A Randomized Phase 2 KINETIC Trial Evaluating SAGE-324/BIIB124 in Individuals with Essential Tremor.

BACKGROUND: SAGE-324/BIIB124 is an investigational positive allosteric modulator of GABAA receptors. OBJECTIVE: KINETIC (NCT04305275), a double-blind, randomized, placebo-controlled, phase 2 study, evaluated SAGE-324/BIIB124 in individuals with essential tremor (ET). METHODS: Individuals aged 18 to 80 years were randomly assigned 1:1 to orally receive 60 mg of SAGE-324/BIIB124 or placebo once daily for 28 days. The primary endpoint was change from baseline in The Essential Tremor Rating Assessment Scale-Performance Subscale (TETRAS-PS) Item 4 (upper-limb tremor) at day 29 with SAGE-324/BIIB124 versus placebo. RESULTS: Between May 2020 and February 2021, 69 U.S. participants were randomly assigned to receive SAGE-324/BIIB124 (n = 34) or placebo (n = 35). There was a significant reduction from baseline in TETRAS-PS Item 4 at day 29 with SAGE-324/BIIB124 versus placebo (least squares mean [standard error]: -2.31 [0.401] vs. -1.24 [0.349], P = 0.0491). The most common treatment-emergent adverse events included somnolence, dizziness, fatigue, and balance disorder. CONCLUSION: These results support further development of SAGE-324/BIIB124 for potential ET treatment. © 2024 Sage Therapeutics, Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

New Preharvest Treatments and Strategies in Managing Phytophthora Brown Rot of Citrus in California.

Brown rot caused by Phytophthora citrophthora, P. nicotianae, P. syringae, and P. hibernalis is an important fruit disease of citrus in California, and the latter two species are quarantine pathogens in some important export markets. The newly registered fungicides oxathiapiprolin (OXA) and mandipropamid (MAN), as well as a premixture of the two (MAN + OXA) were compared with standard fixed copper and potassium phosphite (KPO3) treatments (all with different modes of action) under field conditions in two citrus production regions of California. Fruit were sampled periodically over 8 weeks after application in winter or spring seasons, inoculated with zoospores of P. citrophthora or P. syringae, and brown rot incidence was evaluated. Single applications with all fungicides significantly reduced brown rot incidence of fruit harvested after 8 weeks as compared with the control in seasons with different amounts of precipitation (i.e., 17.2 to 153.9 mm between application and the 8-week sampling). MAN and OXA were similarly or significantly more effective than copper or KPO3. Two applications done in November and January significantly improved the efficacy of KPO3 and copper when compared with a single application of each fungicide done in January. For MAN and OXA, however, a single application was similar in efficacy as two applications. Two-application rotations of MAN, OXA, MAN + OXA, or copper significantly reduced the disease incidence by >84% from the control for at least 8 weeks after the second application. Low-volume (935 liters/ha) applications of MAN, OXA, MAN + OXA, or KPO3, but not copper, were significantly more effective than industry standard high-volume (3,740 liters/ha) applications. Thus, our studies identified and supported registration of new preharvest fungicide treatments to manage brown rot of citrus that are highly effective and persistent, and we optimized treatment strategies. Additionally, rotational programs with fungicides with different modes of action will minimize resistance development in pathogen populations and extend the usage of these fungicides.

Root Absorption and Limited Mobility of Mandipropamid as Compared to Oxathiapiprolin and Mefenoxam After Soil Treatment of Citrus Plants for Managing Phytophthora Root Rot.

Phytophthora root rot can greatly impact citrus production worldwide, especially in newly established orchards by reducing crop yield and increasing the cost of disease management. Mandipropamid is an Oomycota fungicide that is currently registered as a soil treatment for citrus nursery container plants to manage Phytophthora root rot. In this study, we investigated the uptake of mandipropamid into citrus roots and its translocation to stems and leaves after soil application and evaluated its mobility in roots as compared to oxathiapiprolin and mefenoxam using split-root potted plants and trees in the field. A bioassay and liquid chromatography-tandem mass spectrometry were used to detect and quantify fungicides in citrus tissues, and overall, similar results were obtained using the two methods. When applied to the soil of potted, 6- to 7-month-old citrus plants using labeled rates, the majority of mandipropamid was found in root tissues (4.9 to 18.1 µg/g), but small amounts were also present in stems (0.18 to 0.32 µg/g) and leaves (0.03 to 0.22 µg/g). There was no significant increase in concentrations in all three tissues between 1 and 4 weeks after application. Concentrations in all tissues exceeded established EC50 values for mycelial growth inhibition of P. citrophthora and P. nicotianae, the main citrus root rot pathogens in California. In a split-root study where the root systems of single plants were separated, no basipetal phloem-based mobility of mandipropamid or oxathiapiprolin was observed, but relative uptake into roots was higher for mandipropamid. In contrast, low amounts of mefenoxam were also present in roots in the untreated soil. Similar results were obtained in a field study where part of the root system was treated, and fungicides were extracted from nontreated roots. All three fungicides persisted inside roots over the 8-week period of this study. Uptake and persistence inside roots, as well as the previously reported high efficacy against citrus root rot in greenhouse and field studies support the use of mandipropamid in citrus nurseries and potentially in the orchard.

