Essential tremor plus rest tremor: current concepts and controversies.

Since the initial description of Essential Tremor (ET), the entity of ET with rest tremor has proven to be a controversial concept. Some authors argued it could be a late manifestation of ET, others suggested it could be a variant of ET, yet others suggested it could represent a transitional state between ET and Parkinson's disease. The novel tremor classification has proposed the construct of ET-plus to differentiate patients with rest tremor from pure ET. However, there is no clarity of what ET-plus rest tremor represents. With the aim of shedding light on this controversial entity, we have, therefore, systematically reviewed all clinical, electrophysiological, imaging and anatomopathological studies indexed in the Medline database published both before and after the new tremor classification and involving patients with ET-plus rest tremor. Forty-four studies involving 4028 patients were included in this review and analyzed in detail by means of descriptive statistics. The results of the current review suggest that ET-plus rest tremor is a heterogenous group of conditions: thus, rest tremor might represent a late feature of ET, might reflect a different disorder with higher age at onset and lower dependance on genetic susceptibility than ET, might suggest the development of Parkinson's disease or might indicate a misdiagnosis of ET. The reviewed lines of evidence refuse recent claims arguing against the construct of ET-plus, which should be viewed as a syndrome with different possible underpinnings, and highlights methodological issues to be solved in future research.

Expanding the Spectrum of GBA1-Associated Neurodegenerative Diseases in an Italian Family.

BACKGROUND: Heterozygous mutations in GBA1 gene are known as most common genetic risk factor for Parkinson's disease (PD). However, role of GBA1 mutations in non-α-synuclein disorders is unclear. CASES: Case index, 76 year-old woman referred to our movement disorders outpatient clinic for 2-year history of gait impairment, falls and motor slowness, with partial response to levodopa. Clinical and instrumental examinations were consistent with Progressive Supranuclear Palsy-Corticobasal Syndrome (PSP-CBS). Case 2 is older sister reporting depressive symptoms; however, she had dementia (MMSE 18/30), gait apraxia and vertical supranuclear gaze palsy (VSNGP). Case 3 is her deceased older sister who had been diagnosed with Corticobasal Syndrome (CBS). Case 4, older brother had been diagnosed with Parkinson's disease-dementia (PDD) with good response to levodopa. Two affected living siblings harboring same genetic variant. CONCLUSIONS: To our knowledge, this is the first family showing such intrafamilial variability ranging from CBS to PDD to dementia.

Assessing ChatGPT Ability to Answer Frequently Asked Questions About Essential Tremor.

Background: Large-language models (LLMs) driven by artificial intelligence allow people to engage in direct conversations about their health. The accuracy and readability of the answers provided by ChatGPT, the most famous LLM, about Essential Tremor (ET), one of the commonest movement disorders, have not yet been evaluated. Methods: Answers given by ChatGPT to 10 questions about ET were evaluated by 5 professionals and 15 laypeople with a score ranging from 1 (poor) to 5 (excellent) in terms of clarity, relevance, accuracy (only for professionals), comprehensiveness, and overall value of the response. We further calculated the readability of the answers. Results: ChatGPT answers received relatively positive evaluations, with median scores ranging between 4 and 5, by both groups and independently from the type of question. However, there was only moderate agreement between raters, especially in the group of professionals. Moreover, readability levels were poor for all examined answers. Discussion: ChatGPT provided relatively accurate and relevant answers, with some variability as judged by the group of professionals suggesting that the degree of literacy about ET has influenced the ratings and, indirectly, that the quality of information provided in clinical practice is also variable. Moreover, the readability of the answer provided by ChatGPT was found to be poor. LLMs will likely play a significant role in the future; therefore, health-related content generated by these tools should be monitored.

Increased glucosylsphingosine levels and Gaucher disease in GBA1-associated Parkinson's disease.

INTRODUCTION: Gaucher's disease (GD) is caused by biallelic mutations in the GBA1 gene, leading to reduced glucocerebrosidase (GCase) activity and substrate (glucosylceramide and glucosylsphingosine, GlcSph) accumulation. GBA1 variant carriers are at risk of Parkinson's disease (PD), but only those with biallelic mutations cross the threshold of GCase reduction, leading to substrate accumulation and GD. The link between GBA1 mutations, GD and PD is not fully understood. Here we aimed at reporting the results of a large PD population screening with dried blood spot tests for GD. METHODS: We measured GCase activity and GlcSph levels in 1344 PD patients with dried blood spot tests, and performed GBA1 genetic sequencing. RESULTS: While the GCase activity was reduced in GBA1-PD carriers compared to wild type PD, GlcSph was increased in GBA1-PD compared to GBA1-controls, regardless of the underlying type of GBA1 variant. 13.6 % and 0.4 % of PD patients had mono- or biallelic GBA1 mutations respectively. GCase deficiency, lipid accumulation and clinical manifestations of GD was detected in five PD patients with biallelic GBA1 mutations, of whom four had a risk combined with a GD causing variant. CONCLUSIONS: GlcSph appearing higher in PD may represent a reliable biomarker of the disease and deserves to be further investigated. This study highlights the importance of screening PD patients for possible underlying GD, which is a treatable condition that should not be missed. We diagnosed GD cases carrying a "risk" variant in one allele, which is an unprecedented finding deserving further investigation.

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.

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.

A novel phenotype in an Italian family with a rare progranulin mutation.

INTRODUCTION: Progranulin (PGRN) is a secreted glycoprotein encoded in humans by the GRN gene, located on chromosome 17q21. Several nonsense and missense pathogenetic GRN mutations have been described. OBJECTIVE: We herein describe two sisters carrying a rare GRN mutation with extremely different clinical features and family history of dementia and behavioral disorders, with a novel presentation with stridor and dysphonia. METHODS: Patients underwent a multidimensional assessment including neurological and neuropsychological evaluation, structural and functional imaging, and genetic screening. RESULTS: The younger sister presented at the age of 64 with inspiratory stridor, dysphonia and exercise-induced dyspnea. Transnasal fiberoptic laryngoscopy showed bilateral adduction of the vocal cords at rest and paradoxical further adduction of the vocal cords during forced inspiration, suggesting the hypothesis of an adductor laryngeal dystonia. The older sister presented at the age of 63 with a rapidly progressive corticobasal syndrome. The only clinical feature common to both sisters was a dysexecutive syndrome. The c.893G > A mutation in exon 9 of GRN was found in heterozygosis in both sisters, causing a missense Arginine to Histidine substitution in position 298 of the protein (p.R298H). CONCLUSIONS: Our report supports the pathogenicity of the GRN p.R298H mutation, which is first detected in two members from the same family, showing an extremely different phenotypes. Moreover, we report the first case of an FTD-associated mutation presenting with inspiratory stridor and dysphonia linked to adductor laryngeal dystonia, thus expanding the clinical spectrum of GRN-related disorders.