Trial of Globus Pallidus Focused Ultrasound Ablation in Parkinson's Disease.

BACKGROUND: Unilateral focused ultrasound ablation of the internal segment of globus pallidus has reduced motor symptoms of Parkinson's disease in open-label studies. METHODS: We randomly assigned, in a 3:1 ratio, patients with Parkinson's disease and dyskinesias or motor fluctuations and motor impairment in the off-medication state to undergo either focused ultrasound ablation opposite the most symptomatic side of the body or a sham procedure. The primary outcome was a response at 3 months, defined as a decrease of at least 3 points from baseline either in the score on the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, part III (MDS-UPDRS III), for the treated side in the off-medication state or in the score on the Unified Dyskinesia Rating Scale (UDysRS) in the on-medication state. Secondary outcomes included changes from baseline to month 3 in the scores on various parts of the MDS-UPDRS. After the 3-month blinded phase, an open-label phase lasted until 12 months. RESULTS: Of 94 patients, 69 were assigned to undergo ultrasound ablation (active treatment) and 25 to undergo the sham procedure (control); 65 patients and 22 patients, respectively, completed the primary-outcome assessment. In the active-treatment group, 45 patients (69%) had a response, as compared with 7 (32%) in the control group (difference, 37 percentage points; 95% confidence interval, 15 to 60; P = 0.003). Of the patients in the active-treatment group who had a response, 19 met the MDS-UPDRS III criterion only, 8 met the UDysRS criterion only, and 18 met both criteria. Results for secondary outcomes were generally in the same direction as those for the primary outcome. Of the 39 patients in the active-treatment group who had had a response at 3 months and who were assessed at 12 months, 30 continued to have a response. Pallidotomy-related adverse events in the active-treatment group included dysarthria, gait disturbance, loss of taste, visual disturbance, and facial weakness. CONCLUSIONS: Unilateral pallidal ultrasound ablation resulted in a higher percentage of patients who had improved motor function or reduced dyskinesia than a sham procedure over a period of 3 months but was associated with adverse events. Longer and larger trials are required to determine the effect and safety of this technique in persons with Parkinson's disease. (Funded by Insightec; ClinicalTrials.gov number, NCT03319485.).

At home adaptive dual target deep brain stimulation in Parkinson's disease with proportional control.

Continuous deep brain stimulation (cDBS) of the subthalamic nucleus (STN) or globus pallidus is an effective treatment for the motor symptoms of Parkinson's disease. The relative benefit of one region over the other is of great interest but cannot usually be compared in the same patient. Simultaneous DBS of both regions may synergistically increase the therapeutic benefit. Continuous DBS is limited by a lack of responsiveness to dynamic, fluctuating symptoms intrinsic to the disease. Adaptive DBS (aDBS) adjusts stimulation in response to biomarkers to improve efficacy, side effects, and efficiency. We combined bilateral DBS of both STN and globus pallidus (dual target DBS) in a prospective within-participant, clinical trial in six patients with Parkinson's disease (n = 6, 55-65 years, n = 2 females). Dual target cDBS was tested for Parkinson's disease symptom control annually over 2 years, measured by motor rating scales, on time without dyskinesia, and medication reduction. Random amplitude experiments probed system dynamics to estimate parameters for aDBS. We then implemented proportional-plus-integral aDBS using a novel distributed (off-implant) architecture. In the home setting, we collected tremor and dyskinesia scores as well as individualized ß and DBS amplitudes. Dual target cDBS reduced motor symptoms as measured by Unified Parkinson's Disease Rating Scale (UPDRS) to a greater degree than either region alone (P < 0.05, linear mixed model) in the cohort. The amplitude of ß-oscillations in the STN correlated to the speed of hand grasp movements for five of six participants (P < 0.05, Pearson correlation). Random amplitude experiments provided insight into temporal windowing to avoid stimulation artefacts and demonstrated a correlation between STN ß amplitude and DBS amplitude. Proportional plus integral control of aDBS reduced average power, while preserving UPDRS III scores in the clinic (P = 0.28, Wilcoxon signed rank), and tremor and dyskinesia scores during blinded testing at home (n = 3, P > 0.05, Wilcoxon ranked sum). In the home setting, DBS power reductions were slight but significant. Dual target cDBS may offer an improvement in treatment of motor symptoms of Parkinson's disease over DBS of either the STN or globus pallidus alone. When combined with proportional plus integral aDBS, stimulation power may be reduced, while preserving the increased benefit of dual target DBS.

