Subthalamic Nucleus Activity during Cognitive Load and Gait Dysfunction in Parkinson's Disease.

BACKGROUND: Gait freezing is a common, disabling symptom of Parkinson's disease characterized by sudden motor arrest during walking. Adaptive deep brain stimulation devices that detect freezing and deliver real-time, symptom-specific stimulation are a potential treatment strategy. Real-time alterations in subthalamic nucleus firing patterns have been demonstrated with lower limb freezing, however, whether similar abnormal signatures occur with freezing provoked by cognitive load, is unknown. METHODS: We obtained subthalamic nucleus microelectrode recordings from eight Parkinson's disease patients performing a validated virtual reality gait task, requiring responses to on-screen cognitive cues while maintaining motor output. RESULTS: Signal analysis during 15 trials containing freezing or significant motor output slowing precipitated by dual-tasking demonstrated reduced θ frequency (3-8 Hz) firing compared to 18 unaffected trials. CONCLUSIONS: These preliminary results reveal a potential neurobiological basis for the interplay between cognitive factors and gait disturbances including freezing in Parkinson's disease, informing development of adaptive deep brain stimulation protocols. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke.

BACKGROUND: The time to initiate intravenous thrombolysis for acute ischemic stroke is generally limited to within 4.5 hours after the onset of symptoms. Some trials have suggested that the treatment window may be extended in patients who are shown to have ischemic but not yet infarcted brain tissue on imaging. METHODS: We conducted a multicenter, randomized, placebo-controlled trial involving patients with ischemic stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion imaging. The patients were randomly assigned to receive intravenous alteplase or placebo between 4.5 and 9.0 hours after the onset of stroke or on awakening with stroke (if within 9 hours from the midpoint of sleep). The primary outcome was a score of 0 or 1 on the modified Rankin scale, on which scores range from 0 (no symptoms) to 6 (death), at 90 days. The risk ratio for the primary outcome was adjusted for age and clinical severity at baseline. RESULTS: After 225 of the planned 310 patients had been enrolled, the trial was terminated because of a loss of equipoise after the publication of positive results from a previous trial. A total of 113 patients were randomly assigned to the alteplase group and 112 to the placebo group. The primary outcome occurred in 40 patients (35.4%) in the alteplase group and in 33 patients (29.5%) in the placebo group (adjusted risk ratio, 1.44; 95% confidence interval [CI], 1.01 to 2.06; P = 0.04). Symptomatic intracerebral hemorrhage occurred in 7 patients (6.2%) in the alteplase group and in 1 patient (0.9%) in the placebo group (adjusted risk ratio, 7.22; 95% CI, 0.97 to 53.5; P = 0.05). A secondary ordinal analysis of the distribution of scores on the modified Rankin scale did not show a significant between-group difference in functional improvement at 90 days. CONCLUSIONS: Among the patients in this trial who had ischemic stroke and salvageable brain tissue, the use of alteplase between 4.5 and 9.0 hours after stroke onset or at the time the patient awoke with stroke symptoms resulted in a higher percentage of patients with no or minor neurologic deficits than the use of placebo. There were more cases of symptomatic cerebral hemorrhage in the alteplase group than in the placebo group. (Funded by the Australian National Health and Medical Research Council and others; EXTEND ClinicalTrials.gov numbers, NCT00887328 and NCT01580839.).

Hitting the brakes: pathological subthalamic nucleus activity in Parkinson's disease gait freezing.

