Stephen Tisch

Focal hand dystonia is a disabling disorder characterized by task-specific abnormal involuntary movements that disrupt motor control. While the aetiology is unknown, abnormalities in sensory processing, sensorimotor organization, and maladaptive plasticity are thought to contribute to pathogenesis, with both genetic and environmental factors implicated. Current first-line treatments may provide only partial or transient relief. High-intensity focused ultrasound offers a means of focally ablating the target pathways implicated in dystonia. The ventro-oral complex, a relay within the motor thalamus, represents a key node in the corticobasal gangliathalamocortical circuit involved in directing motor output. Surgical radiofrequency lesioning of the Vo-complex confers sustained benefit in focal hand dystonia however the mechanisms that underlie this improvement remain unexplored. Pallidal intervention, via deep brain stimulation, has been shown to modify abnormal cortical motor plasticity in individuals with generalized dystonia, and this modification has been correlated with symptom improvement. It has been hypothesized that, to obtain long-term symptom improvement in focal hand dystonia, similar permanent network or circuit-based modification is required. In this prospective single-arm interventional study, we analysed the clinical and neurophysiological correlates of 11 individuals who underwent high-intensity focused ultrasound ventro-oral complex thalamotomy during 12 months follow-up. These measurements allowed us to identify the immediate and delayed impacts of ventro-oral thalamotomy on symptom burden, motor performance, motor cortex excitability, spatial specificity, and associative plasticity in individuals with focal hand dystonia. These findings were compared to 10 age and sex-matched healthy control participants. Consistent with our hypothesis, ventro-oral complex thalamotomy was associated with symptomatic improvement in focal hand dystonia as measured by standardized rating scales. There was no long-term loss of strength or motor dexterity in the treated limb, although adverse events were common and persisted in two participants. Inducible abnormalities in motor cortex excitability were attenuated following treatment and the spatial specificity of motor cortical responses shifted towards control values. Stimulus response curve analysis demonstrated modification of neuroplastic gain, echoing effects previously reported for pallidal stimulation in generalized dystonia. We concluded that ventro-oral complex thalamotomy may be associated with symptom improvement in focal hand dystonia and is associated with identifiable changes in motor cortex excitability. This work presents an opportunity for further studies to build on the identified mechanistic insights into single target lesioning, and advance the field of personalized circuit-informed strategies for the treatment of movement disorders.

Muscle-specific kinase (MuSK) myasthenia gravis (MG) is an uncommon subtype of acquired autoimmune neuromuscular junction disorder, often associated with a more severe clinical phenotype. Although MG may occasionally co-occur with other autoimmune conditions, the presence of multiple autoimmune diseases, termed poly-autoimmunity, is rare and presents significant diagnostic and therapeutic challenges. We describe the case of a 79-year-old woman with longstanding autoimmune thyroiditis and Sjögren’s syndrome who presented with severe bulbar and axial weakness. Initially suspected to have a Sjögren’s-associated myopathy, she was later diagnosed with MuSK MG. Early empirical treatment with intravenous immunoglobulin was followed by rituximab, resulting in marked clinical improvement and sustained remission more than a year later during follow up. Concurrently, she was diagnosed with latent autoimmune diabetes in adults (LADA), raising her autoimmune burden to four counts. This case underscores the importance of clinical vigilance and multidisciplinary evaluation in patients with poly-autoimmunity and highlights the potential for personalised, mechanism-driven therapeutic approaches.

Background: Dystonia after focal thalamic lesions including from high‐intensity focused ultrasound (HiFU) ablation have been reported. The risk remains uncertain and is increasingly relevant given the exponential rise in thalamic interventions for tremor over the last decade. Objectives: To evaluate the frequency and magnitude of dystonia before and after thalamic HiFU ablation in individuals with essential and dystonic tremor. Method: A blinded video‐based analysis was performed using standardized dystonia and tremor rating scales at baseline and two follow‐up intervals. Generalized linear mixed models assessed longitudinal change. Results: Thirty individuals met the inclusion/exclusion criteria. Whole body and treated limb dystonia severity did not significantly change over time. One individual developed clinically significant dystonia after treatment yielding an estimated risk of approximately 1–2%. Conclusion: Dystonic features were identified in all individuals at baseline, including those diagnosed with essential tremor. Thalamic HiFU ablation was not associated with progression of dystonia severity during follow‐up.

Background: Adductor respiratory laryngeal dystonia (ARLD) is a rare focal dystonia with vocal fold closure during inspiration leading to stridor and dyspnoea. Objectives: To characterize clinical features and outcomes of patients with ARLD at a tertiary movement disorders center. Methods: A retrospective cohort study was conducted of patients with adductor respiratory laryngeal dystonia attending a botulinum toxin injection clinic. Results: Nineteen patients were identified. Most were female (94.7%). Mean age of onset was 51.9 years (range 39–89). Comorbid movement disorders included laryngeal dystonia, cervical dystonia, blepharospasm, dystonic tremor, and Parkinson's disease. Median time from symptom onset to diagnosis was 3.0 years (IQR 2.0–15.0). 92.8% of injections with botulinum toxin were effective, although 46.2% were associated with adverse events. Conclusions: ARLD is associated with diagnostic delay. Symptoms of stridor alongside other movement disorders may provide clues. Treatment with botulinum toxin is effective, though careful dosing is required.

