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.

Increasing prevalence 2015-2019 of amyotrophic lateral sclerosis in Sardinia, Italy.

BACKGROUND: While amyotrophic lateral sclerosis (ALS) incidence has increased during the last decades, structured evidence on increased prevalence is lacking. After reporting a significant yearly increase of ALS incidence over a 10-year period, we checked for increased prevalence in Southern Sardinia over a quinquennium. METHODS: ALS patients (El Escorial Criteria) recruited from the study area and followed at ALS Centre, University of Cagliari, were included. Prevalence was computed for January 1, 2015 and January 1, 2019 and was calculated for the overall ALS population as well as for tracheostomized and non-tracheostomized patients. RESULTS: We observed a non-significant trend for greater ALS prevalence in 2019 than in 2015 (18.31 per 100,000 vs. 15.26 per 100,000; rate ratio: 1.83, p = 0.01). By contrast, a significantly raising 2015 to 2019 ALS prevalence was observed in tracheostomized patients. No significant difference could be detected in non-tracheostomized. CONCLUSIONS: We provided the highest prevalence rate to date reported in the worldwide literature, and also showed a non-significant raising ALS prevalence in the Sardinian population over a quinquennium. The trend in raising ALS prevalence was likely due to extended survival due to invasive interventions.

The Italian tremor Network (TITAN): rationale, design and preliminary findings.

INTRODUCTION: The recently released classification has revised the nosology of tremor, defining essential tremor (ET) as a syndrome and fueling an enlightened debate about some newly conceptualized entities such as ET-plus. As a result, precise information of demographics, clinical features, and about the natural history of these conditions are lacking. METHODS: The ITAlian tremor Network (TITAN) is a multicenter data collection platform, the aim of which is to prospectively assess, according to a standardized protocol, the phenomenology and natural history of tremor syndromes. RESULTS: In the first year of activity, 679 patients have been recruited. The frequency of tremor syndromes varied from 32% of ET and 41% of ET-plus to less than 3% of rare forms, including focal tremors (2.30%), task-specific tremors (1.38%), isolated rest tremor (0.61%), and orthostatic tremor (0.61%). Patients with ET-plus were older and had a higher age at onset than ET, but a shorter disease duration, which might suggest that ET-plus is not a disease stage of ET. Familial aggregation of tremor and movement disorders was present in up to 60% of ET cases and in about 40% of patients with tremor combined with dystonia. The body site of tremor onset was different between tremor syndromes, with head tremor being most commonly, but not uniquely, associated with dystonia. CONCLUSIONS: The TITAN study is anticipated to provide clinically relevant prospective information about the clinical correlates of different tremor syndromes and their specific outcomes and might serve as a basis for future etiological, pathophysiological, and therapeutic research.

The Relationships Between Ataxia and Cognition in Spinocerebellar Ataxia Type 2.

The clinical spectrum of spinocerebellar ataxia type 2 includes motor manifestations and cognitive disturbances in executive functions, memory, and visuoconstructive skills. The relationships between severity of motor disturbances and altered cognition are poorly known. In this study, we assessed patients with spinocerebellar ataxia type 2 and age- and sex-matched healthy control subjects by a test battery including the Mini-mental State Examination, the Wisconsin Card Sorting test, and the Wechsler Memory Scale-Revised. The correlation between severity of motor ataxia (as assessed by a validated and widely used severity scale, the SARA scale, and by an objective automated computerized system of gait analysis) and altered cognition was then evaluated by Spearman correlation analysis. Patients performed worse than healthy controls in almost all administered neuropsychological tests. Nevertheless, only global intellectual abilities and executive functions significantly correlated with the overall severity of ataxia as assessed by the SARA scale, and impaired executive functions alone correlated with performance on several spatio-temporal gait analysis parameters. Our findings would probably suggest a prominent influence of executive functions on motor abilities in patients with spinocerebellar ataxia type 2 and raise the possibility that cognitive pharmaceutical or rehabilitative interventions may be of benefit in the management of motor problems in these patients.

Chronic coffee consumption and striatal DAT-SPECT findings in Parkinson's disease.