Gait freezing is a complex and devastating paroxysmal motor arrest commonly suffered in Parkinson's disease that causes significant impairment to mobility, commonly resulting in falls and subsequent injury. The neurobiological basis of gait freezing in Parkinson's disease is poorly understood and thus, currently available therapies are partially effective at best. We used a validated virtual reality gait paradigm to elicit freezing behaviour intraoperatively in eight patients undergoing subthalamic nucleus deep brain stimulation surgery while microelectrode recordings were obtained. This allowed us to directly test the hypothesis that increases in pathological multi-unit activity in the subthalamic nucleus are associated with freezing onset in real time, manifest as dysfunctional firing of lower limb muscles typical of freezing that were detected by EMG. We present evidence that freezing is related to transient increases in pathological subthalamic nucleus activity. We performed time-frequency analysis to characterize the oscillatory dynamics of subthalamic nucleus activity coincident with freezing onset, demonstrating an increase in pathological beta and theta rhythms that are followed by a temporal chain of activity culminating in characteristically abnormal lower limb muscle firing detected by EMG. Finally, we interrogate the potential clinical utility of our findings by contrasting the subthalamic nucleus activity signature during pathological freezing against purposeful stopping. These results advance our understanding of the neurobiological basis of gait freezing in Parkinson's disease, highlighting the role of the subthalamic nucleus and emergent synchronous activity in basal ganglia circuits in driving non-purposeful motor arrests in individuals with Parkinson's disease. Pathological subthalamic nucleus activity identified in association with freezing is discernible from that of volitional stopping, paving the way towards more effective therapeutics such as adaptive closed-loop deep brain stimulation protocols.

Time to acute stroke treatment in-hours was more than halved after the introduction of the Helsinki Model at Westmead Hospital.

BACKGROUND: Management of acute ischaemic stroke is time critical. Reducing time to treatment with thrombolysis is strongly associated with improved outcomes in properly selected patients. However, there are barriers to ensuring timely treatment in the hospital setting. AIM: To determine if simple, no-cost protocol changes could improve time to treatment for acute ischaemic stroke at a busy tertiary hospital. METHODS: Prospectively collected routine clinical data were compared retrospectively before and after a protocol change designed to mirror the successful model from Helsinki University Central Hospital. Consecutive patients who activated a 'code stroke' (presentation consistent with acute stroke, eligible for acute stroke therapy) during working hours were included. RESULTS: Prior to the protocol change, 143 patients activated a code stroke, and 30 patients received thrombolysis. Following the protocol change, 134 patients activated a code stroke, and 14 patients received thrombolysis. The median time to administer thrombolysis was reduced from 76 min (interquartile range 54-91) to 33 min (27-44), P < 0.01. The median time to perform diagnostic computed tomography was unchanged between the two groups, 23 (14-54) min versus 22 (9-49) min, P = 0.12. However, this was reduced on subgroup analysis of patients whose arrival was pre-notified by the ambulance service, 16 (9-22) min versus 8 (4-14) min, P < 0.01. CONCLUSION: Time to treatment in acute stroke was dramatically improved with a simple intervention. This was achieved without a large stroke team or additional funding, making it highly accessible to other health services also seeking to improve their stroke service.

Postural tremor and chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: Chronic inflammatory demyelinating polyneuropathy (CIDP) typically presents with a combination of sensory and motor impairments. Tremor is recognized as a common and debilitating feature in CIDP, although the underlying mechanisms are unclear. METHODS: Clinical tremor severity and disability scores were collected prospectively in 25 CIDP patients and compared with 22 neuromuscular controls. RESULTS: Postural and kinetic tremor were significantly more frequent in CIDP patients (80%) than in neuromuscular controls (35%; P < 0.005). Tremor severity and tremor-related disability were also significantly greater in CIDP patients than in controls. Accelerometry data confirmed the presence of a 5.5 Hz postural tremor and a 5 Hz kinetic tremor. CONCLUSIONS: Tremor appears to be a common clinical feature of CIDP that results in significant disability. Sensory and motor impairment may be associated with development of tremor in CIDP. Muscle Nerve 55: 338-343, 2017.

Phenotypic insights into ADCY5-associated disease.