Motor network gamma oscillations in chronic home recordings predict dyskinesia in Parkinson's disease.

In Parkinson's disease, imbalances between 'antikinetic' and 'prokinetic' patterns of neuronal oscillatory activity are related to motor dysfunction. Invasive brain recordings from the motor network have suggested that medical or surgical therapy can promote a prokinetic state by inducing narrowband gamma rhythms (65-90 Hz). Excessive narrowband gamma in the motor cortex promotes dyskinesia in rodent models, but the relationship between narrowband gamma and dyskinesia in humans has not been well established. To assess this relationship, we used a sensing-enabled deep brain stimulator system, attached to both motor cortex and basal ganglia (subthalamic or pallidal) leads, paired with wearable devices that continuously tracked motor signs in the contralateral upper limbs. We recorded 984 h of multisite field potentials in 30 hemispheres of 16 subjects with Parkinson's disease (2/16 female, mean age 57 ± 12 years) while at home on usual antiparkinsonian medications. Recordings were done 2-4 weeks after implantation, prior to starting therapeutic stimulation. Narrowband gamma was detected in the precentral gyrus, subthalamic nucleus or both structures on at least one side of 92% of subjects with a clinical history of dyskinesia. Narrowband gamma was not detected in the globus pallidus. Narrowband gamma spectral power in both structures co-fluctuated similarly with contralateral wearable dyskinesia scores (mean correlation coefficient of ρ = 0.48 with a range of 0.12-0.82 for cortex, ρ = 0.53 with a range of 0.5-0.77 for subthalamic nucleus). Stratification analysis showed the correlations were not driven by outlier values, and narrowband gamma could distinguish 'on' periods with dyskinesia from 'on' periods without dyskinesia. Time lag comparisons confirmed that gamma oscillations herald dyskinesia onset without a time lag in either structure when using 2-min epochs. A linear model incorporating the three oscillatory bands (beta, theta/alpha and narrowband gamma) increased the predictive power of dyskinesia for several subject hemispheres. We further identified spectrally distinct oscillations in the low gamma range (40-60 Hz) in three subjects, but the relationship of low gamma oscillations to dyskinesia was variable. Our findings support the hypothesis that excessive oscillatory activity at 65-90 Hz in the motor network tracks with dyskinesia similarly across both structures, without a detectable time lag. This rhythm may serve as a promising control signal for closed-loop deep brain stimulation using either cortical or subthalamic detection.

Neuronal mechanism of a BK channelopathy in absence epilepsy and dyskinesia.

A growing number of gain-of-function (GOF) BK channelopathies have been identified in patients with epilepsy and movement disorders. Nevertheless, the underlying pathophysiology and corresponding therapeutics remain obscure. Here, we utilized a knock-in mouse model carrying human BK-D434G channelopathy to investigate the neuronal mechanism of BK GOF in the pathogenesis of epilepsy and dyskinesia. The BK-D434G mice manifest the clinical features of absence epilepsy and exhibit severe motor deficits and dyskinesia-like behaviors. The cortical pyramidal neurons and cerebellar Purkinje cells from the BK-D434G mice show hyperexcitability, which likely contributes to the pathogenesis of absence seizures and paroxysmal dyskinesia. A BK channel blocker, paxilline, potently suppresses BK-D434G­induced hyperexcitability and effectively mitigates absence seizures and locomotor deficits in mice. Our study thus uncovered a neuronal mechanism of BK GOF in absence epilepsy and dyskinesia. Our findings also suggest that BK inhibition is a promising therapeutic strategy for mitigating BK GOF-induced neurological disorders.