Coffee may interfere with the dopaminergic transmission, and this action would possibly enhance motor activity and exert an antidyskinetic effect in Parkinson's disease (PD). This study aimed to see whether coffee habit could be associated with change in striatal dopamine active transporter (DAT)-single photon emission computed tomography (SPECT) imaging in PD. A total of 83 PD patients (71 current coffee drinkers and 12 never drinkers) underwent a DAT-SPECT study, using [123I]FP-CIT as radionuclide. Socio-demographic and clinical information as well as smoking habit was collected at the time of imaging acquisition. The Unified Parkinson's Disease Rating Scale part III was used to evaluate disease severity. On multivariable analysis, chronic coffee consumption was not associated with any significant change in striatal uptake of the radionuclide. However, the number of years patients drunk coffee was correlated with a significant increase in age at PD onset (p < 0.001). Confirming a previous report, current cigarette smoking was associated with a reduction of radionuclide uptake in putamen and caudate (p < 0.001).

The anatomical basis of upper limb dystonia: lesson from secondary cases.

Upper limb dystonia is a focal dystonia that may affect muscles in the arm, forearm and hand. The neuroanatomical substrates involved in upper limb dystonia are not fully understood. Traditionally, dysfunction of the basal ganglia is presumed to be the main cause of dystonia but a growing body of evidence suggests that a network of additional cortical and subcortical structures may be involved. To identify the brain regions that are affected in secondary upper limb dystonia may help to better understand the neuroanatomical basis of the condition. We considered only patients with focal upper limb dystonia associated with a single localized brain lesion. To identify these patients, we conducted a systematic review of the published literature as well as the medical records of 350 patients with adult-onset dystonia seen over past 15 years at our movement disorder clinic. The literature review revealed 36 articles describing 72 cases of focal upper limb dystonia associated with focal lesions. Among patients at our clinic, four had focal lesions on imaging studies. Lesions were found in multiple regions including thalamus (n = 39), basal ganglia (n = 17), cortex (n = 4), brainstem (n = 4), cerebellum (n = 1), and cervical spine (n = 7). Dystonic tremor was not associated with any particular site of lesion, whereas there was a trend for an inverse association between task specificity and thalamic involvement. These data in combination with functional imaging studies of idiopathic upper limb dystonia support a model in which a network of different regions plays a role in pathogenesis.

Assessment of voice and speech symptoms in early Parkinson's disease by the Robertson dysarthria profile.

Changes in voice and speech are thought to involve 75-90% of people with PD, but the impact of PD progression on voice/speech parameters is not well defined. In this study, we assessed voice/speech symptoms in 48 parkinsonian patients staging <3 on the modified Hoehn and Yahr scale and 37 healthy subjects using the Robertson dysarthria profile (a clinical-perceptual method exploring all components potentially involved in speech difficulties), the Voice handicap index (a validated measure of the impact of voice symptoms on quality of life) and the speech evaluation parameter contained in the Unified Parkinson's Disease Rating Scale part III (UPDRS-III). Accuracy and metric properties of the Robertson dysarthria profile were also measured. On Robertson dysarthria profile, all parkinsonian patients yielded lower scores than healthy control subjects. Differently, the Voice Handicap Index and the speech evaluation parameter contained in the UPDRS-III could detect speech/voice disturbances in 10 and 75% of PD patients, respectively. Validation procedure in Parkinson's disease patients showed that the Robertson dysarthria profile has acceptable reliability, satisfactory internal consistency and scaling assumptions, lack of floor and ceiling effects, and partial correlations with UPDRS-III and Voice Handicap Index. We concluded that speech/voice disturbances are widely identified by the Robertson dysarthria profile in early parkinsonian patients, even when the disturbances do not carry a significant level of disability. Robertson dysarthria profile may be a valuable tool to detect speech/voice disturbances in Parkinson's disease.

Role of dopaminergic neurotransmission in pathophysiology of action tremor in Parkinson's disease.