BACKGROUND: Adenylyl cyclase 5 (ADCY5) mutations is associated with heterogenous syndromes: familial dyskinesia and facial myokymia; paroxysmal chorea and dystonia; autosomal-dominant chorea and dystonia; and benign hereditary chorea. We provide detailed clinical data on 7 patients from six new kindreds with mutations in the ADCY5 gene, in order to expand and define the phenotypic spectrum of ADCY5 mutations. METHODS: In 5 of the 7 patients, followed over a period of 9 to 32 years, ADCY5 was sequenced by Sanger sequencing. The other 2 unrelated patients participated in studies for undiagnosed pediatric hyperkinetic movement disorders and underwent whole-exome sequencing. RESULTS: Five patients had the previously reported p.R418W ADCY5 mutation; we also identified two novel mutations at p.R418G and p.R418Q. All patients presented with motor milestone delay, infantile-onset action-induced generalized choreoathetosis, dystonia, or myoclonus, with episodic exacerbations during drowsiness being a characteristic feature. Axial hypotonia, impaired upward saccades, and intellectual disability were variable features. The p.R418G and p.R418Q mutation patients had a milder phenotype. Six of seven patients had mild functional gain with clonazepam or clobazam. One patient had bilateral globus pallidal DBS at the age of 33 with marked reduction in dyskinesia, which resulted in mild functional improvement. CONCLUSION: We further delineate the clinical features of ADCY5 gene mutations and illustrate its wide phenotypic expression. We describe mild improvement after treatment with clonazepam, clobazam, and bilateral pallidal DBS. ADCY5-associated dyskinesia may be under-recognized, and its diagnosis has important prognostic, genetic, and therapeutic implications. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Botulinum Toxin for the Management of Sjögren Syndrome-Associated Recurrent Parotitis.

Recurrent parotitis is a rare manifestation of Sjögren syndrome. The management of recurrent parotitis is challenging because conservative methods may be of limited efficacy and invasive approaches carry the risk of complications. Botulinum toxin has been shown to reduce salivary flow, and consequently, the results of its use in the management of recurrent parotitis have been encouraging. A 65-year-old female patient with recurrent parotitis due to Sjögren syndrome was referred to us, complaining of weekly bouts of inflammation. She required a course of antibiotics monthly to control bacterial superinfections. We treated her with onabotulinumtoxinA injections into both parotid glands at regular intervals. After her second injection cycle, she denied further inflammatory bouts, has not required antibiotics in more than 36 months, and denied any side effects. Botulinum toxin may be a safe and effective method of treating Sjögren syndrome-associated recurrent parotitis.

Treatment of proximal upper limb tremor with botulinum toxin therapy.

BACKGROUND: Proximal-dominant upper limb tremor is highly disabling, and there is no effective medical therapy. In this study, we evaluated the efficacy of botulinum toxin (BTX) injections for the treatment of proximal tremor. METHODS: We conducted a retrospective analysis of open-label treatment with BTX in 19 patients with proximal tremor. The response to therapy was graded into four categories according to self-reported improvements in tremor and function. RESULTS: In total, 63% of patients reported moderate or marked benefit, defined as functional improvements sufficient enough to allow feeding or drinking from a cup; whereas 21% of patients reported mild benefit; and 15% of patients reported no benefit. One patient developed severe weakness of shoulder abduction and withdrew from the treatment; otherwise, the therapy was free of side effects. CONCLUSIONS: The current findings support the efficacy of BTX therapy in the treatment of proximal upper limb tremor with minimal side effects.

DHDDS and NUS1: A Converging Pathway and Common Phenotype.

BACKGROUND: Variants in dehydrodolichol diphosphate synthetase (DHDDS) and nuclear undecaprenyl pyrophosphate synthase 1 (NUS1) cause a neurodevelopmental disorder, classically with prominent epilepsy. Recent reports suggest a complex movement disorder and an overlapping phenotype has been postulated due to their combined role in dolichol synthesis. CASES: We describe three patients with heterozygous variants in DHDDS and five with variants affecting NUS1. They bear a remarkably similar phenotype of a movement disorder dominated by multifocal myoclonus. Diagnostic clues include myoclonus exacerbated by action and facial involvement, and slowly progressive or stable, gait ataxia with disproportionately impaired tandem gait. Myoclonus is confirmed with neurophysiology, including EMG of facial muscles. LITERATURE REVIEW: Ninety-eight reports of heterozygous variants in DHDDS, NUS1 and chromosome 6q22.1 structural alterations spanning NUS1, confirm the convergent phenotype of hypotonia at birth, developmental delay, multifocal myoclonus, ataxia, dystonia and later parkinsonism with or without generalized epilepsy. Other features include periodic exacerbations, stereotypies, anxiety, and dysmorphisms. Although their gene products contribute to dolichol biosynthesis, a key step in N-glycosylation, transferrin isoform profiles are typically normal. Imaging is normal or non-specific. CONCLUSIONS: Recognition of their shared phenotype may expedite diagnosis through chromosomal microarray and by including DHDDS/NUS1 in movement disorder gene panels.

