The study suggests that SNP has the potential to enhance L-DOPA's effects in the stepping test without exacerbating abnormal involuntary movements, thereby offering new possibilities for optimizing Parkinson's disease therapy. In conclusion, this study highlights the involvement of the NO signalling pathway in the pathophysiology of LIDs.

Ethics of deep brain stimulation for neuropsychiatric disorders.

Deep Brain Stimulation (DBS) has emerged as a revolutionary neurosurgical technique with significant implications for the treatment of various neuropsychiatric disorders. Initially developed for movement disorders like Parkinson's disease, DBS has expanded to psychiatric conditions such as obsessive-compulsive disorder, depression, anorexia nervosa, dystonia, essential tremor, and Tourette's syndrome. This paper explores the clinical efficacy and ethical considerations of DBS in treating these disorders. While DBS has shown substantial promise in alleviating symptoms and improving quality of life, it raises ethical challenges, including issues of informed consent, patient selection, long-term management, and equitable access to treatment. The irreversible nature of DBS, potential adverse effects, and the high cost of the procedure necessitate a rigorous ethical framework to guide its application. The ongoing evolution of neuromodulation requires continuous ethical analysis and the development of guidelines to ensure that DBS is used responsibly and equitably across different patient populations. This paper underscores the need for a balanced approach that integrates clinical efficacy with ethical considerations to optimize patient outcomes and ensure sustainable practice.

[Neurodevelopmental impact of a mutation in the RHOBTB2 gene]. / Impact neurodéveloppemental d'une mutation sur le gène RHOBTB2.

RHOBTB2 was first described as epileptogenic when it presents a missense variant in 2016 and studied more specifically in 2018. It is a gene that causes rare, but potentially severe childhood epileptic encephalopathy. In 2021, research confirmed that heterozygous mutations of RHOBTB2 included other clinical signs besides these encephalopathies. Thus, these infantile epilepsies are mainly associated with highly variable phenotypes, with developmental delay, post-traumatic encephalitis, paroxysmal movement disorders and iconographic brain damage. In this work, after presenting a clinical case, we will recall the role of RhoGTPases on neuronal development. We will then discuss a study which highlighted the neurodevelopmental impact of mutations on the RHOBTB2 gene by carrying out work on Drosophila melanogaster flies. Finally, we will compare the presented clinical case with a literature review.

Le gène RHOBTB2 est décrit pour la première fois comme épileptogène alors qu'il présente un variant faux-sens en 2016, puis est étudié plus précisément en 2018. Il s'agit d'un gène qui est à l'origine d'encéphalopathies épileptiques infantiles rares, mais pouvant être sévères. En 2021, des recherches ont confirmé que les mutations hétérozygotes de RHOBTB2 englobaient d'autres signes cliniques que ces encéphalopathies. Ainsi, ces épilepsies infantiles sont associées, principalement, avec des phénotypes fortement variables, à un retard développemental, à des encéphalites post-traumatiques, à des troubles paroxystiques des mouvements et à des atteintes iconographiques de l'encéphale. Dans ce travail, après avoir présenté un cas clinique, nous rappellerons le rôle des RhoGTPases sur le développement neuronal. Nous discuterons ensuite d'une étude qui a mis en évidence l'impact neurodéveloppemental de mutations sur le gène RHOBTB2 en réalisant des travaux sur des mouches Drosophila melanogaster. Pour terminer, nous mettrons le cas clinique présenté en parallèle avec une revue de la littérature réalisée par rapport à ce gène.

The Role of Striatal Cav1.3 Calcium Channels in Therapeutics for Parkinson's Disease.