BACKGROUND: Rest tremor (RT), a tremor that occurs in a body part that is completely supported against gravity, is together with rigidity and bradykinesia among the core features of Parkinson's disease (PD). In addition to classical RT, many PD patients also have action tremor (AT) occurring during sustained postures or voluntary movement. Earlier studies showed a good correlation between striatal dopamine transporter (DAT) binding, measured with [(123)I] FP-CIT SPET and bradykinesia. By contrast, neither rigidity nor rest tremor seems to be closely related to the degree of dopaminergic denervation as measured by DAT imaging. Little is known about the relationship, if any, between the severity of action tremor and striatal DAT binding. SUBJECTS AND METHODS: A cross-sectional study was conducted in 94 patients (57 men and 37 women) with Parkinson's disease staging 1-2 on the Hoehn-Yahr scale. Data on the severity of action tremor and other motor signs were collected using the Unified Parkinson's Disease Rating Scale part III. DAT imaging was performed after injection of 111-185MBq of (123)I-FP-CIT. Images were visualized on Workstation Xeleris 3.0 (GE Healthcare) and reconstructed with dedicated software by a nuclear physician blinded about the clinical information of patients. Spearman correlation coefficient was performed to evaluate the relationship between putamen DAT binding and severity of bradykinesia, severity of rigidity, RT and AT respectively. Multivariable logistic regression analysis was used to assess the association between age, sex, disease duration, and levodopa equivalent daily dose and investigated variables after adjusting for possible confounders. RESULTS: In this group of patients with early PD, DAT binding in the putamen significantly correlated with the severity of bradykinesia (Spearman r=-0.35, P<0.001) but not with the severity of rigidity (Spearman r=0.02, P=0.8), RT (Spearman r=0.05, P=0.6), or AT (Spearman r=-0.03, P=0.7). The findings were confirmed by multivariable regression analysis adjusted by age, sex, disease duration, and levodopa equivalent daily dose. CONCLUSION: Our study confirms the good correlation between putamen DAT binding and bradykinesia and the lack of correlation between putamen DAT binding and rigidity/RT. In addition, we failed to found any significant correlation between putamen DAT binding and severity of action tremor, which suggests a contribution of non-dopaminergic mechanisms to its pathophysiology.

Are Cognitive Symptoms Part of the Phenotypic Spectrum of Idiopathic Adult-Onset Dystonia? Summary of Evidence from Controlled Studies.

BACKGROUND: Cognitive dysfunction has been reported in idiopathic adult-onset dystonia (IAOD), but whether this is a primary or secondary component of the disorder remains uncertain. OBJECTIVE: Here, we aimed to analyze the key domains of abnormal cognitive performance in IAOD and whether this is associated with motor or mood changes. METHODS: Article selection for our critical review was guided by PRISMA guidelines (mesh terms "dystonia" and "cognitive," publication period: 2000-2022). Only peer-reviewed, English-language original case-control studies involving patients with IAOD who were not exposed to dopamine- or acetylcholine-modulating agents and validated cognitive assessments were included. RESULTS: Abstract screening ultimately yielded 22 articles for full-text review and data extraction. A greater proportion of studies (17 of 22, 82%) reported abnormal cognitive performance in IAOD. Most of these studies focused on blepharospasm (BSP) and cervical dystonia (10 and 14, respectively). Most studies reporting cognitive impairment (11 of 17) identified multidomain impairment in cognition. Executive functions were the domain most frequently explored (14 of 22 studies), 79% of which detected worse performance in people with dystonia. Results related to other domains were inconclusive. Cognitive abnormalities were independent of motor symptoms in most studies (7 of 12) that explored this relationship and independent of mood status in all 8 that investigated this. CONCLUSIONS: Within IAOD, cognitive dysfunction (in particular, executive dysfunction) has been documented mainly in BSP and cervical dystonia. More comprehensive testing is warranted to assess abnormalities in other domains and in other forms of IAOD, as well as to evaluate longitudinal progression of cognitive disturbances in this condition.

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.

Tremor in primary adult-onset dystonia: prevalence and associated clinical features.

