Does sex influence the natural history of idiopathic adult-onset dystonia?

BACKGROUND: Several earlier studies showed a female predominance in idiopathic adult-onset dystonia (IAOD) affecting the craniocervical area and a male preponderance in limb dystonia. However, sex-related differences may result from bias inherent to study design. Moreover, information is lacking on whether sex-related differences exist in expressing other dystonia-associated features and dystonia spread. OBJECTIVE: To provide accurate information on the relationship between sex differences, motor phenomenology, dystonia-associated features and the natural history of IAOD. METHODS: Data of 1701 patients with IAOD from the Italian Dystonia Registry were analysed. RESULTS: Women predominated over men in blepharospasm, oromandibular, laryngeal and cervical dystonia; the sex ratio was reversed in task-specific upper limb dystonia; and no clear sex difference emerged in non-task-specific upper limb dystonia and lower limb dystonia. This pattern was present at disease onset and the last examination. Women and men did not significantly differ for several dystonia-associated features and tendency to spread. In women and men, the absolute number of individuals who developed dystonia tended to increase from 20 to 60 years and then declined. However, when we stratified by site of dystonia onset, different patterns of female-to-male ratio over time could be observed in the various forms of dystonia. CONCLUSIONS: Our findings provide novel evidence on sex as a key mediator of IAOD phenotype at disease onset. Age-related sexual dimorphism may result from the varying exposures to specific age-related and sex-related environmental risk factors interacting in a complex manner with biological factors such as hormonal sex factors.

Does thyroid diseases contribute to the natural history of idiopathic adult-onset dystonia? Data from the Italian Dystonia Registry.

A few earlier observations and recent controlled studies pointed to the possible contribution of thyroid diseases in idiopathic adult-onset dystonia (IAOD). The aim of this study was to investigate the association between thyroid status and clinical characteristics of IAOD, focusing on dystonia localization, spread, and associated features such as tremors and sensory tricks. Patients were identified from those included in the Italian Dystonia Registry, a multicentre dataset of patients with adult-onset dystonia. The study population included 1518 IAOD patients. Patients with hypothyroidism and hyperthyroidism were compared with those without any thyroid disease. In the 1518 IAOD patients, 167 patients (11%; 95% CI 9.5-12.6%) were diagnosed with hypothyroidism and 42 (2.8%; 95% CI 1.99-3.74) with hyperthyroidism. The three groups were comparable in age at dystonia onset, but there were more women than men in the groups with thyroid disease. Analysing the anatomical distribution of dystonia, more patients with blepharospasm were present in the hyperthyroidism group, but the difference did not reach statistical significance after the Bonferroni correction. The remaining dystonia-affected body sites were similarly distributed in the three groups, as did dystonia-associated features and spread. Our findings provided novel information indicating that the high rate of thyroid diseases is not specific for any specific dystonia subpopulation and does not appear to influence the natural history of the disease.

Oromandibular dystonia: from onset to spread a multicenter italian study.

BACKGROUND: Detailed information about the epidemiological and phenomenological differences among the aetiological subtypes of oromandibular dystonia (OMD) is lacking. Moreover, the OMD tendency to spread to other body sites has never been investigated. AIM: To compare the main demographic and clinical features of OMD in different aetiological groups and assess the risk of spread. MATERIALS AND METHODS: We retrospectively analysed data from patients contained in the Italian Dystonia Registry. The risk of spread was assessed by Kaplan Meyer curves and Cox regression analysis. RESULTS: The study included 273 patients (175 women) aged 55.7 years (SD 12.7) at OMD onset. Female predominance was observed. Idiopathic dystonia was diagnosed in 241 patients, acquired dystonia in 22. In 50/273 patients, dystonia started in the oromandibular region (focal OMD onset); in 96/273 patients the onset involved the oromandibular region and a neighbouring body site (segmental/multifocal OMD onset); and in 127/273 patients OMD was a site of spread from another body region. Sensory trick (ST) and positive family history predominated in the idiopathic group. No dystonia spread was detected in the acquired group, whereas spread mostly occurred within the first five years of history in 34% of the focal OMD onset idiopathic patients. Cox regression analysis revealed ST as a significant predictor of spread (HR, 12.1; 95% CI, 2.5 - 18.8; P = 0.002). CONCLUSION: This large study provides novel information about the clinical phenomenology of idiopathic and acquired OMD. We pointed out a possible role of oestrogens in favouring dystonia development. Moreover, we described for the first time the association between ST and dystonia spread, revealing possible common pathophysiological mechanisms. Our findings may be suggested as a referral point for future pathophysiological and therapeutic studies on OMD.