Parkinson's disease (PD) is a relentlessly progressive neurodegenerative disorder with typical motor symptoms that include rigidity, tremor, and akinesia/bradykinesia, in addition to a host of non-motor symptoms. Motor symptoms are caused by progressive and selective degeneration of dopamine (DA) neurons in the SN pars compacta (SNpc) and the accompanying loss of striatal DA innervation from these neurons. With the exception of monogenic forms of PD, the etiology of idiopathic PD remains unknown. While there are a number of symptomatic treatment options available to individuals with PD, these therapies do not work uniformly well in all patients, and eventually most are plagued with waning efficacy and significant side-effect liability with disease progression. The incidence of PD increases with aging, and as such the expected burden of this disease will continue to escalate as our aging population increases (Dorsey et al. Neurology 68:384-386, 2007). The daunting personal and socioeconomic burden has pressed scientists and clinicians to find improved symptomatic treatment options devoid side-effect liability and meaningful disease-modifying therapies. Federal and private sources have supported clinical investigations over the past two-plus decades; however, no trial has yet been successful in finding an effective therapy to slow progression of PD, and there is currently just one FDA approved drug to treat the antiparkinsonian side-effect known as levodopa-induced dyskinesia (LID) that impacts approximately 90% of all individuals with PD. In this review, we present biological rationale and experimental evidence on the potential therapeutic role of the L-type voltage-gated Cav1.3 calcium (Ca2+) channels in two distinct brain regions, with two distinct mechanisms of action, in impacting the lives of individuals with PD. Our primary emphasis will be on the role of Cav1.3 channels in the striatum and the compelling evidence of their involvement in LID side-effect liability. We also briefly discuss the role of these same Ca2+ channels in the SNpc and the longstanding interest in Cav1.3 in this brain region in halting or delaying progression of PD.

Spontaneous Graft-Induced Dyskinesias Are Independent of 5-HT Neurons and Levodopa Priming in a Model of Parkinson's Disease.

BACKGROUND: The risk of graft-induced dyskinesias (GIDs) presents a major challenge in progressing cell transplantation as a therapy for Parkinson's disease. Current theories implicate the presence of grafted serotonin neurons, hotspots of dopamine release, neuroinflammation and established levodopa-induced dyskinesia. OBJECTIVE: To elucidate the mechanisms of GIDs. METHODS: Neonatally desensitized, dopamine denervated rats received intrastriatal grafts of human embryonic stem cells (hESCs) differentiated into either ventral midbrain dopaminergic progenitor (vmDA) (n = 15) or ventral forebrain cells (n = 14). RESULTS: Of the eight rats with surviving grafts, two vmDA rats developed chronic spontaneous GIDs, which were observed at 30 weeks post-transplantation. GIDs were inhibited by D2 -like receptor antagonists and not affected by 5-HT1A/1B/5-HT6 agonists/antagonists. Grafts in GID rats showed more microglial activation and lacked serotonin neurons. CONCLUSIONS: These findings argue against current thinking that rats do not develop spontaneous GID and that serotonin neurons are causative, rather indicating that GID can be induced in rats by hESC-derived dopamine grafts and, critically, can occur independently of both previous levodopa exposure and grafted serotonin neurons. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Adaptive changes in striatal projection neurons explain the long duration response and the emergence of dyskinesias in patients with Parkinson's disease.

Neuronal activity in the brain is tightly regulated. During operation in real time, for instance, feedback and feedforward loops limit excessive excitation. In addition, cell autonomous processes ensure that neurons' average activity is restored to a setpoint in response to chronic perturbations. These processes are summarized as homeostatic plasticity (Turrigiano in Cold Spring Harb Perspect Biol 4:a005736-a005736, 2012). In the basal ganglia, information is mainly transmitted through disinhibition, which already constraints the possible range of neuronal activity. When this tightly adjusted system is challenged by the chronic decline in dopaminergic neurotransmission in Parkinson's disease (PD), homeostatic plasticity aims to compensate for this perturbation. We here summarize recent experimental work from animals demonstrating that striatal projection neurons adapt excitability and morphology in response to chronic dopamine depletion and substitution. We relate these cellular processes to clinical observations in patients with PD that cannot be explained by the classical model of basal ganglia function. These include the long duration response to dopaminergic medication that takes weeks to develop and days to wear off. Moreover, dyskinesias are considered signs of excessive dopaminergic neurotransmission in Parkinson's disease, but they are typically more severe on the body side that is more strongly affected by dopamine depletion. We hypothesize that these clinical observations can be explained by homeostatic plasticity in the basal ganglia, suggesting that plastic changes in response to chronic dopamine depletion and substitution need to be incorporated into models of basal ganglia function. In addition, better understanding the molecular mechanism of homeostatic plasticity might offer new treatment options to avoid motor complications in patients with PD.