OBJECTIVE: To investigate the frequency and the main clinical features of tremor in primary adult-onset dystonia (PAOD). METHODS: This cross-sectional study was conducted on 429 patients with PAOD from eight Italian movement disorder centres. RESULTS: Of the 429 dystonic patients, 72 (16.7%) had tremor. Although sex and age at dystonia onset were similar in dystonic patients who had tremor and those who did not, patients who had tremor were affected more often by focal cervical dystonia and less often by focal blepharospasm. Dystonia had a greater tendency to spread in patients with tremor. According to the Movement Disorder Society Consensus Statement, tremor was classified as dystonic tremor (DT) in 43 patients and tremor associated with dystonia (TAWD) in 23 patients. Six patients had both types of tremor. Taking into account potential confounding by age at onset and body distribution of the corresponding dystonia type, all the clinical features in patients with DT and in those with TAWD were comparable except the tendency of dystonia to spread, which was greater in patients with DT. CONCLUSIONS: Tremor is a relatively common feature occurring in about 17% of patients with primary late-onset dystonia. The association between tremor and dystonia spread suggests that this form of tremor may be a dystonic manifestation. Similarities in phenotypic features of DT and TAWD predominated over differences, suggesting that the two forms of tremor may be manifestations of the same disease. Differences in gender and body distribution of tremor between patients with dystonia and tremor and those of patients with essential tremor also suggest that tremor in dystonia and essential tremor are different entities.

AChR+ Ocular Myasthenia and Facial Hemispasm: A Case Report of Unusual Association and Botulinum Toxic Type A Safety and Efficacy.

INTRODUCTION: Hemifacial spasm represents segmental myoclonus of muscles innervated by the facial nerve, which is usually and successfully treated with botulinum toxin. Botulinum toxin (BTX) acts as an acetylcholine release inhibitor at presynaptic cholinergic junctions and therefore is considered contraindicated (or administrable with caution) in patients with neuromuscular disorders like Myasthenia Gravis (MG). Moreover, to date, the association of hemifacial spasm and ocular MG is extremely rare and only a few cases have been described. CASE PRESENTATION: We report the case of a 73 years old man with a 3-year history of ocular MG who developed a left hemifacial spasm. The patient underwent hemispasm, treatment with BTX type A (abobotulinum toxin-A, total dose of 50 IU) that resulted in safe and successful 6 months re-evaluation. CONCLUSION: Our results suggest that in selected cases with concomitant MG and conditions characterized by orbicularis oculi spasms or hemispasm, BTX therapy may not be contraindicated and could be given at longer intervals due to prolonged effects.

Impact of occupational categories on the incidence of amyotrophic lateral sclerosis in Sardinia Island, Italy.

OBJECTIVE: Occupation is one of the potential risk factors for amyotrophic lateral sclerosis (ALS) for which previous controlled studies produced inconsistent results. The aim of this study is to assess the impact of several groups of occupational categories on ALS incidence. METHODS: ALS patients from the southern part of Sardinia who had onset during 2012-2021 and fulfilled El Escorial revised diagnostic criteria were included. The risk of ALS was estimated in relation to the occupation held in 2011, as obtained from the 2011 Census that classified working activities in ten groups. Each occupational group was compared with a reference category represented by all other occupations, and rate ratio were calculated. Additive interaction between activity at work and age at ALS onset/sex on ALS incidence was calculated. RESULTS: Employment in agriculture/breeding and in the armed forces were significantly associated with increasing ALS risk. None of the other assessed occupation groups was associated with change in the risk of ALS. Geographic analysis indicated that the effect of agriculture/breeding was particularly evident in the areas of higher risk for the general population. By contrast, an inverse pattern of spatial risk was associated with armed forces activity at work. The increased risk of ALS associated to agriculture/breeding was more evident in older people. No significant interaction was detected between working in the armed forces and older age/sex. CONCLUSIONS: The significant interaction between agriculture/breeding and age suggests that the mechanisms leading to ALS are complex and involve several factors.

Validation of a guideline to reduce variability in diagnosing cervical dystonia.

