BackgroundFunctional Motor Disorders (FMDs) represent a diagnostic and therapeutic challenge in pediatric neurology, particularly among adolescents. Their clinical presentation is common but often nonspecific, leading to frequent misdiagnoses and diagnostic delays. We aimed to characterize FMDs in adolescents and to examine the frequency of isolated and combined phenotypes and their associations with demographic and clinical variables.MethodsIn this observational study, data were obtained from the Italian Registry of FMDs, including patients with a clinically definite diagnosis of FMD consecutively enrolled at 25 Italian tertiary movement disorders centers.ResultsAmong 847 patients, 93 (10.9%) had adolescent-onset FMDs. Motor phenotypes did not differ significantly between adolescent- and adult-onset FMDs, with the exception of parkinsonism, which was observed only in the latter. Compared with adult-onset FMDs, adolescent-onset FMDs were associated with a longer disease duration, a higher number of medical consultations before diagnosis, and a higher frequency of functional seizures and infections, but with lower rates of insomnia, fatigue, and antipsychotic use. In multivariable analysis, adolescent-onset FMDs remained independently associated with a greater number of medical consultations (adjusted OR 1.07; 95% CI 1.02-1.13), the presence of functional seizures (adjusted OR 2.06; 95% CI 1.09-3.8), and with lower occurrence of insomnia (adjusted OR 0.49; 95% CI 0.27-0.92) and fatigue (adjusted OR 0.51; 95% CI 0.30-0.86). Pain was more likely to be associated with the combined FMDs phenotype.ConclusionsAdolescent-onset FMDs are common and are associated with several non-motor symptoms in tertiary movement disorders centers. Early and accurate diagnosis may help to reduce unnecessary investigations and inappropriate treatments.

Background: The relationship between essential tremor (ET) and Parkinson's disease (PD) remains controversial. Beyond viewing ET as a discrete risk factor for PD, recent frameworks propose that an ET phenotype may represent a clinical presentation of prodromal PD (pPD), consistent with the current reconceptualization of ET as a syndrome. Whether co-occurring subtle motor signs alter pPD probability in ET remains unknown. Methods: Using the MDS research criteria, we calculated pPD probability in a large cohort of ET patients with and without subtle motor signs (rest tremor, hypomimia, isolated rigidity, reduced arm swing, altered repetitive movements, global slowing). Multivariable regression was used to identify independent predictors of pPD probability. Results: Among 599 ET patients (median disease duration: 12 years), only 6 (1.0%) met criteria for probable pPD. Although ET patients with subtle motor signs exhibited higher continuous pPD probability scores than those without, the frequency of possible or probable pPD did not differ significantly between groups. In multivariable regression, neither ET nor individual subtle motor signs, but hypomimia, were independent predictors of pPD probability, which was primarily driven by older age and male sex. Conclusions: Long-standing ET, whether isolated or accompanied by subtle motor signs, is not associated with pPD, with the possible exception of co-occurring hypomimia.

BACKGROUND:The role of occupational background in functional motor disorders (FMDs) remains poorly defined. Controlled data using standardized occupational classifications and information on education level are limited. OBJECTIVE:To assess the association between occupational background and FMDs in working-age individuals and to examine the role of education level in this relationship. METHODS:We conducted a case-control study using data from the Italian Registry of Functional Motor Disorders. Patients aged 30-65 years with available occupational information were included and compared with healthy controls. Occupations were classified according to the 2021 Italian National Institute of Statistics classification. Education level was expressed as years of schooling. Multivariable logistic regression models were used to assess the association between occupational categories and FMD status after adjustment for age, sex, and years of schooling. RESULTS:A total of 479 patients with FMDs and 252 healthy controls were included. Patients had fewer years of schooling than controls, and the distribution of occupational categories differed between groups. In particular, qualified professions in commercial activities and services, artisans and skilled workers, and machine operators were more frequently represented among patients. In multivariable analysis, these occupational categories and years of schooling remained independently associated with FMD status. Healthcare professions did not differ between patients and controls. CONCLUSIONS:Occupational background and education level were independently associated with FMDs in working-age individuals. These findings support the view that occupational factors may be relevant as possible precipitating or maintaining factors within the biopsychosocial model of FMDs, without implying a causal relationship.