Continuous dopaminergic stimulation counteracts L-DOPA-induced overactivity of Ca2+ in 6-OHDA-lesioned rats.

In the clinical treatment of Parkinson's disease (PD), the emergence of L-DOPA-induced dyskinesia (LID) and other motor symptoms remains a restrictive factor for the use of levodopa (L-DOPA). Our objective was to test the effect of continuous dopaminergic stimulation (CDS) on LID and the mechanism of its effect on the calcium (Ca2+) signaling pathway. 6-OHDA (6-hydroxydopamine)-treated rats were administered 1% CMC-Na, L-DOPA, rotigotine behenate (RGTB), and L-DOPA + RGTB, respectively, for 28 days. During the treatment, the abnormal involuntary movement (AIM) scores were conducted on days 1, 5, 10, 14, 19, 23 and 28 after the first dose. Subsequently, the number of tyrosine hydroxylase (TH)-positive neurons was detected by immunohistochemistry. Additionally, the changes in Ca2+ were detected using a laser confocal technique, and the related proteins, such as neuronal NOS (nNOS), BAX, BCL2, CaMKII, P-CaMKII, and PSD-95, were measured by Western blot. Transmission electron microscopy (TEM) was used to investigate the changes in synaptic structure. The data showed that CDS reduced the AIM scores, increased the expression of TH in the substantia nigra (SN), decreased the expression of nNOS and BAX/BCL2ratio in the striatum, reduced the Ca2+ influx induced by L-DOPA and inhibited the Ca2+ signaling pathways of dopamine neurons in the striatum. Moreover, the overactivity of synapses induced by L-DOPA was inhibited by CDS. These data further support the hypothesis that continuous delivery of a dopamine agonist reduces the risk of LID induction. Moreover, RGTB could be a promising treatment for PD by simulating CDS.

Deep Brain Stimulation of the Pallidofugal Pathways to Rescue Severe Life-Threatening Dyskinesias after STN-DBS Lead Implantation.

We present a patient with severe life-threatening dyskinesias due to a persistent microlesion effect after STN-DBS electrode implantation. The pallidofugal pathways were identified using patient-specific tractography, and steering the current toward this white matter structure resulted in complete resolution of the severe dyskinesias.

Subthalamic nucleus deep brain stimulation programming settings do not correlate with Parkinson's disease severity.

BACKGROUND: Deep brain stimulation (DBS) is a well-established treatment for Parkinson's disease (PD). While the success of DBS is dependent on careful patient selection and accurate lead placement, programming parameters play a pivotal role in tailoring therapy on the individual level. Various algorithms have been developed to streamline the initial programming process, but the relationship between pre-operative patient characteristics and post-operative device settings is unclear. In this study, we investigated how PD severity correlates with DBS settings. METHODS: We conducted a retrospective review of PD patients who underwent DBS of the subthalamic nucleus at one US tertiary care center between 2014 and 2018. Pre-operative patient characteristics and post-operative programming data at various intervals were collected. Disease severity was measured using the Unified Parkinson's Disease Rating Scale score (UPDRS) as well as levodopa equivalent dose (LED). Correlation analyses were conducted looking for associations between pre-operative disease severity and post-operative programming parameters. RESULTS: Fifty-six patients were analyzed. There was no correlation between disease severity and any of the corresponding programming parameters. Pre-operative UPDRS scores on medication were similar to post-operative scores with DBS. Settings of amplitude, frequency, and pulse width increased significantly from 1 to 6 months post-operatively. Stimulation volume, inferred by the distance between contacts used, also increased significantly over time. CONCLUSIONS: Interestingly, we found that patients with more advanced disease responded to electrical stimulation similarly to patients with less advanced disease. These data provide foundational knowledge of DBS programming parameters used in a single cohort of PD patients over time.

Tremor as a symptom of degenerative cervical myelopathy: a systematic review.