BACKGROUND: Cervical dystonia is characterized by a variable pattern of neck muscle involvement. Due to the lack of a diagnostic test, cervical dystonia diagnosis is based on clinical examination and is therefore subjective. The present work was designed to provide practical guidance for clinicians in confirming or refuting suspected cervical dystonia. METHODS: Participants were video recorded according to a standardized protocol to assess 6 main clinical features possibly contributing to cervical dystonia diagnosis: presence of repetitive, patterned head/neck movements/postures inducing head/neck deviation from neutral position (item 1); sensory trick (item 2); and red flags related to conditions mimicking dystonia that should be absent in dystonia (items 3-6). Inter-/intra-rater agreement among three independent raters was assessed by k statistics. To estimate sensitivity and specificity, the gold standard was cervical dystonia diagnosis reviewed at each site by independent senior neurologists. RESULTS: The validation sample included 43 idiopathic cervical dystonia patients and 41 control subjects (12 normal subjects, 6 patients with isolated head tremor, 4 with chorea, 6 with tics, 4 with head ptosis due to myasthenia or amyotrophic lateral sclerosis, 7 with orthopedic/rheumatologic neck diseases, and 2 with ocular torticollis). The best combination of sensitivity and specificity was observed considering all the items except for an item related to capability to voluntarily suppress spasms (sensitivity: 96.1%; specificity: 81%). CONCLUSIONS: An accurate diagnosis of cervical dystonia can be achieved if, in addition to the core motor features, we also consider some clinical features related to dystonia mimics that should be absent in dystonia.

Clinical correlates of "pure" essential tremor: the TITAN study.

Background: To date, there are no large studies delineating the clinical correlates of "pure" essential tremor (ET) according to its new definition. Methods: From the ITAlian tremor Network (TITAN) database, we extracted data from patients with a diagnosis of "pure" ET and excluded those with other tremor classifications, including ET-plus, focal, and task-specific tremor, which were formerly considered parts of the ET spectrum. Results: Out of 653 subjects recruited in the TITAN study by January 2022, the data of 208 (31.8%) "pure" ET patients (86M/122F) were analyzed. The distribution of age at onset was found to be bimodal. The proportion of familial cases by the age-at-onset class of 20 years showed significant differences, with sporadic cases representing the large majority of the class with an age at onset above 60 years. Patients with a positive family history of tremor had a younger onset and were more likely to have leg involvement than sporadic patients despite a similar disease duration. Early-onset and late-onset cases were different in terms of tremor distribution at onset and tremor severity, likely as a function of longer disease duration, yet without differences in terms of quality of life, which suggests a relatively benign progression. Treatment patterns and outcomes revealed that up to 40% of the sample was unsatisfied with the current pharmacological options. Discussion: The findings reported in the study provide new insights, especially with regard to a possible inversed sex distribution, and to the genetic backgrounds of "pure" ET, given that familial cases were evenly distributed across age-at-onset classes of 20 years. Deep clinical profiling of "pure" ET, for instance, according to age at onset, might increase the clinical value of this syndrome in identifying pathogenetic hypotheses and therapeutic strategies.

Phenotypic Variability in Acquired and Idiopathic Dystonia.

Background: To date, a few studies have systematically investigated differences in the clinical spectrum between acquired and idiopathic dystonias. Objectives: To compare demographic data and clinical features in patients with adult-onset acquired and idiopathic dystonias. Methods: Patients were identified from among those included in the Italian Dystonia Registry, a multicenter Italian dataset of patients with adult-onset dystonia. Study population included 116 patients with adult-onset acquired dystonia and 651 patients with isolated adult-onset idiopathic dystonia. Results: Comparison of acquired and idiopathic dystonia revealed differences in the body distribution of dystonia, with oromandibular dystonia, limb and trunk dystonia being more frequent in patients with acquired dystonia. The acquired dystonia group was also characterized by lower age at dystonia onset, greater tendency to spread, lower frequency of head tremor, sensory trick and eye symptoms, and similar frequency of neck pain associated with CD and family history of dystonia/tremor. Conclusions: The clinical phenomenology of dystonia may differ between acquired and idiopathic dystonia, particularly with regard to the body localization of dystonia and the tendency to spread. This dissimilarity raises the possibility of pathophysiological differences between etiologic categories.