Cortically Evoked Movement in Humans Reflects History of Prior Executions, Not Plan for Upcoming Movement.

Human motor behavior involves planning and execution of actions, some more frequently. Manipulating probability distribution of a movement through intensive direction-specific repetition causes physiological bias toward that direction, which can be cortically evoked by transcranial magnetic stimulation (TMS). However, because evoked movement has not been used to distinguish movement execution and plan histories to date, it is unclear whether the bias is because of frequently executed movements or recent planning of movement. Here, in a cohort of 40 participants (22 female), we separately manipulate the recent history of movement plans and execution and probe the resulting effects on physiological biases using TMS and on the default plan for goal-directed actions using a timed-response task. Baseline physiological biases shared similar low-level kinematic properties (direction) to a default plan for upcoming movement. However, manipulation of recent execution history via repetitions toward a specific direction significantly affected physiological biases, but not plan-based goal-directed movement. To further determine whether physiological biases reflect ongoing motor planning, we biased plan history by increasing the likelihood of a specific target location and found a significant effect on the default plan for goal-directed movements. However, TMS-evoked movement during preparation did not become biased toward the most frequent plan. This suggests that physiological biases may either provide a readout of the default state of primary motor cortex population activity in the movement-related space, but not ongoing neural activation in the planning-related space, or that practice induces sensitization of neurons involved in the practiced movement, calling into question the relevance of cortically evoked physiological biases to voluntary movements.SIGNIFICANCE STATEMENT Human motor performance depends not only on ability to make movements relevant to the environment/body's current state, but also on recent action history. One emerging approach to study recent movement history effects on the brain is via physiological biases in cortically-evoked involuntary movements. However, because prior movement execution and plan histories were indistinguishable to date, to what extent physiological biases are due to pure execution-dependent history, or to prior planning of the most probable action, remains unclear. Here, we show that physiological biases are profoundly affected by recent movement execution history, but not ongoing movement planning. Evoked movement, therefore, provides a readout of the default state within the movement space, but not of ongoing activation related to voluntary movement planning.

Suppression of presynaptic corticostriatal glutamate activity attenuates L-dopa-induced dyskinesia in 6-OHDA-lesioned Parkinson's disease mice.

A common adverse effect of Parkinson's disease (PD) treatment is L-dopa-induced dyskinesia (LID). This condition results from both dopamine (DA)-dependent and DA-independent mechanisms, as glutamate inputs from corticostriatal projection neurons impact DA-responsive medium spiny neurons in the striatum to cause the dyskinetic behaviors. In this study, we explored whether suppression of presynaptic corticostriatal glutamate inputs might affect the behavioral and biochemical outcomes associated with LID. We first established an animal model in which 6-hydroxydopamine (6-OHDA)-lesioned mice were treated daily with L-dopa (10 mg/kg, i.p.) for 2 weeks; these mice developed stereotypical abnormal involuntary movements (AIMs). When the mice were pretreated with the NMDA antagonist, amantadine, we observed suppression of AIMs and reductions of phosphorylated ERK1/2 and NR2B in the striatum. We then took an optogenetic approach to manipulate glutamatergic activity. Slc17a6 (vGluT2)-Cre mice were injected with pAAV5-Ef1a-DIO-eNpHR3.0-mCherry and received optic fiber implants in either the M1 motor cortex or dorsolateral striatum. Optogenetic inactivation at either optic fiber implant location could successfully reduce the intensity of AIMs after 6-OHDA lesioning and L-dopa treatment. Both optical manipulation strategies also suppressed phospho-ERK1/2 and phospho-NR2B signals in the striatum. Finally, we performed intrastriatal injections of LDN 212320 in the dyskenesic mice to enhance expression of glutamate uptake transporter GLT-1. Sixteen hours after the LDN 212320 treatment, L-dopa-induced AIMs were reduced along with the levels of striatal phospho-ERK1/2 and phospho-NR2B. Together, our results affirm a critical role of corticostriatal glutamate neurons in LID and strongly suggest that diminishing synaptic glutamate, either by suppression of neuronal activity or by upregulation of GLT-1, could be an effective approach for managing LID.