BACKGROUND: AO Spine RECODE-DCM (Research objectives and common data elements for degenerative cervical myelopathy) has highlighted that the subjective disability reported by people living with DCM is much broader than routinely considered today by most professionals. This includes a description of tremor. The objective of this review was to study the incidence and possible aetiology of tremor in degenerative cervical myelopathy (DCM). METHODS: A systematic review registered in PROSPERO (CRD42020176905) was conducted in Embase and MEDLINE for papers studying tremor and DCM published on or before the 20th of July 2020. All manuscripts describing an association between tremor and DCM in humans were included. Articles relating to non-human animals, and those not available in English were excluded. An analysis was conducted in accordance with PRISMA and SWiM guidelines for systematic reviews. RESULTS: Out of a total of 4402 screened abstracts, we identified 7 case reports and series describing tremor in 9 DCM patients. Papers were divided into three groups for the discussion. The first group includes DCM correctly identified on presentation, with tremor as a described symptom. The second group includes cases where DCM was misdiagnosed, often as Parkinson's disease. The third group includes a single case with a previous history of DCM, presenting with an otherwise unexplained tremor. This grouping allows for the clustering of cases supporting various arguments for the association between tremor and DCM. CONCLUSION: DCM can be associated with tremor. The current evidence is restricted to case series. Further study is warranted to establish tremor prevalence, and its significance to assessment and management.

Shedding light on dyskinesias.

Dopamine replacement therapy with L-DOPA remains the most widely prescribed treatment for Parkinson disease. However, prolonged treatment due to disease progression frequently causes unwanted motor movements known as levodopa-induced dyskinesias. Previous studies have established that alterations to the efferent circuitry of the striatum, a principal component of the basal ganglia, are in part responsible for the pathological motor consequences of prolonged levodopa treatment. While the role of the striatal direct pathway is widely accepted, the engagement of the striatal indirect pathway in dyskinetic pathophysiology is still under consideration. However, recent investigations have finally shown that the activity of both striatal pathways changes as a consequence of dopamine depletion and dyskinetic behavioural conditions. In addition, it has been reported that drug-induced structural alterations to indirect pathway medium spiny neurons, together with associated changes in synaptic plasticity and firing patterns, could contribute importantly to the development of dyskinesia. These findings, together with recent opto- and chemogenetic studies, suggest that a critical imbalance in the activity between both striatal pathways is sufficient to cause dyskinesia in both rodent and primate models of Parkinson disease. In animal models, and in human patients, dyskinetic behaviours elicited by this efferent pathway imbalance can be achieved even in the absence of dopamine denervation. In this review, we summarize recent and past findings to better understand this complex pathology with the aim of pursuing specific cell-type therapies to re-balance efferent striatal activity.

Differences in the Presentation and Progression of Parkinson's Disease by Sex.

BACKGROUND: Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. OBJECTIVES: We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data. METHODS: We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD. RESULTS: Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort. CONCLUSIONS: We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management. © 2020 International Parkinson and Movement Disorder Society.

Hyperkinetic manifestations in superficial siderosis: evidence for pathogenic network disruption.

Superficial siderosis (SS) of central nervous system is a rare condition characterized by hemosiderin deposition diffusely involving supratentorial and infratentorial compartments. SS usually manifests with ataxia and sensorineural hearing loss. Basal ganglia are almost always spared by the degenerative process, and movement disorders are only rarely reported. We describe the case of an aged woman with apparently idiopathic SS presenting with cerebellar ataxia, hearing loss, and orofacial dyskinesias. Together with some previously reported patients affected by SS and presenting with dystonic manifestations, our case reinforces the current hypothesis supporting a wide network disruption, rather than a direct basal ganglia damage, as the likely underlying cause of some dystonic syndromes.

Motor complications in Parkinson's disease: 13-year follow-up of the CamPaIGN cohort.

BACKGROUND: Long-term population-representative data on motor fluctuations and levodopa-induced dyskinesias in Parkinson's disease is lacking. METHODS: The Cambridgeshire Parkinson's Incidence from GP to Neurologist (CamPaIGN) cohort comprises incident PD cases followed for up to 13 years (n = 141). Cumulative incidence of motor fluctuations and levodopa-induced dyskinesias and risk factors were assessed using Kaplan-Meyer and Cox regression analyses. RESULTS: Cumulative incidence of motor fluctuations and levodopa-induced dyskinesias was 54.3% and 14.5%, respectively, at 5 years and 100% and 55.7%, respectively, at 10 years. Higher baseline UPDRS-total and SNCA rs356219(A) predicted motor fluctuations, whereas higher baseline Mini-mental State Examination and GBA mutations predicted levodopa-induced dyskinesias. Early levodopa use did not predict motor complications. Both early motor fluctuations and levodopa-induced dyskinesias predicted reduced mortality in older patients (age at diagnosis >70 years). CONCLUSIONS: Our data support the hypothesis that motor complications are related to the severity of nigrostriatal pathology rather than early levodopa use and indicate that early motor complications do not necessarily confer a negative prognosis. © 2019 International Parkinson and Movement Disorder Society.