Does Olfactory Dysfunction Correlate with Disease Progression in Parkinson's Disease? A Systematic Review of the Current Literature.

BACKGROUND: Loss of olfaction is a well-established early feature of Parkinson's disease (PD). Although olfactory dysfunction has been widely described as a prodromal feature of PD in the literature, whether it can be considered a biomarker of PD progression is still a matter of debate. OBJECTIVE: The aim of this work is to define the possible relationship between the progression of olfactory dysfunction and other putative clinical hallmarks of PD over time, through a systematic review of the current literature. METHODS: We conducted a systematic review of the literature on PubMed from inception to March 2022. We included only longitudinal studies conducted on patients with diagnosis of idiopathic PD who underwent olfactory function testing at baseline and repeated it at least once during follow-up. RESULTS: Among 5740 records identified through database searching, nine longitudinal studies met full criteria and underwent data extraction. CONCLUSIONS: Olfaction seemed to decrease over time, albeit with a degree of fluctuation. Moreover, smell detection ability seems to deteriorate more rapidly in the early phase of disease, indicating a possible association with disease progression. More studies are needed to better understand the role of olfaction as a biomarker of PD progression over time.

Incidence of amyotrophic lateral sclerosis in Sardinia, Italy: age-sex interaction and spatial-temporal variability.

Objective: This study assessed amyotrophic lateral sclerosis (ALS) incidence in Sardinia, Italy, and the combined contribution of age and gender to disease risk. We also checked disease incidence for spatial-temporal variability. Methods: ALS patients from all neurological centers of the study area who had onset during 2010-2019 and fulfilled El Escorial revised diagnostic criteria were included. Incidence was calculated for the overall study area and each province separately. Additive interaction between age and sex on ALS incidence was assessed. Results: The average crude annual incidence rate was 3.6/100,000 person-years (95% CI, 3.2-4.1), 3.1/100,000 person-years (95% CI, 2.7-3.5) when age-adjusted. Incidence was greater among people aged ≥65 years and men, with the two variables undergoing significant additive interaction. Incidence increased yearly over the study period, with annual incidence correlating with the increasing yearly frequency of people aged ≥65 years, but not with the proportion of incident cases carrying genetic mutations. Stratifying by province, the rates from Oristano and South Sardinia were higher than the rate from Cagliari. ALS patients from areas at different risk were comparable for frequency of clinical/genetic features. Conclusion: ALS incidence in Sardinia was in the upper part of the European range of variability. We also provided new information about age and sex as risk factors for ALS, showing male sex as a modifier of the effect of aging on ALS incidence. Spatial-temporal variations in ALS incidence correlated to changes in the proportion of the aging population rather than to the distribution of genetic factors.

A Bayesian approach to Essential Tremor plus: A preliminary analysis of the TITAN cohort.

BACKGROUND: The construct of Essential Tremor plus (ET-plus) refers to patients who also have rest tremor and/or mild neurologic signs of unknown significance. It is unclear whether soft signs represent confounding factors or are useful in suspecting an alternative condition. METHODS: Using a Bayesian approach to ET-plus patients recruited in The ITAlian tremor Network (TITAN), we analyzed the probability that these patients do not have ET. RESULTS: The data of 274 ET-plus patients were extracted from the TITAN database. The majority of patients (240/274; 87.5%) had a single soft sign. The post-test probability of not having ET was different according to the specific soft sign: namely, 0.64 (rest tremor); 0.46 (questionable dystonia); 0.85 (questionable bradykinesia); 0.19 (soft gait impairment); and 0.09 (questionable cognitive issues). In patients with multiple soft signs, the post-test probability of not having ET was higher than 50% for 7 out of 11 combinations, accounting for 44.1% of subjects. Overall, the post-test probability of not having ET was higher than 50% in up to 71.5% of ET-plus patients. DISCUSSION: We have here shown that: 1) the soft signs differently contribute in modulating the probability that a patient does not have ET; and 2) the effect of multiple soft signs are not always addictive. Future studies are needed to collect prevalence figures of soft signs in different neurological disorders as well as in the elderly and to calculate their value in predicting the development of an alternative tremor syndrome.