BACKGROUND:Pain is a frequent and disabling symptom in patients with Functional Motor Disorders (FMD), yet its clinical correlates and impact have not been characterized in large, representative cohorts. The aims of this study were to identify clinical predictors and correlates of pain intensity and interference among FMD patients. METHODS:We conducted a cross-sectional analysis within the Italian Registry of Functional Motor Disorders, including 466 adults with FMD recruited from 25 movement disorders centers. Pain was assessed using the Brief Pain Inventory (BPI), which captures pain experienced during the 24 h prior to assessment, alongside sociodemographic, clinical, and psychometric data on depression, anxiety, alexithymia, fatigue, and quality of life. RESULTS:Pain was reported by 78.8% of participants. Fibromyalgia strongly predicted pain, whereas comorbid epilepsy was linked to reduced risk. The presence of pain was associated with a poorer self-reported sense of physical health. Among patients with pain, higher intensity and interference were associated with younger age, Restless Legs Syndrome, Irritable Bowel Syndrome, physical trauma as a precipitating factor for FMD, anxiety, and poorer physical and mental health. Painkillers were prescribed to 41.6% of patients, yet 39.27% reported pain despite medications, and 39.48% had pain while not receiving analgesics. CONCLUSIONS:Pain is highly prevalent in FMD when assessed over the previous 24 h and is frequently reported in patients who are either not receiving analgesics or continue to experience pain despite treatment. Multiple factors influence its intensity and interference in daily life. Longitudinal studies are needed to clarify causal relationships and to inform pain management strategies.

Background: Executive dysfunction may be an early marker of neurodegenerative disorders, even if it is difficult to detect objectively. Subjective cognitive decline (SCD) may reflect subtle deficits in executive functions (EFs); however, SCD is also strongly influenced by affective factors such as depression. Whether depressive symptoms alter the link between EFs and SCD remains unclear. The present study tested whether depressive symptoms moderate the association between executive functioning and SCD. Methods: In this cross-sectional study, 65 outpatients completed a comprehensive assessment including executive functions (FAB), self-reported cognitive difficulties (CFI self-report), and depressive symptoms (PHQ-9). Descriptive statistics were performed, as well as a moderation analysis using PHQ-9 as moderator of the relationship between FAB and CFI self-report. Results: Participants (age: 69.28 ± 9.03) showed preserved EFs (FAB = 15.42, SD = 2.11), mild depressive symptoms (PHQ-9 = 6.57, SD = 5.02), and modest subjective difficulties (CFI = 4.87, SD = 2.57). The FAB main effect was positive but non-significant (β = 0.155, p = 0.266), while PHQ-9 was a significant positive predictor (β = 0.470, p ≤ 0.001). The interaction effect was significant (95% CI: [−0.166, −0.015], β = −0.343, p = 0.020). Specifically, simple slope analysis showed that at low levels of depression (−1 SD), better executive functioning was associated with higher SCD (β = 0.498, p = 0.039). Instead, the association was negative but non-significant at moderate (β = 0.155, p = 0.266) and high levels of depression (+1 SD) (β = −0.188, p = 0.229). Conclusions: In SCD, depressive symptoms are a stronger correlate of subjective cognitive difficulties than executive functions. Moreover, higher depression may modulate the executive functions–complaint link, reducing and potentially reversing it as symptom burden increases. Screening and treatment of depressive symptoms should be integrated into SCD assessment and care. Longitudinal and multicenter studies are needed to more deeply understand these preliminary results.

Background Alexithymia, a personality trait characterised by difficulty in identifying and expressing emotions, may contribute to the onset and clinical presentation of functional motor disorders (FMDs), although this association remains underexplored. Methods From the Italian Registry of FMDs, we selected individuals recruited between November 2011 and January 2023, diagnosed with FMD according to Gupta and Lang criteria and assessed for various neurological and psychological features with validated rating scales. The main statistical analysis included regression models using the Toronto Alexithymia Scale 20 items as an explanatory variable for a set of clinical measures, adjusting for sociodemographic factors and correcting for multiple testing. Results In a cohort of 483 individuals, 20.7% had possible alexithymia and 31.5% had definite alexithymia. Higher levels of alexithymia were strongly associated with increased severity of depression (β=0.31, p<0.001), anxiety (β=0.32, p<0.001), general psychological distress (β=−0.27, p<0.001), fatigue (β=0.05, p<0.001) and pain (β=0.32, p<0.001) and moderately associated with a slower onset of FMD (β=0.02, p=0.003). Subscale analyses revealed that difficulties identifying feelings contributed most to these associations. No significant association was observed with motor symptom severity. Conclusions Emotional processing difficulties of individuals with FMD and alexithymia might increase their vulnerability to mental health problems, pain and fatigue, possibly aggravating the overall prognosis. Further research is needed to elucidate the underlying mechanisms linking alexithymia to FMD and to explore the efficacy of interventions targeting emotional awareness and regulation in this population and to prevent long-term mental health burdens.