Endocannabinoid levels in patients with Parkinson's disease with and without levodopa-induced dyskinesias.

Levodopa-induced dyskinesias (LID) in Parkinson's disease (PD) are frequent complications, and the endocannabinoid system has a role on its pathophysiology. To test the hypothesis that the functioning of the endocannabinoid system would be altered in PD and in LID by measuring plasma and CSF levels of α-N-arachidonoylethanolamine (AEA) and 2-arachidonoyl-glycerol (2-AG) in patients with PD with and without LID and in healthy controls. Blood and CSF samples were collected from 20 healthy controls, 23 patients with PD without LID, and 24 patients with PD with LID. The levels of AEA and 2-AG were measured using a highly sensitive column switching ultrahigh-performance liquid chromatography-tandem mass spectrometry method. When pooled together, patients with PD had lower plasma and CSF levels of 2-AG and higher CSF levels of AEA compared to healthy controls (Mann-Whitney statistics = 303.0, p = 0.02). Patients with PD without LID had lower CSF levels of 2-AG (Kruskal-Wallis statistics = 7.76, p = 0.02) and higher CSF levels of AEA levels than healthy controls (Kruskal-Wallis statistics = 8.81, p = 0.01). The findings suggest that the endocannabinoid system participates in the pathophysiology of PD symptoms, but its role in the pathophysiology of LID is still unclear.

Association Among Dyskinesia of the Lumbar Spine Segment, Inclination Angle of the Lumbosacral Spine, and Low Back Pain in Young Athletes: A Predictive Correlational Study.

OBJECTIVE: This predictive correlational study aimed to investigate the association among low back pain (LBP), dyskinesia of the lumbosacral spine segment (determined by inertial sensors), and inclination angles: the inclination angle of the lumbosacral spine (alpha), the inclination angle of the thoracolumbar spine (beta), and the inclination angle of the upper thoracic section (gamma). Our hypothesis was that young athletes with LBP had a particular dyskinesia: nonphysiological movements of the lumbosacral segment of the spine. METHODS: The study group consisted of 108 young athletes aged 10 to 16 years (male/female 44%/56%; 12.3 ± 1.8 years; 160.1 ± 12.0 cm; 51.1 ± 13.8 kg; 4.3 ± 2.4 training years; 3.7 ± 2.1 training h/wk). The alpha, beta, and gamma angles were measured with a digital inclinometer. The position of the lumbosacral segment at the maximum extension was determined with the inertial sensors, positioned at the 11th thoracic vertebra (T11), the third lumbar spine vertebra (L3), and the second sacral spine vertebra (S2). The data were analyzed using Student's t tests, tetrachoric correlation coefficients, and logistic regression. RESULTS: There was a significant statistical difference in alpha angles (t = 9.4, P < .001) and lumbar positions in extension (t = 6.4, P < .001) between groups with LBP and without LBP. The logistic regression indicated that LBP in young athletes was significantly associated with the increased alpha angle and nonphysiological lumbar position in extension measured by a sensor at the third lumbar spine vertebra. CONCLUSION: There was a strong association among LBP, increased inclination angle of the lumbosacral spine, and dyskinesia of the lumbar spine segment in young athletes.

[A REVIEW ABOUT SPONTANEOUS MOVEMENTS DISORDERS IN SCHIZOPHRENIA]. / Una revisión sobre los Trastornos Espontáneos del Movimiento (TEM) en la esquizofrenia.