Background: Tremor is a common feature of multiple neurological conditions, and while medications can be effective in mild cases, surgical interventions are often required in moderate–severe syndromes or when medication side‐effects are unacceptable. Over decades, the field of functional neurosurgery has evolved from traditional radiofrequency ablation to deep brain stimulation, and more recently, to incisionless high frequency ultrasonic lesional techniques. All these modalities remain valuable tools for the clinicians and can be used to treat a variety of stereotactic targets with several targeting methods. This evolution has broadened access to surgical treatments for individuals with tremor and has provided both clinicians and patients with a wider range of therapeutic options. Consequently, selecting the most appropriate surgical treatment for an individual has arguably become more complex, relying on a combination of evidence base, personal, medical, social, and economic factors. Objective: In view of the evolving landscape of functional neurosurgery in tremor, driven by the resurgence of lesional procedures following the success of high‐intensity focused ultrasound, there is a need for a focused, updated review to support clinicians and patients selecting the most appropriate surgical treatment in tremor. Results: This educational review discusses the evidence behind, and surgical approaches to, essential tremor, Parkinson's disease tremor and dystonic tremor. Conclusions: Key topics addressed in the educational review include outcomes of different surgical treatments across tremor syndromes and stereotactic targets, waning benefit after surgical treatment, and optimization of patient selection with regards to high‐intensity focused ultrasound and deep brain stimulation.

There have been promising outcomes from the use of unilateral High-intensity focused ultrasound (HiFUS) thalamotomy in tremor-dominant Parkinson’s disease. However, the reliability of this treatment has been questioned due to the high rate of tremor relapse. Authors have hypothesized that treatment failure is due to insufficient HiFUS lesion size, though detailed volumetric lesion analyses are lacking. To report the blinded tremor outcomes of unilateral HiFUS thalamotomy in tremor-dominant Parkinson’s disease and correlate these outcomes with lesion characteristics, including the dentatorubrothalamic tract ablation overlap, which may provide valuable insights into the mechanisms behind tremor relapse and ultimately refine the optimal HiFUS target for tremor in Parkinson’s disease. Retrospective review of consecutively treated tremor-dominant Parkinson’s disease patients followed under a uniform protocol. Blinded tremor analysis was completed on pre- and post-operative videos. Patients were classified into two groups: ‘responder’ (≥50% improvement in Hand Tremor Score) or ‘suboptimal responder’ (<50% improvement in Hand Tremor Score) at the last follow-up. 17 patients with tremor-dominant Parkinson’s disease underwent a unilateral HiFUS thalamotomy at our centre. Pre- and post-operative videos were available in 15 patients for analysis. Baseline median Hand Tremor Score was 11.0 (9.5–14.5), improving to 6.0 (1–13.5) over a median 24-month (3–36) follow-up period (P = 0.098). Seven patients had ≥50% improvement in Hand Tremor Score, while eight patients had <50% improvement in Hand Tremor Score at the last follow-up. At the final follow-up, the median change in Hand Tremor Score from baseline was 91% in responders, compared to an 8% increase in the suboptimal responders (P < 0.002). Levodopa daily dose equivalent increased by 17% in responders (P = 0.043), and the difference between responders and suboptimal responders was significant at the final follow-up (P = 0.024). There was a trend for larger lesions in the suboptimal responders, 157.5mm3 (113.4–215) compared to 119.7mm3 (111.6–237.6) in responders. Further, the dentatorubrothalamic core lesion overlap was greater in the suboptimal responders, 41.7% (40.5–48.8%), compared to the responders, 27.1% (13.8–39.3%), (P = 0.010), and was associated with a higher Hand Tremor Score at the final follow-up. We found that unilateral HiFUS thalamotomy in tremor-dominant Parkinson’s Disease resulted in sustained tremor reduction in approximately 50% of patients but was also in the context of higher levodopa replacement. These favourable outcomes did not correlate with DRTT ablation overlap or lesion size, providing indirect evidence that the most efficacious HiFUS thalamic tremor target differs between essential tremor and tremor-dominant Parkinson’s Disease.

Clinically-relevant variants in the STUB1 gene have been associated with an autosomal dominant spinocerebellar ataxia 48 (SCA48), a recently described inherited neurodegenerative condition that is characterised by cognitive and psychiatric changes. To describe the clinical phenotype and genetic findings of three new Australian probands with STUB1 to expand the current understanding of the spectrum of clinical presentation and natural history of SCA48. Clinical and genetic review of patients diagnosed with SCA48 ataxia drawn from our centres. The third case was derived from a collaborating centre (Royal Brisbane Hospital). We identified three unrelated SCA48 patients with heterozygous pathogenic STUB1 variants. All presented with slowly progressive cerebellar ataxia with tremor and additional findings of dysarthria, parkinsonism, hypertonia, cognitive and psychiatric symptoms. Age of onset varied from 34 to 65 years of age. Brain MRI showed significant diffuse cerebellar atrophy, affecting the vermis and cerebellar hemispheres. We identified two novel pathogenic variants of STUB1 gene, and one previously reported pathogenic variant. Genetic testing for intermediate expansions of TBP (SCA17) identified TBP repeats within the normal range of 25–40 in all 3 probands. Our case series expands the clinical spectrum of SCA48. We highlight the importance of tremor as part of the clinical phenotype including upper limb rest tremor and Parkinsonian signs. Our cases lacked pathological TBP expansions and provide additional evidence that STUB1 (SCA48) can manifest as a monogenic disease.