Caenorhabditis elegans provides an efficient drug screening platform for GNAO1-related disorders and highlights the potential role of caffeine in controlling dyskinesia.

Dominant GNAO1 mutations cause an emerging group of childhood-onset neurological disorders characterized by developmental delay, intellectual disability, movement disorders, drug-resistant seizures and neurological deterioration. GNAO1 encodes the α-subunit of an inhibitory GTP/GDP-binding protein regulating ion channel activity and neurotransmitter release. The pathogenic mechanisms underlying GNAO1-related disorders remain largely elusive and there are no effective therapies. Here, we assessed the functional impact of two disease-causing variants associated with distinct clinical features, c.139A > G (p.S47G) and c.662C > A (p.A221D), using Caenorhabditis elegans as a model organism. The c.139A > G change was introduced into the orthologous position of the C. elegans gene via CRISPR/Cas9, whereas a knock-in strain carrying the p.A221D variant was already available. Like null mutants, homozygous knock-in animals showed increased egg laying and were hypersensitive to aldicarb, an inhibitor of acetylcholinesterase, suggesting excessive neurotransmitter release by different classes of motor neurons. Automated analysis of C. elegans locomotion indicated that goa-1 mutants move faster than control animals, with more frequent body bends and a higher reversal rate and display uncoordinated locomotion. Phenotypic profiling of heterozygous animals revealed a strong hypomorphic effect of both variants, with a partial dominant-negative activity for the p.A221D allele. Finally, caffeine was shown to rescue aberrant motor function in C. elegans harboring the goa-1 variants; this effect is mainly exerted through adenosine receptor antagonism. Overall, our findings establish a suitable platform for drug discovery, which may assist in accelerating the development of new therapies for this devastating condition, and highlight the potential role of caffeine in controlling GNAO1-related dyskinesia.

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.

An Apple a Day to Keep the Parkinson's Disease Doctor Away?

It is challenging to reliably assess the motor features of Parkinson's disease in real-time. This has motivated the search for new digital outcomes that can objectively and remotely measure the severity of parkinsonian motor impairments over an extended period of time. The United States Food and Drug Administration (FDA) has recently granted a 510(k) clearance to the Rune Labs Kinematics System, an ambulatory, smartwatch-based monitoring system to remotely track tremor and dyskinesias in persons with Parkinson's disease. The FDA clearance means that this new digital approach can be regarded as being safe for use in daily practice, with acceptable correlations to clinically based measures. However, the immediate implications for clinicians are limited, because it remains to be demonstrated whether the digital signals correlate well to clinically meaningful outcomes at patient level. The impact on research is also restricted for now, as more validation studies are needed before this new digital approach can be used as primary or secondary endpoint in clinical trials. ANN NEUROL 2023;93:681-685.

Are patients with GBA-Parkinson disease good candidates for deep brain stimulation? A longitudinal multicentric study on a large Italian cohort.

