The diagnostic framework and the therapeutic management of patients with adult dystonia can represent a challenge for clinical neurologists. The objective of the present paper is to delineate diagnostic and therapeutic recommendations for dystonia provided by a panel of Italian experts afferent to the Italian Society of Neurology, the Italian Academy for the Study of Parkinson's Disease and Movement Disorders, and the Italian Network on Botulinum Toxin. We first discuss the clinical approach and the instrumental assessment useful for diagnostic purpose. Then, we analyze the pharmacological, surgical, and rehabilitative therapeutic options for adult dystonia. Finally, we propose a hospital-territory network model for adult dystonia management. 

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Diagnostic and therapeutic recommendations in adult dystonia: a joint document by the Italian Society of Neurology, the Italian Academy for the Study of Parkinson’s Disease and Movement Disorders, and the Italian Network on Botulinum Toxin

PURPOSE The effects of neuromodulation are virtually unexplored in adductor laryngeal dystonia (AdLD), a disorder characterized by involuntary contraction of intrinsic laryngeal muscles. Recent findings indicated that intracortical inhibition is reduced in people with AdLD. Low-frequency repetitive transcranial magnetic stimulation (rTMS) induces prolonged intracortical inhibition, but the effects in AdLD are unexplored. This pilot and feasibility study aimed to examine the safety, feasibility, and effects of a single session 1 Hz rTMS over the laryngeal motor cortex (LMC) in people with AdLD and healthy individuals. METHODS The stimulation location was individualized and determined through TMS-evoked responses in the thyroarytenoid muscles using fine-wire electrodes. 1200 pulses of 1 Hz rTMS were delivered to the left LMC in two groups: Control (n = 6) and AdLD (n = 7). Tolerance, adverse effects, intracortical inhibition, and voice recordings were collected immediately before and after rTMS. Voice quality was assessed with acoustic-based and auditory-perceptual measures. RESULTS All participants tolerated the procedures, with no unexpected adverse events or worsening of symptoms. No significant effects on intracortical inhibition were observed. In the AdLD group, there was a large-effect size after rTMS in vocal perturbation measures and a small-effect size in decreased phonatory breaks. CONCLUSIONS One rTMS session over the LMC is safe and feasible, and demonstrated trends of beneficial effects on voice quality and phonatory function in AdLD. These preliminary findings support further investigation to assess clinical benefits in a future randomized sham-controlled trial. CLINICALTRIALS.GOV: NCT02957942, registered on November 8, 2016.

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Effects of low-frequency repetitive transcranial magnetic stimulation in adductor laryngeal dystonia: a safety, feasibility, and pilot study.

Laryngeal dystonia (LD) is isolated task-specific focal dystonia selectively impairing speech production. The first choice of LD treatment is botulinum neurotoxin (BoNT) injections into the affected laryngeal muscles. However, whether BoNT has a lasting therapeutic effect on disorder pathophysiology is unknown. We investigated short-term and long-term effects of BoNT treatment on brain function in patients with LD.A total of 161 participants were included in the functional MRI study. Statistical analyses examined central BoNT effects in patients with LD who were stratified based on the effectiveness and duration of treatment.Patients with LD who were treated and benefited from BoNT injections had reduced activity in the left precuneus compared with BoNT-naive and treatment nonbenefiting patients. In addition, BoNT-treated patients with adductor LD had decreased activity in the right thalamus, whereas BoNT-treated abductor patients with LD had reduced activity in the left inferior frontal cortex. No statistically significant differences in brain activity were found between patients with shorter (1-5 years) and longer (13-28 years) treatment durations. However, patients with intermediate treatment duration of 6-12 years showed reduced activity in the right cerebellum compared with patients with both shorter and longer treatment durations and reduced activity in the right prefrontal cortex compared with patients with shorter treatment duration.Our findings suggest that the left precuneus is the site of short-term BoNT central action in patients with LD, whereas the prefrontal-cerebellar axis is engaged in the BoNT response in patients with intermediate treatment duration of 6-12 years. Involvement of these structures points to indirect action of BoNT treatment on the dystonic sensorimotor network through modulation of motor sequence planning and coordination. 

Short- and Long-term Central Action of Botulinum Neurotoxin Treatment in Laryngeal Dystonia

Dystonia, chorea, hemiballismus and other dyskinesias

Currently, no clinically feasible objective measures exist that are specific to the signs of adductor laryngeal dystonia (LD), deterring effective diagnosis and treatment. This project sought to establish concurrent validity of a new automated acoustic outcome measure, designed to be specific to adductor laryngeal dystonia (AdLD): the spectral aggregate of the high-passed fundamental frequency contour (SAHfo).Twenty speakers with AdLD read voiced phoneme-loaded (more symptomatic) and voiceless phoneme-loaded (less symptomatic) sentences. LD discontinuities (defined as phonatory breaks, frequency shifts, and creak), the acoustic ramifications of laryngeal spasms, were manually identified. The frequency content of the fo contour was examined as a function of time, and content above 1000 Hz was summed to automatically calculate SAHfo. Multiple linear regression analysis was applied to SAHfo based on LD discontinuities and sentence type (voiced or voiceless phoneme-loaded).The regression model accounted for 41.1% of the variance in SAHfo. Both the LD discontinuities and sentence type were statistically related to SAHfo.Results of this study provide evidence of concurrent validity. SAHfo is an automatic outcome measure specific to acoustic signs of AdLD that may be useful to track treatment progress. 

Spectral Aggregate of the High-Passed Fundamental Frequency and Its Relationship to the Primary Acoustic Features of Adductor Laryngeal Dystonia

Objective. To delineate research priorities for improving clinical management of laryngeal dystonia, the NIH convened a multi-disciplinary panel of experts for a one-day workshop to examine the current progress in understanding its etiopathophysiology and clinical care. Methods. The participants reviewed the current terminology of disorder and discussed advances in understanding its pathophysiology since a similar workshop was held in 2005. Clinical and research gaps were identified, and recommendations for future directions were delineated. Results. The panel unanimously agreed to adopt the term “laryngeal dystonia” instead of “spasmodic dysphonia” to reflect the current progress in characterizations of this disorder. Laryngeal dystonia was recognized as a multifactorial, phenotypically heterogeneous form of isolated dystonia. Its etiology remains unknown, whereas the pathophysiology likely involves large-scale functional and structural brain network disorganization. Current challenges include the lack of clinically validated diagnostic markers and outcome measures and the paucity of therapies that address the disorder pathophysiology. Conclusion. Research priorities should be guided by challenges in clinical management of laryngeal dystonia. Identification of disorder-specific biomarkers would allow the development of novel diagnostic tools and unified measures of treatment outcome. Elucidation of the critical nodes within neural networks that cause or modulate symptoms would allow the development of targeted therapies that address the underlying pathophysiology. Given the rarity of laryngeal dystonia, future rapid research progress may be facilitated by multi-center, national and international collaborations.

Laryngeal Dystonia

Papers

Laryngeal Dystonia: Multidisciplinary Update on Terminology, Pathophysiology, and Research Priorities.