Botulinum toxin in clinical practice: state of the art of administration provisions in Italy.

Botulinum neurotoxin type A is a remarkable therapeutic approach for muscle hyperactivity syndromes, pain, and related disorders. Despite its wide application in neurology, there is a poor knowledge on delivery protocols and dispatch from the healthcare providers. In this study, we reported the result of a 2020 survey about the administration provisions of botulinum neurotoxin type A in Italy. Seven questions including information on characteristics of botulinum neurotoxin facilities, prescription, reimbursement, and execution modalities were adopted. Sixty participants answered the survey. Despite the wide availability of dedicated centers all over the national territory, there was a surprising lack of standardized and shared administration provisions. Most of the Italian medical structures delivered botulinum neurotoxin through outpatient clinics located in public hospital facilities, through the "F file" reimbursement modality. However, there was no agreement on the reimbursement request modality, creating differences in public costs relative to the botulinum toxin consumption across Italy.

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.

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.

Consensus guidelines for botulinum toxin therapy: general algorithms and dosing tables for dystonia and spasticity.

Botulinum toxin (BT) therapy is a complex and highly individualised therapy defined by treatment algorithms and injection schemes describing its target muscles and their dosing. Various consensus guidelines have tried to standardise and to improve BT therapy. We wanted to update and improve consensus guidelines by: (1) Acknowledging recent advances of treatment algorithms. (2) Basing dosing tables on statistical analyses of real-life treatment data of 1831 BT injections in 36 different target muscles in 420 dystonia patients and 1593 BT injections in 31 different target muscles in 240 spasticity patients. (3) Providing more detailed dosing data including typical doses, dose variabilities, and dosing limits. (4) Including total doses and target muscle selections for typical clinical entities thus adapting dosing to different aetiologies and pathophysiologies. (5) In addition, providing a brief and concise review of the clinical entity treated together with general principles of its BT therapy. For this, we collaborated with IAB-Interdisciplinary Working Group for Movement Disorders which invited an international panel of experts for the support.

A video of best practice recommendations for making botulinum toxin therapy safe during the COVID-19 pandemic.

The physician and patient come into close contact during botulinum toxin treatments, increasing the chances of COVID-19 infection. Therefore, it is essential to use an effective injection method that can prevent infection with SARS-CoV-2 virus. In order to minimize the risk of SARS-CoV-2 transmission during botulinum toxin treatment in the COVID-19 era, the Italian Botulinum Toxin Network study group of the Italian Society of Neurology has prepared a video of best practice recommendations on how to organize the work of a clinic performing botulinum toxin treatments.

Neuroimaging in idiopathic adult-onset focal dystonia.

We aimed to study the attitude of Italian neurologists in the use of conventional MRI in patients with idiopathic adult-onset focal dystonia. Patients were included in the Italian Dystonia Registry by experts working in different Italian centers. MRI was available for 1045 of the 1471 (71%) patients included in the analysis. Using logistic regression analysis, we found that MRI was more likely to be performed in patients with cervical dystonia, spasmodic dysphonia, or non-task-specific upper limb dystonia, whereas it was less likely to be performed in patients with blepharospasm or task-specific upper limb dystonia. We did not find differences in the number of MRIs performed between neurological centers in Northern, Central, and Southern Italy. We conclude that although the diagnosis of idiopathic adult-onset dystonia is mainly based on clinical grounds, many movement disorder experts rely on MRI to confirm a diagnosis of idiopathic dystonia. We suggest that neuroimaging should be used in patients with adult-onset focal dystonia to rule out secondary forms.

Coverage of the requirements of first and second level stroke unit in Italy.