BACKGROUND: GBA variants increase the risk of developing Parkinson disease (PD) and influence its outcome. Deep brain stimulation (DBS) is a recognised therapeutic option for advanced PD. Data on DBS long-term outcome in GBA carriers are scarce. OBJECTIVE: To elucidate the impact of GBA variants on long-term DBS outcome in a large Italian cohort. METHODS: We retrospectively recruited a multicentric Italian DBS-PD cohort and assessed: (1) GBA prevalence; (2) pre-DBS clinical features; and (3) outcomes of motor, cognitive and other non-motor features up to 5 years post-DBS. RESULTS: We included 365 patients with PD, of whom 73 (20%) carried GBA variants. 5-year follow-up data were available for 173 PD, including 32 mutated subjects. GBA-PD had an earlier onset and were younger at DBS than non-GBA-PD. They also had shorter disease duration, higher occurrence of dyskinesias and orthostatic hypotension symptoms.At post-DBS, both groups showed marked motor improvement, a significant reduction of fluctuations, dyskinesias and impulsive-compulsive disorders (ICD) and low occurrence of most complications. Only cognitive scores worsened significantly faster in GBA-PD after 3 years. Overt dementia was diagnosed in 11% non-GBA-PD and 25% GBA-PD at 5-year follow-up. CONCLUSIONS: Evaluation of long-term impact of GBA variants in a large Italian DBS-PD cohort supported the role of DBS surgery as a valid therapeutic strategy in GBA-PD, with long-term benefit on motor performance and ICD. Despite the selective worsening of cognitive scores since 3 years post-DBS, the majority of GBA-PD had not developed dementia at 5-year follow-up.

Defining the Genetic Landscape of Congenital Mirror Movements in 80 Affected Individuals.

BACKGROUND: Congenital mirror movements (CMM) is a rare neurodevelopmental disorder characterized by involuntary movements from one side of the body that mirror voluntary movements on the opposite side. To date, five genes have been associated with CMM, namely DCC, RAD51, NTN1, ARHGEF7, and DNAL4. OBJECTIVE: The aim of this study is to characterize the genetic landscape of CMM in a large group of 80 affected individuals. METHODS: We screened 80 individuals with CMM from 43 families for pathogenic variants in CMM genes. In large CMM families, we tested for presence of pathogenic variants in multiple affected and unaffected individuals. In addition, we evaluated the impact of three missense DCC variants on binding between DCC and Netrin-1 in vitro. RESULTS: Causal pathogenic/likely pathogenic variants were found in 35% of probands overall, and 70% with familial CMM. The most common causal gene was DCC, responsible for 28% of CMM probands and 80% of solved cases. RAD51, NTN1, and ARHGEF7 were rare causes of CMM, responsible for 2% each. Penetrance of CMM in DCC pathogenic variant carriers was 68% and higher in males than females (74% vs. 54%). The three tested missense variants (p.Ile164Thr; p.Asn176Ser; and p.Arg1343His) bind Netrin-1 similarly to wild type DCC. CONCLUSIONS: A genetic etiology can be identified in one third of CMM individuals, with DCC being the most common gene involved. Two thirds of CMM individuals were unsolved, highlighting that CMM is genetically heterogeneous and other CMM genes are yet to be discovered. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Unraveling the interplay between dyskinesia and overactive bladder symptoms in Parkinson's disease: a comprehensive cohort study based on the long-term follow-up database of Parkinson's disease.

OBJECTIVES: Overactive bladder (OAB) and dyskinesia are frequent complications in patients with Parkinson's disease (PD). However, the correlation between OAB and dyskinesia has been insufficiently explored. The purpose of this study was to examine the relationship between dyskinesia, OAB, and clinical characteristics among individuals with PD. METHODS: 1338 PD patients were included in the present study. Demographic features were compared between patients with or without dyskinesia and OAB symptoms. Logistic regression was conducted on dyskinesia to screen clinically relevant factors. Overactive Bladder Symptom Score (OABSS) was further used to stratify the association between the severity of OAB and the occurrence of dyskinesia. RESULTS: This study indicates that both dyskinesia and OAB are significantly related to disease severity and cognitive status. PD patients with dyskinesia and OAB having higher UPDRS scores (p < 0.001), H-Y scores (p < 0.001), NMSQ (p < 0.001) and MoCA scores (p < 0.001), and lower MMSE scores (p < 0.001) are identified. The multivariate logistic regression confirms that disease duration (p = 0.041), LEDD (p < 0.001), UPDRSII (p < 0.001), MoCA (p = 0.024), urgency (p < 0.001), frequency (p < 0.001), and nocturia (p = 0.002) are independent risk factors for dyskinesia. Trend analysis indicates that the risk of dyskinesia significantly increases when patients exhibit moderate to severe OAB symptoms (OABSS > 5) (p < 0.001). No significant interactions were found between OABSS and age, gender, disease duration, LEDD, and NMSQ scores in different subgroups, indicating that dyskinesia is more pronounced in patients with OABSS > 5. DISCUSSION: This study provides compelling evidence supporting the strong correlation between OAB and dyskinesia in PD patients, emphasizing the presence of shared pathogenic mechanisms between these two conditions. Our findings underscore the importance of considering both OAB and dyskinesia in the clinical management of PD, investigating the intricate connections between OAB and dyskinesia could unveil valuable insights into the complex pathophysiology of PD and potentially identify novel therapeutic targets for more effective PD treatment strategies.