BACKGROUND:Functional motor disorder (FMD) is a diagnosis of inclusion based on the presence of positive signs on clinical examination, and only a few tests are validated as biomarkers for FMD identification. OBJECTIVES:The aim of this study was to assess the relative frequency of different types of conventional instrumental investigations (such as magnetic resonance imaging/computed tomography [MRI/CT] scan, dopamine transporter single-photon emission computed tomography (DaT-SPECT), electroencephalography (EEG), neurophysiological tests, and other tests) in FMD patients before diagnosis and to identify the clinical and demographic features associated with their use. METHODS:Data were obtained from the Italian Registry of Functional Motor Disorders, a multicenter initiative involving patients with a diagnosis of clinically definite FMD. Patients were consecutively enrolled at 25 Italian centers during 2 phases. Data collection initially took place between September 2018 and August 2019, and during phase 2, between January 2020 and December 2022. RESULTS:Among the 853 patients included during the 2 phases of the registry, we identified 794 patients (93.1%) who underwent 1 or more categories of conventional investigations. Overall, conventional investigations were more likely to be performed in older FMD patients (Odds ratio [OR]: 1.02; P = 0.013). Interestingly, we found that more than one category of investigation was more likely to be performed in FMD patients presenting with weakness (OR: 1.85; P = 0.002) and with additional functional symptoms (OR: 1.54; P = 0.026). CONCLUSIONS:Our findings provide novel insights into the complex diagnostic process of FMD patients. This study highlights the need to identify reliable biomarkers that may help physicians diagnose FMD earlier and carefully select the most appropriate conventional investigations.

BackgroundTremor disorders remain as clinical diagnoses and the rate of misdiagnosis between the commonest non-parkinsonian tremors is relatively high.ObjectivesTo 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).MethodsWe 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.ResultsThree-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.ConclusionsPure 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.

BackgroundFunctional motor disorders (FMD) are a frequent neurological condition affecting patients with movement disorders. Commonly described in younger adults, their manifestation can be also associated to an elderly onset.ObjectiveTo assess the prevalence and describe the clinical manifestations of FMD with elderly and younger onset and their relationship with demographical and clinical variables.MethodsWe recruited patients with a "clinically definite" diagnosis of FMD from the Italian Registry of FMD. Patients underwent extensive clinical assessments. For elderly onset, we set a chronological cut-off at 65 years or older according to WHO definition. Multivariate regression models were implemented to estimate adjusted odds ratio of elderly FMD onset related to clinical characteristics.ResultsAmong the 410 patients, 34 (8.2%) experienced elderly-onset FMD, with a mean age at onset of 70.9 years. The most common phenotype was tremor (47.1%), followed by gait disorders, weakness, and dystonia (29.4%, 23.5%, 14.7%, respectively). Eleven elderly patients had a combined phenomenology: 9 exhibited two phenotypes, 2 had three phenotypes. Weakness was isolated in 3/8 patients and combined with another phenotype in 5/8, manifesting as paraplegia (n = 4); upper limb diplegia (n = 2), hemiparesis/hemiplegia (n = 1), and tetraparesis/tetraplegia (n= 1). Non-motor and other functional neurological disorders occurred more frequently in the younger group (89.1%) than the elderly (73.5%). Neurological and non-neurological comorbidities were more prevalent in the elderly group (82.4%) as opposed to the younger (32.7%). In a multivariate regression analysis, elderly-onset FMD was significantly associated with neurological comorbidities, including parkinsonism (OR 6.73) and cerebrovascular diseases (OR 5.48).ConclusionsThese results highlight the importance of achieving an accurate diagnosis of FMD in the elderly, as it is crucial for effectively managing FMD symptoms and addressing neurological comorbidities.

BackgroundTo date, there are no large studies delineating the clinical correlates of “pure” essential tremor (ET) according to its new definition.MethodsFrom 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.ResultsOut 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.DiscussionThe 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.