BACKGROUND AND AIM: In the scientific literature, there is unanimous consensus that hospitalization in stroke unit (SU) is the most important treatment for stroke patients. In this regard, the Act number 70/2015 by the Italian government identified specific skills that contribute to a classification of SU and outlined a "hub and spoke" stroke network. The aim of our study was to check the coverage of requirements of first and second level SU in the national territory and to shed light on any deficit or misdistribution of resources. MATERIAL AND METHODS: In 2019, a survey on the current situation related to stroke care in Italy was carried out by the Italian Society of Neurology (SIN), The Italian Stroke Organization (ISO), and the Association for the Fight against Stroke (A.L.I.Ce). RESULTS: First level SU was found to be 58 against a requirement, according to the Act 70/2015, of 240. Second level SU was found to be 52 compared with an expected requirement of 60. Neurointerventionists were 280 nationally, with a requirement of 240. A misdistribution of resources within individual regions was often seen. CONCLUSIONS: The survey demonstrated a severe shortage of beds dedicated to cerebrovascular diseases, mainly because of lack of first level SU, especially in central and southern Italy. It also suggests that the current hub and spoke system is not yet fully implemented across the country and that resources should be better distributed in order to ensure uniform and fair care for all stroke patients on the whole territory.

Effect of the COVID-19 pandemic and the lockdown measures on the local stroke network.

INTRODUCTION: The COVID-19 outbreak highly impacted the acute ischemic stroke care management. The primary end point of the study was to evaluate the impact of the COVID-19 outbreak and the following lockdown measures on our hub-and-spoke network; the secondary end point was to evaluate if the impact of the COVID-19 outbreak was different in hub-and-spoke centers. METHODS: This was a retrospective multicenter observational study conducted at the Stroke Units of Policlinico Gemelli, Ospedale San Filippo Neri, Ospedale di Belcolle, and Ospedale San Camillo de Lellis. We collected clinical reports of all consecutive patients admitted with diagnosis of acute ischemic stroke or transient ischemic attack (TIA) during the phase 1 of the lockdown period (11 March 2020-4 May 2020). As controls, we used all consecutive patients admitted for acute ischemic stroke or TIA in the same period of the previous year. RESULTS: A total of 156 and 142 clinical reports were collected in 2019 and 2020, respectively. During the COVID-19 outbreak, we observed a reduction of number of thrombolysis, a reduction of the length of hospitalization, and an increase of pneumonia. Regarding performance indicators, we observed an increase in onset-to-door time and in door-to-groin time. We did not observe any statistically significant interaction between year (2019 vs 2020) and facility of admission (hub vs spoke) on all variables analyzed. DISCUSSION: Our observational study, involving hub-and-spoke stroke network of a wide regional area, indicates that the COVID-19 outbreak impacted on the acute stroke management. This impact was equally observed in hub as well as in spoke centers.

Idiopathic Non-task-Specific Upper Limb Dystonia, a Neglected Form of Dystonia.

OBJECTIVE: The objective of this study was to describe the clinical and demographic features of idiopathic non-task-specific upper limb dystonia compared with the task-specific form. METHODS: In this retrospective study, adult patients with idiopathic upper limb dystonia, either focal or as part of a segmental/multifocal dystonia, from the Italian Dystonia Registry were enrolled. In patients with focal upper limb dystonia, dystonia spread was estimated by survival analysis. RESULTS: Of the 1522 patients with idiopathic adult-onset dystonia included in the Italian Dystonia Registry, we identified 182 patients with upper limb dystonia. Non-task-specific dystonia was present in 61.5% of enrolled cases. Women predominated among non-task-specific patients, whereas men predominated in the task-specific group. Peak age of upper limb dystonia onset was in the sixth decade in the non-task-specific group and in the fourth decade in the task-specific group. In both groups, upper limb dystonia started as focal dystonia or as part of a segmental dystonia. Segmental onset was more frequent among non-task-specific patients, whereas focal onset predominated among task-specific patients. Dystonic action tremor was more frequent among non-task-specific patients. No significant differences between groups emerged in terms of sensory trick frequency, rest tremor, or family history of dystonia. In patients with focal upper limb dystonia, dystonia spread was greater in the non-task-specific group. CONCLUSION: Novel information on upper limb dystonia patients suggests that non-task-specific and task-specific upper limb dystonia have different demographic and clinical features. However, it remains to be determined whether these differences also reflect pathophysiological differences. © 2020 International Parkinson and Movement Disorder Society.

Demographic and clinical determinants of neck pain in idiopathic cervical dystonia.

Cervical dystonia is associated with neck pain in a significant proportion of cases, but the mechanisms underlying pain are largely unknown. In this exploratory study, we compared demographic and clinical variables in cervical dystonia patients with and without neck pain from the Italian Dystonia Registry. Univariable and multivariable logistic regression analysis indicated a higher frequency of sensory trick and a lower educational level among patients with pain.

Botulinum toxin for the management of spasticity in multiple sclerosis: the Italian botulinum toxin network study.

