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.

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.

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.

Do cerebrovascular risk factors impact the clinical expression of idiopathic isolated adult-onset dystonia?

BACKGROUND: Although acquired dystonia may develop following ischaemic/haemorrhagic stroke, the relationship between cerebrovascular disease and idiopathic dystonia has been poorly investigated. This cross sectional study aimed at evaluating the impact of cerebrovascular risk factors on the clinical expression of idiopathic adult onset dystonia (IAOD), with reference to dystonia localization and dystonia-associated features. METHODS: Data were obtained from the Italian Dystonia Registry. Patients with IAOD were stratified into two groups according to the presence of diabetes mellitus and/or arterial hypertension and/or dyslipidemia and/or heart disease. The two groups were compared for demographic features, dystonia phenotype, and dystonia-associated features (sensory trick, tremor, eye symptoms in blepharospasm, and neck pain in cervical dystonia). RESULTS: A total of 1108 patients participated into the study. Patients who reported one cerebrovascular factor or more (n = 555) had higher age and longer disease duration than patients who did not. On multivariable logistic regression analysis, blepharospasm was the only localization, and sensory trick was the only dystonia-associated feature that was significantly associated with cerebrovascular risk factors. Linear regression analysis showed that the strength of the association between cerebrovascular factors and blepharospasm/sensory trick increased with increasing the number of cerebrovascular factors per patient. CONCLUSIONS: Results of the present study showed that cerebrovascular risk factors may be associated with specific features of IAOD that is development of blepharospasm and sensory trick. Further studies are needed to better understand the meaning and the mechanisms underlying this association.

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.

Diagnostic utility of Sudoscan for detecting bortezomib-induced painful neuropathy: a study on 18 patients with multiple myeloma.

Introduction: In the past few years, treatment of multiple myeloma has undergone a deep change for the employment of novel treatment comprising proteasome inhibitors. Bortezomib is a first-line drug in therapy of multiple myeloma. The onset of peripheral neuropathy is a dose-limiting collateral effect of the drug. This neuropathy is a distal symmetric neuropathy that affects both large and small fibers. Nerve conduction study (NCS) can be used for the diagnosis of bortezomib neuropathy, but this technique demonstrates alterations of the large nerve fibers. Sudoscan is a novel technique utilized to offer an evaluation of sudomotor function. The main objective of this study was to compare the sensitivity and diagnostic specificity of Sudoscan with respect to the nerve conduction study after bortezomib treatment. Material and methods: A total of 18 multiple myeloma patients were studied, 10 (55.5%) men and 8 (44.5%) women. Patients were analyzed at baseline and after 6 months of treatment with bortezomib. Subjects were submitted to nerve conduction study and electrochemical skin conductance evaluation with the Sudoscan device. Patients were also submitted to a clinical measure of pain and neuropathy. Results: At baseline NCS showed that only the mean sural SAP amplitude was below the 2SD lower limit of normal in 3 (16.7%) patients, while at same time we found an alteration of Sudoscan profiles in 2 (11.1%) patients. After 6 months of treatment, the NCS profiles were altered in 13 (72.2%) patients, and the Sudoscan profiles were modified in 11 (61.1%) subjects. Conclusions: Our results suggest that Sudoscan can be considered for the diagnosis of bortezomib-induced neuropathy. It is objective, reproducible, and surely easier than the traditional nerve conduction study. Sudoscan may be a useful help to manage the therapeutic interventions in multiple myeloma.

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.

Essential tremor and cognitive impairment: who, how, and why.

BACKGROUND AND AIMS: Recent years have witnessed the switch from considering essential tremor (ET) a monosymptomatic disorder to consider it as part of a spectrum, including other neurological signs, such as mild cognitive impairment and dementia, thus defining it as "ET plus." There are few data on cognitive impairment in ET patients. The aim of this review is to analyze the clinical characteristics of ET patients developing cognitive impairment, their neuropsychological profile, the underpinning mechanisms, and the possible biomarkers. METHODS: The authors performed a narrative review on cognitive decline in essential tremor, including articles written in English since the year 2000. DISCUSSION: The most recent pathogenetic theories of cognitive impairment in ET rely on the cerebellar dysfunction, being part of the Cerebellar Cognitive Affective Syndrome spectrum. Cognitive impairment in ET patients could be assessed through many tests that demonstrate the involvement of different domains, such as attention, executive functions, and language. There are some clinical characteristics of ET that may indicate a greater risk of developing cognitive impairment, namely, cerebellar symptoms, falls, age at onset, and family history. However, there are no established clinical, neurophysiological, neuropathological, and fluid biomarkers of cognitive impairment in ET. CONCLUSIONS: Increasing data are showing in ET the presence of cerebellar symptoms and cognitive impairment. Further studies are needed to better understand cognition in ET patients, and to define the boundary between ET and ET plus, since deeper phenotyping might have important clinical and therapeutic implications.