Genome sequencing reanalysis increases the diagnostic yield in dystonia.

PURPOSE: We investigated the contribution of genomic data reanalysis to the diagnostic yield of dystonia patients who remained undiagnosed after prior genome sequencing. METHODS: Probands with heterogeneous dystonia phenotypes who underwent initial genome sequencing (GS) analysis in 2019 were included in the reanalysis, which was performed through gene-specific discovery collaborations and systematic genomic data reanalysis. RESULTS: Initial GS analysis in 2019 (n = 111) identified a molecular diagnosis in 11.7 % (13/111) of cases. Reanalysis between 2020 and 2023 increased the diagnostic yield by 7.2 % (8/111); 3.6 % (4/111) through focused gene-specific clinical correlation collaborative efforts [VPS16 (two probands), AOPEP and POLG], and 3.6 % (4/111) by systematic reanalysis completed in 2023 [NUS1 (two probands) and DDX3X variants, and a microdeletion encompassing VPS16]. Seven of these patients had a high phenotype-based dystonia score ≥3. Notable unverified findings in four additional cases included suspicious variants of uncertain significance in FBXL4 and EIF2AK2, and potential phenotypic expansion associated with SLC2A1 and TREX1 variants. CONCLUSION: GS data reanalysis increased the diagnostic yield from 11.7 % to 18.9 %, with potential extension up to 22.5 %. While optimal timing for diagnostic reanalysis remains to be determined, this study demonstrates that periodic re-interrogation of dystonia GS datasets can provide additional genetic diagnoses, which may have significant implications for patients and their families.

Active exercise for individuals with cervical dystonia: a pilot randomized controlled trial.

OBJECTIVE: To investigate the feasibility and effectiveness of an active exercise program for cervical dystonia. DESIGN: Pilot randomized controlled, single-blind trial of a 12-week intervention followed by a four-week follow-up period. SETTING: Supervised physiotherapy and outcome measurement sessions were conducted in a hospital outpatient physiotherapy setting. Participants also performed exercises at home. SUBJECTS: Twenty participants with idiopathic cervical dystonia were randomized into an experimental (n = 9) or control (n = 11) group. Two participants from the experimental group and one from the control group dropped out. INTERVENTIONS: The experimental group undertook a semi-supervised active exercise program aimed at correcting the dystonic head position, plus relaxation. The control group performed relaxation only. MAIN OUTCOME MEASURES: Feasibility of the intervention was assessed by recording adherence, muscle soreness, and adverse events. The primary outcome measure was blinded analysis of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) score. RESULTS: The active exercise program was feasible and safe, with participants in the experimental group completing 84% of prescribed training sessions in the 12-week intervention period. There were no adverse events in either group, while mild muscle soreness was reported by 66% of the experimental group. There was no significant difference between groups at post-test or follow-up. The difference between groups of -1.9 (95% confidence interval (CI) -9.0-5.2) on the TWSTRS demonstrates a trend towards greater improvement for the experimental group. CONCLUSION: Active exercise for people with cervical dystonia is feasible and can be completed with good adherence and no adverse effects.

A single centre prospective study of three device-assisted therapies for Parkinson's disease.