BACKGROUND: Botulinum toxin (BT) is an effective and safe treatment for spasticity, with limited evidence in multiple sclerosis (MS). We aim to describe the use of BT for the management of MS spasticity in the clinical practice, its combination with other anti-spastic treatments in MS and possible MS clinical correlates. METHODS: This is a multicentre cross-sectional observational study including 386 MS patients, receiving BT for spasticity in 19 Italian centres (age 53.6 ± 10.9 years; female 228 (59.1%); disease duration 18.7 ± 9.2 years; baseline Expanded Disability Status Scale (EDSS) 6.5 (2.0-9.0)). RESULTS: BT was used for improving mobility (n = 170), functioning in activities of daily living (n = 56), pain (n = 56), posturing-hygiene (n = 63) and daily assistance (n = 41). BT formulations were AbobotulinumtoxinA (n = 138), OnabotulinumtoxinA (n = 133) and IncobotulinumtoxinA (n = 115). After conversion to unified dose units, higher BT dose was associated with higher EDSS (Coeff = 0.591; p < 0.001), higher modified Ashworth scale (Coeff = 0.796; p < 0.001) and non-ambulatory patients (Coeff = 209.382; p = 0.006). Lower BT dose was used in younger patients (Coeff = - 1.746; p = 0.009), with relapsing-remitting MS (Coeff = - 60.371; p = 0.012). BT dose was higher in patients with previous BT injections (Coeff = 5.167; p = 0.001), and with concomitant treatments (Coeff = 43.576; p = 0.022). Three patients (0.7%) reported on post-injection temporary asthenia/weakness (n = 2) and hypophonia (n = 1). CONCLUSION: BT was used for spasticity and its consequences from the early stages of MS, without significant adverse effects. MS-specific goals and injection characteristics can be used to refer MS patients to BT treatment, to decide for the strategy of BT injections and to guide the design of future clinical trials and observational studies.

The influence of sex on non-motor wearing-off in Parkinson's disease: A WORK-PD post-hoc study.

INTRODUCTION: The wearing-off phenomenon is characterized by the recurrence of motor and non-motor symptoms of Parkinsonism during a period free from levodopa. It is a pivotal aspect marking the end of the pharmacological "honeymoon" period in Parkinson's disease (PD). A growing body of literature is connecting sex with the likelihood of developing fluctuations. We investigated such an association in a post-hoc analysis of the large WORK-PD study. METHODS: WORK-PD analyzed the usability of the wearing-off questionnaire 19 (WOQ19) in clinical practice and included cross-sectional data on age, disease duration, time on levodopa, Hoehn and Yahr stage, and WOQ19 scores of 532 PD patients. In the present study, we selected patients with an exposure time to levodopa of at least 1 year. RESULTS: A total of 380 patients were included. Women reported a higher number of wearing-off symptoms than men (6.09 ±â€¯3.39 vs 4.96 ±â€¯3.11, p = 0.0006). Sex groups also differed in non-motor symptoms (2 ±â€¯1.9 vs 1.5 ±â€¯1.5, p = 0.021), particularly behavioral wearing-off scores being higher in women (p < 0.001). The latter were primarily featured by anxiety-related phenomena. Finally, there was a significant interaction between behavioral symptoms, sex, and age at onset (df = 2, F = 9.79, p < 0.0001), whereas no such interaction was observed with levodopa exposure and motor impairment, unlike motor symptoms. DISCUSSION: Women showed a greater propensity than men to experience wearing-off, particularly non-motor fluctuations on the anxiety spectrum. The latter may demonstrate a lesser reliance on dopamine compared to motor symptoms. This observation could be underpinned by biological variances between genders at the neurotransmitter level.

Comprehensive Observational and Longitudinal study on the Outbreak of Stroke-related Spasticity focusing on the Early Onset management with Botulinum NeuroToxin (COLOSSEO-BoNT): protocol for a real-world prospective observational study on upper limb spasticity.