Diametric neural ensemble dynamics in parkinsonian and dyskinetic states.

Loss of dopamine in Parkinson's disease is hypothesized to impede movement by inducing hypo- and hyperactivity in striatal spiny projection neurons (SPNs) of the direct (dSPNs) and indirect (iSPNs) pathways in the basal ganglia, respectively. The opposite imbalance might underlie hyperkinetic abnormalities, such as dyskinesia caused by treatment of Parkinson's disease with the dopamine precursor L-DOPA. Here we monitored thousands of SPNs in behaving mice, before and after dopamine depletion and during L-DOPA-induced dyskinesia. Normally, intermingled clusters of dSPNs and iSPNs coactivated before movement. Dopamine depletion unbalanced SPN activity rates and disrupted the movement-encoding iSPN clusters. Matching their clinical efficacy, L-DOPA or agonism of the D2 dopamine receptor reversed these abnormalities more effectively than agonism of the D1 dopamine receptor. The opposite pathophysiology arose in L-DOPA-induced dyskinesia, during which iSPNs showed hypoactivity and dSPNs showed unclustered hyperactivity. Therefore, both the spatiotemporal profiles and rates of SPN activity appear crucial to striatal function, and next-generation treatments for basal ganglia disorders should target both facets of striatal activity.

Botulinum neurotoxin as early treatment in acute-onset lesional hemiballism.

BACKGROUND: Hemiballism (HB) and hemichorea (HC) are the most frequent secondary movement disorders, usually caused by cerebrovascular diseases. In only a minority of cases, these involuntary movements are not self-limited, and they may severely compromise patients' quality of life, so that symptomatic treatments are required. Typical and atypical neuroleptics as well as tetrabenazine are considered therapies of choice. However, anecdotal reports of antiseizures medications and botulinum neurotoxin injection effectiveness have been described. METHODS: We described a case of severely disabling acute-onset lesional HB/HC, where high dosage of first- and second-line therapies was contraindicated due to patient's comorbidities. RESULTS: After botulin neurotoxin (BoNT) injections in his left upper limb muscles (biceps brachii, triceps brachii, teres major, and deltoid), the patient experienced gradual reduction of hyperkinetic movements. The gradual discontinuation of topiramate (TPM) did not worsen the clinical picture. DISCUSSION: The reduction of hyperkinetic movements led to rhabdomyolysis resolution as well as cutaneous injuries healing with renal function improvement, so that the patient was able to be eligible for rehabilitation, which was prevented by HB/HC itself. The clinical improvement was consistent with BoNT pharmacokinetic. The administration of BoNT early after the onset of lesional HB/HC remarkably modified the clinical management and drove toward comorbidities resolution and rehabilitation. CONCLUSION: The present case highlights the effectiveness of unconventional therapeutic options in disabling acute onset lesional HB/HC when first-line therapies are contraindicated. Particularly, this report may encourage BoNT application in the early stage of movement disorder emergencies.

Diabetic striatopathy: an updated overview of current knowledge and future perspectives.