Objective Epidemiological data to characterize the individual risk profile of patients with spontaneous cervical artery dissection (sCeAD) are rather inconsistent. Methods and Results In the setting of the Italian Project on Stroke in Young Adults Cervical Artery Dissection (IPSYS CeAD), we compared the characteristics of 1,468 patients with sCeAD (mean age = 47.3 ± 11.3 years, men = 56.7%) prospectively recruited at 39 Italian centers with those of 2 control groups, composed of (1) patients whose ischemic stroke was caused by mechanisms other than dissection (non‐CeAD IS) selected from the prospective IPSYS registry and Brescia Stroke Registry and (2) stroke‐free individuals selected from the staff members of participating hospitals, matched 1:1:1 by sex, age, and race. Compared to stroke‐free subjects, patients with sCeAD were more likely to be hypertensive (odds ratio [OR] = 1.65, 95% confidence interval [CI] = 1.37–1.98), to have personal history of migraine with aura (OR = 2.45, 95% CI = 1.74–3.34), without aura (OR = 2.67, 95% CI = 2.15–3.32), and family history of vascular disease in first‐degree relatives (OR = 1.69, 95% CI = 1.39–2.05), and less likely to be diabetic (OR = 0.65, 95% CI = 0.47–0.91), hypercholesterolemic (OR = 0.75, 95% CI = 0.62–0.91), and obese (OR = 0.41, 95% CI = 0.31–0.54). Migraine without aura was also associated with sCeAD (OR = 1.81, 95% CI = 1.47–2.22) in comparison with patients with non‐CeAD IS. In the subgroup of patients with migraine, patients with sCeAD had higher frequency of migraine attacks and were less likely to take anti‐migraine preventive medications, especially beta‐blockers, compared with the other groups. Interpretation The risk of sCeAD is influenced by migraine, especially migraine without aura, more than by other factors, increases with increasing frequency of attacks, and seems to be reduced by migraine preventive medications, namely beta‐blockers. ANN NEUROL 2023;94:585–595

Background: Non-genetic risk factors play a relevant role in Parkinson's disease (PD) development but the relationship between these factors and PD clinical features is unknown. Objective: The aim of the present multicenter study was to investigate possible relationship between risk factors and clinical motor and non-motor features in a large sample of PD patients. Methods: Six hundred ninety-four patients with PD participated. Patients underwent a clinical evaluation assessing motor symptoms and motor complications as well as non-motor symptoms severity. Information regarding pharmacological treatment was also collected. Risk and protective factors were previously identified in the present population and included coffee consumption, cigarette smoking, and physical activity as protective factors and a family history of PD, dyspepsia, exposure to toxic agents and general anesthesia as risk factors. Multiple regression models were used to investigate the relationship between risk factors and clinical variables. Results: Coffee consumption predicted older age at onset (B: 0.527; CI: 0.195; 0.858) and milder motor symptom severity (B: 1.383; CI: 2.646;-0.121). Non-motor symptom severity was more severe in patients with dyspepsia before PD (B: 13.601; CI 5.019; 22.182) and milder in patients who performed physical activity before PD (B: 11.355; CI: 16.443;-6.266). We found no relationship between risk factors and motor complications, motor subtype and pharmacological treatment. Conclusions: Risk and protective factors of PD development may influence PD clinical features. This finding may represent the first step in the development of new preventive approaches able to delay disease onset and mitigate the extent of clinical manifestations.

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.

Introduction Functional Motor Disorders (FMDs) represent nosological entities with no clear phenotypic characterization, especially in patients with multiple (combined FMDs) motor manifestations. A data-driven approach using cluster analysis of clinical data has been proposed as an analytic method to obtain non-hierarchical unbiased classifications. The study aimed to identify clinical subtypes of combined FMDs using a data-driven approach to overcome possible limits related to “a priori” classifications and clinical overlapping. Methods Data were obtained by the Italian Registry of Functional Motor Disorders. Patients identified with multiple or “combined” FMDs by standardized clinical assessments were selected to be analyzed. Non-hierarchical cluster analysis was performed based on FMDs phenomenology. Multivariate analysis was then performed after adjustment for principal confounding variables. Results From a study population of n = 410 subjects with FMDs, we selected n = 188 subjects [women: 133 (70.7%); age: 47.9 ± 14.4 years; disease duration: 6.4 ± 7.7 years] presenting combined FMDs to be analyzed. Based on motor phenotype, two independent clusters were identified: Cluster C1 (n = 82; 43.6%) and Cluster C2 (n = 106; 56.4%). Cluster C1 was characterized by functional tremor plus parkinsonism as the main clinical phenotype. Cluster C2 mainly included subjects with functional weakness. Cluster C1 included older subjects suffering from anxiety who were more treated with botulinum toxin and antiepileptics. Cluster C2 included younger subjects referring to different associated symptoms, such as pain, headache, and visual disturbances, who were more treated with antidepressants. Conclusion Using a data-driven approach of clinical data from the Italian registry, we differentiated clinical subtypes among combined FMDs to be validated by prospective studies.