INTRODUCTION: Poststroke spasticity (PSS) affects up to 40% of patients who had a stroke. Botulinum neurotoxin type A (BoNT-A) has been shown to improve spasticity, but the optimal timing of its application remains unclear. While several predictors of upper limb PSS are known, their utility in clinical practice in relation to BoNT-A treatment has yet to be fully elucidated. The COLOSSEO-BoNT study aims to investigate predictors of PSS and the effects of BoNT-A timing on spasticity-related metrics in a real-world setting. METHODS AND ANALYSIS: The recruitment will involve approximately 960 patients who have recently experienced an ischaemic stroke (within 10 days, V0) and will follow them up for 24 months. Parameters will be gathered at specific intervals: (V1) 4, (V2) 8, (V3) 12, (V4) 18 months and (V5) 24 months following enrolment. Patients will be monitored throughout their rehabilitation and outpatient clinic journeys and will be compared based on their BoNT-A treatment status-distinguishing between patients receiving treatment at different timings and those who undergo rehabilitation without treatment. Potential predictors will encompass the Fugl-Meyer assessment, the National Institute of Health Stroke Scale (NIHSS), stroke radiological characteristics, performance status, therapies and access to patient care pathways. Outcomes will evaluate muscle stiffness using the modified Ashworth scale and passive range of motion, along with measures of quality of life, pain, and functionality. ETHICS AND DISSEMINATION: This study underwent review and approval by the Ethics Committee of the Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy. Regardless of the outcome, the findings will be disseminated through publication in peer-reviewed journals and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: NCT05379413.

Comparing Essential Tremor with and without Soft Dystonic Signs and Tremor Combined with Dystonia: The TITAN Study.

BACKGROUND: Tremor disorders remain as clinical diagnoses and the rate of misdiagnosis between the commonest non-parkinsonian tremors is relatively high. OBJECTIVES: To compare the clinical features of Essential Tremor without other features (pure ET), ET plus soft dystonic signs (ET + DS), and tremor combined with dystonia (TwD). METHODS: We compared the clinical features of patients with pure ET, ET + DS, and TwD enrolled in The ITAlian tremor Network (TITAN). Linear regression models were performed to determine factors associated with health status and quality of life. RESULTS: Three-hundred-eighty-three patients were included. Sex distribution was significantly different between the groups with males being more represented in pure ET and females in TwD. The initial site of tremor was different between the groups with about 40% of TwD having head tremor and ET + DS unilateral upper limb tremor at onset. This pattern mirrored the distribution of overt dystonia and soft dystonic signs at examination. Sensory trick, task-specificity, and position-dependence were more common, but not exclusive, to TwD. Pure ET patients showed the lowest degree of alcohol responsiveness and ET + DS the highest. Midline tremor was more commonly encountered and more severe in TwD than in the other groups. Regression analyses demonstrated that tremor severity, sex, age, and to a lesser degree the variable "group", independently predicted health status and quality of life, suggesting the existence of other determinants beyond tremor. CONCLUSIONS: Pure ET and TwD manifest with a phenotypic overlap, which calls for the identification of diagnostic biomarkers. ET + DS shared features with both syndromes, suggesting intra-group heterogeneity.

MOG-IgG positive optic neuritis after SARS-CoV-2 infection.

BACKGROUND: Many neurologic complications have been described after severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) including atypical cases of optic neuritis (ON), positive to myelin oligodendrocyte glycoprotein (MOG) IgG. OBJECTIVE: To report a case of MOG-IgG-associated ON and discuss why SARS-CoV-2 infection could be a potential trigger. METHODS: Retrospective single case report. RESULTS: We report a case of ON with positive MOG-IgG developed 15 days after presentation of SARS-CoV-2 infection. CONCLUSION: This report suggests that SARS-CoV-2 infection may have triggered autoantibodies production against MOG leading to ON.

Post-COVID simultaneous onset of Graves' disease and ocular myasthenia gravis in a patient with a complex ocular motility impairment.

A 74-years-old man experienced severe diplopia one month after recovery from an uncomplicated SARS-CoV-2 infection. Neurological examination was normal whereas ophthalmological examination showed bilateral exophthalmos with a complex ocular motility disorder characterized by a pseudo-internuclear ophthalmoplegia after fatigue associated to impairment of elevation and infraduction. Antibodies against TSH and acetylcholine receptors were positive; subsequent hormonal tests, ultrasonography of thyroid gland, single fiber electromyography and orbit MRI confirmed the diagnosis of concomitant Graves Disease (GD) and Myasthenia Gravis (MG). The coexistence between MG and GD is not rare but simultaneous onset after viral infection is very unsual. The complex ocular disorder simulated a deficit of the oculomotor nerve nuclei, and on clinical examination it posed some problems in the diagnosis. We suggest that recent SARS-COV-2 infection may have triggered a complex autoimmune response.