PURPOSE: Diabetic striatopathy (DS) is a rare complication of poorly controlled diabetes mellitus (DM), characterized by hyperglycemia associated with chorea/ballism and characteristic reversible basal ganglia abnormalities on computed tomography (CT) and/or magnetic resonance imaging (MRI). We propose a narrative review of the literature on this topic, currently unknown to most, and about which physicians should be aware. We intend to summarize, critically review, and take to mean the evidence on this disorder, describing its typical features. METHODS: We searched Pubmed for English-language sources using the following keywords in the title and the abstract: diabetic striatopathy, hyperglycemic non-ketotic hemichorea/hemiballism, chorea/hemichorea associated with non-ketotic hyperglycemia, diabetic hemiballism/hemichorea, chorea, hyperglycemia, and basal ganglia syndrome. We collected scientific articles, including case reports, reviews, systematic reviews, and meta-analyses from the years 1975 to 2023. We eliminated duplicate, non-English language or non-related articles. RESULTS: Older Asian women are more frequently affected. Suddenly or insidiously hemichorea/hemiballism, mainly in the limbs, and high blood glucose with elevated HbA1c in the absence of ketone bodies have been observed. Furthermore, CT striatal hyperdensity and T1-weighted MRI hyperintensity have been observed. DS is often a treatable disease following proper hydration and insulin administration. Histopathological findings are variable, and no comprehensive hypothesis explains the atypical cases reported. CONCLUSION: DS is a rare neurological manifestation of DM. If adequately treated, although treatment guidelines are lacking, the prognosis is good and life-threatening complications may occur occasionally. During chorea/hemiballism, we recommend blood glucose and HbA1c evaluation. Further studies are needed to understand the pathogenesis.

Footloose (footloose), footloose.

A 78-year-old woman without past relevant medical history presented to the emergency department for acute transient dysarthria. NIHSS was 0/42. Neurological examination revealed chorea-like movements over the left limbs, especially the foot. No other neurological signs were present. CT perfusion showed right cortical hypoperfusion due to right M2 occlusion, basal-ganglia perfusion was normal. Brain MRI revealed a small focus of restricted diffusion in the right insula, sparing basal ganglia. Based on the neuroimaging features and clinical correlation, despite the NIHSS score, we decided to treat the patient with alteplase, after iv-thrombolysis hyperkinetic movements ceased completely. Brain-MRI performed 72 h after symptom onset confirmed a confined insular ischemic lesion without the involvement of deep gray matter structures. Hyperkinetic movement disorders, such as hemichorea hemiballismus, are rare presentations of stroke, basal ganglia are mainly involved even if the insular cortex has been described too. Clinical decision on whether to treat ischemic stroke does not include movement disorders. Our case underscores NIHSS limitations in clinical practice.

Neural Drive and Motor Unit Characteristics of the Serratus Anterior in Individuals With Scapular Dyskinesis.

OBJECTIVE: Scapular dyskinesis is one of the causes of shoulder disorders and involves muscle weakness in the serratus anterior. This study investigated whether motor unit (MU) recruitment and firing property, which are important for muscle exertion, have altered in serratus anterior of the individuals with scapular dyskinesis. METHODS: Asymptomatic adults with (SD) and without (control) scapular dyskinesis were analyzed. Surface electromyography (sEMG) waveforms were collected at submaximal voluntary contraction of the serratus anterior. The sEMG waveform was decomposed into MU action potential amplitude (MUAPAMP), mean firing rate (MFR), and recruitment threshold. MUs were divided into low, moderate, and high thresholds, and MU recruitment and firing properties of the groups were compared. RESULTS: High-threshold MUAPAMP was significantly smaller in the SD group than in the control group. The control group also exhibited recruitment properties that reflected the size principle, however, the SD group did not. Furthermore, the SD group had a lower MFR than the control group. CONCLUSIONS: Individuals with scapular dyskinesis exhibit altered MU recruitment properties and lower firing rates of the serratus anterior; this may be detrimental to muscle performance. Thus, it may be necessary to improve the neural drive of the serratus anterior when correcting scapular dyskinesis.

Focused Ultrasound for Treatment of Movement Disorders: A Review of Non-Food and Drug Administration Approved Indications.