Comparative studies assessing outcomes with the three device-assisted therapies could help to individualise treatment for patients living with Parkinson's disease. We designed a single-centre non-randomised prospective observational study assessing the quality of life (QoL), motor and non-motor outcomes at 6 and 12-months in patients treated with subcutaneous apomorphine continuous 16-hours infusion (APO), levodopa-carbidopa intestinal gel (LCIG) or subthalamic nucleus deep brain stimulation (STN-DBS). In this study, 66 patients were included (13 APO; 19 LCIG; 34 STN-DBS). At baseline, cognitive, non-motor and motor scores were significantly less severe in the STN-DBS group, whereas the LCIG group had a longer disease duration and higher non-motor scores. In the APO group, there were no statistically significant changes in non-motor, motor and QoL scales. The LCIG group had significant changes in QoL and motor scales that were significant after multiple comparison analysis at 6 and 12-months. The STN-DBS group showed improvement in QoL scores and non-motor and motor scores at 6 and 12-months after multiple comparison analysis. In this real-life prospective study, device-assisted therapies showed differences in their effects on QoL and motor and non-motor function at 12-months. However, there were also differences in baseline characteristics of the patient groups that were not based on pre-determined selection criteria. Differences in characteristics of patients offered and/or treatment with different device-assisted therapies may reflect within-centre biases that may, in turn, influence perceptions of treatment efficacy or outcomes. Treatment centres should be aware of this potential confounder when assessing and offering device-assisted treatment options to their patients and potential baseline differences need to be taken into consideration when comparing the results of non-randomised studies.

SPG11 presenting with dystonic tremor in childhood.

This is a unique case of SPG11 mutation presenting as childhood onset dystonic tremor without weakness or spastic paraplegia. Hereditary spastic paraplegia is the most common phenotype of SPG11 mutation though there are reports of an extended phenotype of SPG11 including dopa-responsive dystonia and tremor.

Investigating the Precise Localization of the Grasping Action in the Mid-Cingulate Cortex and Future Directions.

Objective: To prospectively study the cingulate cortex for the localization and role of the grasping action in humans during electrical stimulation of depth electrodes. Methods: All the patients (n = 23) with intractable focal epilepsy and a depth electrode stereotactically placed in the cingulate cortex, as part of their pre-surgical epilepsy evaluation from 2015 to 2017, were included. Cortical stimulation was performed and examined for grasping actions. Post-implantation volumetric T1 MRIs were co-registered to determine the exact electrode position. Results: Five patients (male: female 4:1; median age 31) exhibited contralateral grasping actions during electrical stimulation. All patients had electrodes implanted in the ventral bank of the right cingulate sulcus adjacent to the vertical anterior commissure (VAC) line. Stimulation of other electrodes in adjacent regions did not elicit grasping. Conclusion: Grasping action elicited from a localized region in the mid-cingulate cortex (MCC) directly supports the concept of the cingulate cortex being crucially involved in the grasping network. This opens an opportunity to explore this region with deep brain stimulation as a motor neuromodulation target for treatment in specific movement disorders or neurorehabilitation.

Driving restrictions following deep brain stimulation surgery.

BACKGROUND: There are currently no Australian guidelines to assist clinicians performing deep brain stimulation (DBS) procedures in setting postoperative driving restrictions. PURPOSE: We aimed to provide recommendations for post-DBS driving restrictions to guide practice in Australia. METHODS: A review of current Australian and international driving guidelines, literature regarding the adverse effects of DBS and literature regarding the long-term effect of neurostimulation on driving was conducted using Elton B Stephens Company discovery service-linked databases. Australian neurologists and neurosurgeons who perform DBS were surveyed to gain insight into existing practice. RESULTS: No guidance on driving restrictions following DBS surgery was found, either in existing driving guidelines or in the literature. There was a wide difference seen in the rates of reported adverse effects from DBS surgery. The most serious adverse events (haemorrhage, seizure and neurological dysfunction) were uncommon. Longer term, there does not appear to be any adverse effect of DBS on driving ability. Survey of Australian practitioners revealed a universal acceptance of the need for and use of driving restrictions after DBS but significant heterogeneity in how return to driving is managed. CONCLUSION: We propose a 6-week driving restriction for private licences and 6-month driving restriction for commercial licences in uncomplicated DBS. We also highlight some of the potential pitfalls and pearls to assist clinicians to modify these recommendations where needed. Ultimately, we hope this will stimulate further examination of this issue in research and by regulatory bodies to provide more robust direction for practitioners performing DBS implantation.