Objective To explore the impact of antithrombotic therapy discontinuation in the postacute phase of cervical artery dissection (CeAD) on the mid-term outcome of these patients. Methods In a cohort of consecutive patients with first-ever CeAD, enrolled in the setting of the multicentre Italian Project on Stroke in Young Adults Cervical Artery Dissection, we compared postacute (beyond 6 months since the index CeAD) outcomes between patients who discontinued antithrombotic therapy and patients who continued taking antithrombotic agents during follow-up. Primary outcome was a composite of ischaemic stroke and transient ischaemic attack. Secondary outcomes were (1) Brain ischaemia ipsilateral to the dissected vessel and (2) Recurrent CeAD. Associations with the outcome of interest were assessed by the propensity score (PS) method. Results Of the 1390 patients whose data were available for the outcome analysis (median follow-up time in patients who did not experience outcome events, 36.0 months (25th-75th percentile, 62.0)), 201 (14.4%) discontinued antithrombotic treatment. Primary outcome occurred in 48 patients in the postacute phase of CeAD. In PS-matched samples (201 vs 201), the incidence of primary outcomes among patients taking antithrombotics was comparable with that among patients who discontinued antithrombotics during follow-up (5.0% vs 4.5%; p(log rank test)=0.526), and so was the incidence of the secondary outcomes ipsilateral brain ischaemia (4.5% vs 2.5%; p(log rank test)=0.132) and recurrent CeAD (1.0% vs 1.5%; p(log rank test)=0.798). Conclusions Discontinuation of antithrombotic therapy in the postacute phase of CeAD does not appear to increase the risk of brain ischaemia during follow-up.

The aim of this study is to assess changes in the body distribution and the semeiology of functional motor disorder (FMD) in patients who reported only one or more than one body site affected at FMD onset. Data were obtained from the Italian Registry of Functional Motor Disorders, which included patients with a diagnosis of clinically definite FMDs. The relationship between FMD features and spread to other body sites was estimated by multivariate Cox regression analysis. We identified 201 (49%) patients who reported only one body site affected at FMD onset and 209 (51%) who reported multiple body sites affected at onset. FMD spread from the initial site to another site in 43/201 (21.4%) patients over 5.7 ± 7.1 years in those with only one site affected at FMD onset; FMD spread to an another body site in 29/209 (13.8%) over 5.5 ± 6.5 years. The spread of FMD was associated with non-motor functional symptoms and psychiatric comorbidities only in the patients with one body site affected at FMD onset. Our findings provide novel insight into the natural history of FMD. The number of body sites affected at onset does not seem to have a consistent influence on the risk of spread. Furthermore, our findings suggest that psychiatric comorbidities and non-motor functional symptoms may predict the spread of FMD symptoms, at least in patients with one body site affected at onset.

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.

Numerous reports support the possible occurrence of acute disseminated encephalomyelitis (ADEM) following COVID-19. Herein, we report a case of ADEM in a 53-year-old man 2 weeks after SARS-CoV-2 infection. We reviewed the reports of adult cases of ADEM and its variant acute necrotizing hemorrhagic leukoencephalitis (ANHLE) to check for possible prognostic factors and clinical/epidemiological peculiarities. We performed a descriptive analysis of clinical and cerebrospinal fluid data. Ordinal logistic regressions were performed to check the effect of clinical variables and treatments on ADEM/ANHLE outcomes. We also compared ADEM and ANHLE patients. We identified a total of 20 ADEM (9 females, median age 53.5 years) and 23 ANHLE (11 females, median age 55 years). Encephalopathy was present in 80% of ADEM and 91.3% of ANHLE patients. We found that the absence of encephalopathy predicts a better clinical outcome in ADEM (OR 0.027, 95% CI 0.001-0.611, p = 0.023), also when correcting for the other variables (OR 0.032, 95% CI 0.001-0.995, p = 0.05). Conversely, we identified no significant prognostic factor in ANHLE patients. ANHLE patients showed a trend towards a worse clinical outcome (lower proportion of good/complete recovery, 4.5% vs 16.7%) and higher mortality (36.4% vs 11.1%) as compared to ADEM. Compared to pre-pandemic ADEM, we observed a higher median age of people with post-COVID-19 ADEM and ANHLE, a shorter interval between infection and neurological symptoms, and a worse prognosis both in terms of high morbidity and mortality. Despite being affected by the retrospective nature of the study, these observations provide new insights into ADEM/ANHLE following SARS-CoV-2 infection.