Pimozide and pancreatic cancer in diabetic chorea: a case report.

PURPOSE/AIM: Diabetic chorea is a rare movement disorder associated with diabetes mellitus. We report the case of a patient that benefited from pimozide and died of pancreatic cancer. CASE REPORT: A 70-year-old woman presented with pollakiuria and involuntary movements of left limbs since three months. Laboratory tests revealed high serum levels of glycemia and glycated haemoglobin. She was admitted to internal medicine department and discharged one week later: insulin was administered with normalization of blood glucose levels and the involuntary movements gradually disappeared. Three weeks later she was admitted to neurological department due to the recurrence of the involuntary movements. Glycemia and other routine laboratory tests were normal. Neurological examination showed choreic movements involving left limbs. MRI showed a hyperintensity on T1- and T2-weighted sequences of right putamen and caudate nucleus head. Haloperidol was administered without improvement, it was successively substituted with tetrabenazine and the patient was discharged with an unvaried clinical picture. Two months later tetrabenazine was discontinued because of inefficacy and pimozide was started. The choreic movements considerably diminished after few days. Four months later, a pancreatic cancer was diagnosed and the patient died in the same month. CONCLUSION: Clinical and radiological features were suggestive of diabetic chorea. Our patient benefited exclusively from pimozide, it could be reasonable to use pimozide in resistant form and also propose it as first choice treatment. Another important element is the diagnosis of pancreatic cancer some months after chorea onset: a causal link could exist.

Cortical Excitability and Connectivity in Patients With Brain Tumors.

Background: Brain tumors can cause different changes in excitation and inhibition at the neuronal network level. These changes can be generated from mechanical and cellular alterations, often manifesting clinically as seizures. Objective/Hypothesis: The effects of brain tumors on cortical excitability (CE) have not yet been well-evaluated. The aim of the current study was to further investigate cortical-cortical and cortical-spinal excitability in patients with brain tumors using a more extensive transcranial magnetic stimulation protocol. Methods: We evaluated CE on 12 consecutive patients with lesions within or close to the precentral gyrus, as well as in the subcortical white matter motor pathways. We assessed resting and active motor threshold, short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inhibition (SAI), long-latency afferent inhibition, cortical silent period, and interhemispheric inhibition. Results: CE was reduced in patients with brain tumors than in healthy controls. In addition, SICI, ICF, and SAI were lower in the affected hemisphere compared to the unaffected and healthy controls. Conclusions: CE is abnormal in hemispheres affected by brain tumors. Further studies are needed to determine if CE is related with motor impairment.

Spread of segmental/multifocal idiopathic adult-onset dystonia to a third body site.

BACKGROUND: Adult-onset focal dystonia can spread to involve one, or less frequently, two additional body regions. Spread of focal dystonia to a third body site is not fully characterized. MATERIALS AND METHODS: We retrospectively analyzed data from the Italian Dystonia Registry, enrolling patients with segmental/multifocal dystonia involving at least two parts of the body or more. Survival analysis estimated the relationship between dystonia features and spread to a third body part. RESULTS: We identified 340 patients with segmental/multifocal dystonia involving at least two body parts. Spread of dystonia to a third body site occurred in 42/241 patients (17.4%) with focal onset and 10/99 patients (10.1%) with segmental/multifocal dystonia at onset. The former had a greater tendency to spread than patients with segmental/multifocal dystonia at onset. Gender, years of schooling, comorbidity, family history of dystonia/tremor, age at dystonia onset, and disease duration could not predict spread to a third body site. Among patients with focal onset in different body parts (cranial, cervical, and upper limb regions), there was no association between site of focal dystonia onset and risk of spread to a third body site. DISCUSSION AND CONCLUSION: Spread to a third body site occurs in a relative low percentage of patients with idiopathic adult-onset dystonia affecting two body parts. Regardless of the site of dystonia onset and of other demographic/clinical variables, focal onset seems to confer a greater risk of spread to a third body site in comparison to patients with segmental/multifocal dystonia at onset.