Spontaneous movements disorders are frequently observed in schizophrenia. Together with the negative and cognitive symptoms, they comprise manifestations more linked to the damage of this complex condition, although they are insufficient to make the diagnosis. When the psychotic symptoms express these phenomena, they have probably been causing deleterious effects for years. Within these intrinsic components, motor disorders are the most delayed, paradoxically, as a consequence of the progress of phar-macotherapy. Treatment with antipsychotics modified the clinical symptoms of schizophrenia by developing improvements in positive symptoms, disorganization and agitation, but also produced a change of another order, with the side effects that, many times, had difficulty in being distinguished from the pathology itself. Above all, the specific neuroleptics share to a greater or lesser extent of the production of extrapyramidal symptoms, classically expressed in motor alterations. Therefore, these abnormal movements are often mistakenly associated with antipsychotic medication in an exclusive manner, overshadowing primary motor manifestations.The objective of this work is to highlight the characteristics, importance and relationship with the conventional therapy of spon-taneous movements disorders in schizophrenia.

Subthalamic nucleus deep brain stimulation improves dyskinesias in Parkinson's disease beyond levodopa reduction.

Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves motor fluctuations and dyskinesias in patients with Parkinson's disease (PD). Dyskinesia improvement with STN DBS is believed to result entirely from levodopa reduction. However, some studies suggest that STN DBS may also directly suppress dyskinesias. To determine whether bilateral STN DBS improves dyskinesias beyond what would be expected from levodopa reduction alone, we analyzed pre-operative and post-operative dyskinesia scores (sum of MDS-UPDRS items 4.1 and 4.2) from 61 PD patients with bilateral STN DBS. A multiple regression model (adjusted for disease severity, disease duration, active contacts above the STN, use of amantadine, high pre-operative levodopa-equivalent dose (LED), sex, and interaction between active contacts above the STN and amantadine use) was created to describe the relationship between dyskinesia scores and LED prior to DBS. Using this model, a post-operative dyskinesia score was estimated from post-operative LED and compared to the actual post-operative dyskinesia score. The regression model was statistically significant overall (p = 0.003, R2 = 0.34, adjusted R2 = 0.24). The actual post-operative dyskinesia score (1.0 ± 1.4) was significantly lower than the score predicted by the model (3.0 ± 1.1, p < 0.0001). Dyskinesias after STN DBS improved more than predicted by levodopa reduction alone. Our data support the idea that STN stimulation may directly improve dyskinesias.

Oropharyngeal Dysphagia in Adults With Dyskinetic Cerebral Palsy and Cervical Dystonia: A Preliminary Study.

OBJECTIVES: To investigate the characteristics of oropharyngeal dysphagia in adults with dyskinetic cerebral palsy (DCP) and cervical dystonia (CD). DESIGN: Exploratory observational cross-sectional study. SETTING: University hospital. PARTICIPANTS: Seventeen patients with DCP (8 men, 9 women; age, 45.7±6.3y) enrolled in a randomized controlled trial on the effects of botulinum toxin injection on CD. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Baseline clinical assessments and videofluoroscopic swallowing studies (VFSSs) were conducted. VFSS findings were evaluated using the videofluoroscopic dysphagia scale (VDS) and the penetration-aspiration scale (PAS). The Gross Motor Function Classification System (GMFCS) and Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) scores were also assessed. Relationships between outcomes were evaluated using Spearman's rank correlation. RESULTS: The clinical assessment revealed abnormalities in chewing (n=10, 58.8%), tongue movement (n=10, 58.8%), and laryngeal elevation (n=8, 47.1%). The most common abnormality on the VDS was inadequate mastication (n=13, 76.5%), followed by premature bolus loss, vallecular residue, and penetration/aspiration (all: n=10, 58.8%). A maximum PAS score of 8 was observed in 8 of 17 patients (47.1%). Total and pharyngeal VDS scores were significantly correlated with TWSTRS scores (ρ=0.543, P=.024 and ρ=0.539, P=.026, respectively); the VDS oral score did not correlate with the TWSTRS score (ρ=0.446, P=.073). There was no significant correlation between VDS score and GMFCS level (ρ=0.212, P=.414). CONCLUSIONS: This preliminary observational study presents the characteristics of oropharyngeal dysphagia in adults with DCP and CD. Pharyngeal stage difficulties were negatively correlated with severity of CD, but not with GMFCS level. Screening for dysphagia may be recommended in adults with DCP and severe CD.