INTRODUCTION: MRI-guided focused ultrasound (FUS) is an incisionless thermo-ablative procedure that may be used to treat medication-refractory movement disorders, with a growing number of potential anatomic targets and clinical applications. As of this article's publication, the only US Food and Drug Administration (FDA)-approved uses of FUS for movement disorders are thalamotomy for essential tremor (ET) and tremor-dominant Parkinson's Disease (PD), and pallidotomy for other cardinal symptoms of PD. We present a state-of-the-art review on all non-FDA approved indications of FUS for movement disorders, beyond the most well-described indications of ET and PD. Our objective was to summarize the safety and efficacy of FUS in this setting and provide a roadmap for future directions of FUS for movement disorders. METHODS: A state-of-the-art review was conducted on use of FUS for non-FDA approved movement disorders. All movement disorders excluding FDA-approved uses for ET and PD were included. RESULTS: A total of 25 studies on 172 patients were included. In patients with tremor plus dystonia syndromes (n = 6), ventralis intermediate nucleus of the thalamus (VIM)-FUS gave >50% tremor reduction, with no improvement in dystonia and worsened dystonia in 2/6 patients. Ventral-oralis complex (VO)-FUS gave >50% improvement for focal hand dystonia (n = 6) and 100% return to musical performance in musician's dystonia (n = 6). In patients with multiple sclerosis (MS) and tremor (n = 3), improvement in tremor was seen in 2 patients with a favorable skull density ratio; no MS disease change was noted after VIM-FUS. In patients with tremor and comorbid ataxia syndromes (n = 3), none were found to have worsened ataxia after VIM-FUS; all had clinically significant tremor improvement. Subthalamic nucleus (STN)-FUS for PD (n = 49) gave approximately 50% improvement in PD motor symptoms, with dystonia and mild dyskinesias as possible adverse effects. Cerebellothalamic tract (CTT-FUS) for ET (n = 42) gave 55-90% tremor improvement, with gait dysfunction as a rare persistent adverse effect. Pallidothalamic tract (PTT-FUS) for PD (n = 50) gave approximately 50% improvement in motor symptoms, with mild speech dysfunction as a possible adverse effect. CONCLUSION: VIM-FUS appeared safe and effective for heterogenous tremor etiologies, and VO-FUS appeared most effective for isolated segmental dystonia. STN-FUS was effective for PD symptom reduction; postoperative dystonia and mild on-medication dyskinesias required medical management. Tractography-based targeting with CTT-FUS for ET and PTT-FUS for PD demonstrated promising early results. Larger prospective trials with long-term follow-up are needed to the evaluate the safety and efficacy non-FDA approved indications for FUS.

Case-Based Understanding of the Role of the Scapula in Common Shoulder Pathologies.

Scapular dyskinesis is an extremely common component of shoulder pathology, especially in the overhead athlete; despite its prevalence, proper diagnosis and management of scapular disorders remains an enigma for many clinicians. An understanding of the contribution of the scapula to pathomechanics and clinical symptoms is necessary to optimize both surgical and nonsurgical treatment of shoulder disorders. Without correction of scapular dysfunction, even effective management of the pathoanatomy is unlikely to produce optimal results. It is important to examine the role of the scapula in common shoulder pathologies and elucidate a case-based treatment strategy for both surgical and nonsurgical shoulder disorders.

Scapular Dyskinesia: How to Differentiate Between Etiologies.

It is important to discuss the importance of synchronous balance between periscapular muscles for scapulothoracic motion and resultant scapulohumeral rhythm. Abnormalities in this balance can lead to scapular dyskinesia and winging, affecting shoulder motion and leading to impingement. Strategies exist to diagnose and differentiate between pathologies such as muscle paralysis (eg, trapezius or serratus anterior) or overactivity (eg, pectoralis minor). The physician should be aware of the role of diagnostic imaging, as well as the unique considerations for patients with Ehlers-Danlos syndrome. Overall, a comprehensive physical examination to accurately diagnose and treat scapular pathologies is particularly important.