Multimodal Surgical Treatment of High-Grade Gliomas in the Motor Area: The Impact of the Combination of Navigated Transcranial Magnetic Stimulation and Fluorescein-Guided Resection.

BACKGROUND: Fluorescein-guided surgery of high-grade gliomas (HGGs) increases the extent of tumor resection but its efficacy has been questioned, especially for tumors located close to functional networks. In these cases, navigated transcranial magnetic stimulation (nTMS) may be used to plan and guide a safe resection. The aim of this study was to assess the impact of these techniques combined with intraoperative neurophysiologic mapping (IONM) to achieve the maximal safe resection of tumors located in the motor area. METHODS: We collected data of patients operated using a multimodal combination of sodium fluorescein-guided resection, nTMS motor planning, and IONM for HGGs in the motor area. The nTMS planning accuracy, extent of resection, and postoperative motor and functional status were compared with a matched control group of patients with HGG operated on only by IONM-guided resection. RESULTS: Forty-one patients treated by multimodal approach (group A) and 41 controls (group B) were included. The nTMS-based planning reliably identified the tumor/motor pathway spatial relationship (accuracy, 92.68%). We obtained in group A versus controls a higher gross total resection rate (73.17% vs. 51.22%; P = 0.04), and a reduction of cases with new permanent motor deficits (9.75% vs. 29.27%; P = 0.04) or Karnofsky Performance Status worsening (12.19% vs. 31.71%; P = 0.03). CONCLUSIONS: This study supports the role of the combination of sodium fluorescein-guided resection and nTMS-based planning for surgery of HGGs close to the motor pathway. This multimodal approach in combination with IONM may lead to customized preoperative planning, increased extent of resection, and improved functional outcome, compared with standard IONM-guided surgery.

Endogenous orientation of visual attention in auditory space.

Visuospatial attention is asymmetrically distributed with a leftward bias (i.e. pseudoneglect), while evidence for asymmetries in auditory spatial attention is still controversial. In the present study, we investigated putative asymmetries in the distribution of auditory spatial attention and the influence that visual information might have on its deployment. A modified version of the Posner task (i.e. the visuo-audio spatial task [VAST]) was used to investigate spatial processing of auditory targets when endogenous orientation of spatial attention was mediated by visual cues in healthy adults. A line bisection task (LBT) was also administered to assess the presence of a leftward bias in deployment of visuospatial attention. Overall, participants showed rightward and leftward biases in the VAST and the LBT, respectively. In the VAST, sound localization was enhanced by visual cues. Altogether, these findings support the existence of a facilitation effect for auditory targets originating from the right side of space and provide new evidence for crossmodal links in endogenous spatial attention between vision and audition.

Pain processing in functional and idiopathic dystonia: An exploratory study.

BACKGROUND: Pain is often experienced by patients with functional dystonia and idiopathic cervical dystonia and is likely to be determined by different neural mechanisms. OBJECTIVE: In this exploratory study, we tested the sensory-discriminative and cognitive-emotional component of pain in patients with functional and idiopathic dystonia. METHODS: Ten patients with idiopathic cervical dystonia, 12 patients with functional dystonia, and 16 age- and sex-matched healthy controls underwent psychophysical testing of tactile and pain thresholds and pain tolerance. We delivered electrical pulses of increasing intensity to the index finger of each hand and the halluces of each foot. Pain threshold and pain tolerance were respectively defined as the (1) intensity at which sensation changed from unpainful to faintly painful and (2) intensity at which painful sensation was intolerable. RESULTS: No differences were found between the three groups for tactile and pain thresholds assessed in hands and feet. Pain tolerance was significantly increased in all body regions only in functional dystonia. Patients with continuous functional dystonia had higher pain tolerance compared to subjects with paroxysmal functional dystonia and idiopathic cervical dystonia. There was no correlation between pain tolerance and pain scores, depression, anxiety, disease duration, and motor disability in both groups. CONCLUSIONS: Patients with functional dystonia have a dissociation between the sensory-discriminative and cognitive-emotional components of pain, as revealed by normal pain thresholds and increased pain tolerance. Abnormal connectivity between the motor and limbic systems might account for abnormal pain processing in functional dystonia. © 2018 International Parkinson and Movement Disorder Society.