Development and Validation of the Orthostatic Tremor Severity and Disability Scale (OT-10).

BACKGROUND: Limited tools are available for the assessment of orthostatic tremor severity and disability. OBJECTIVES: To develop and validate a self-administered orthostatic tremor scale. METHODS: After expert consensus and literature review generating a list of 42 items, the scale was developed and modified for validation after a patient focus group, multiple rounds of Delphi panels, and cognitive interviews. Clinimetric evaluations included assessing content validity, internal consistency, measurement error and reliability, construct validity, and concurrent validity anchored on the examiner's Clinical Global Impression score. RESULTS: Eleven items ranked on a Likert scale from 0 (no disability/severity) to 5 (maximal disability/severity) were evaluated in 54 orthostatic tremor patients (16 men and 38 women; mean age: 69.17 ± 9.64 years; disease duration: 13.83 ± 11.24 years) to probe severity and disability over the preceding 1-week period. The 11-item scale showed good internal consistency (Cronbach's alpha = 0.863) and acceptable (>0.40) item-to-total correlation. However, one item was removed at the final Delphi panel because of significant floor effect, poor item-to-total correlation, and poor factor-loading, leaving the scale with 10 items (10-item Orthostatic Tremor Severity and Disability Scale). Test-retest reliability at 2 weeks was excellent (two-way random intraclass correlation coefficient > 0.90), and the individual item test-retest reliability showed good agreement, with a threshold weighted kappa >0.60 for all items. Exploratory factor analyses revealed a parsimonious two-factor construct accounting for 57.7% of the scale's variance. The 10-item Orthostatic Tremor Severity and Disability Scale scores correlated with the CGI. CONCLUSIONS: The self-administered 10-item Orthostatic Tremor Severity and Disability Scale scale is valid and reliable for capturing orthostatic tremor-related severity and disability. © 2020 International Parkinson and Movement Disorder Society.

Mobility of Oxathiapiprolin and Mefenoxam in Citrus Seedlings After Root Application and Implications for Managing Phytophthora Root Rot.

Oxathiapiprolin is highly effective in the management of Phytophthora root rot of citrus; however, its uptake into plants after soil application is not known. This was investigated and compared with mefenoxam using potted citrus seedlings sampled 7, 10, 13, and 16 days after soil treatments. Bioassays and high-performance liquid chromatography tandem mass spectroscopy (HPLC-MS/MS) were used to quantify fungicide amounts in plant extracts. Distinct inhibition zones of mycelial growth of Phytophthora citrophthora were observed in bioassays when root, stem, or leaf extracts were added to filter paper disks on agar plates. Based on the two quantification methods, concentrations of both fungicides in the three tissue types and at all sampling times were above the mean effective concentration that provides 50% growth reduction values of the baseline sensitivities. Relative concentrations at the four sampling times sometimes varied between the two methods but, for both methods, concentrations of oxathiapiprolin were significantly higher in roots and leaves as compared with stems 10 days after treatment and statistically similar in the three tissues after 7 days. For mefenoxam, concentrations significantly increased in roots between 7 and 16 days after treatment and were significantly the highest in roots as compared with stems or leaves 16 days after treatment. Regressions of oxathiapiprolin and mefenoxam concentrations using HPLC-MS/MS on those calculated from bioassay standard curves indicated that the bioassays overestimated fungicide amounts in the extracts. The bioassay, however, can be considered an alternative option comparable with costly residue analyses in fungicide mobility studies in plants. Uptake of oxathiapiprolin at sufficient but low concentrations into plant roots provides an explanation for its long-lasting high activity in the management of Phytophthora root rot.

Current Opinions and Consensus for Studying Tremor in Animal Models.

Tremor is the most common movement disorder; however, we are just beginning to understand the brain circuitry that generates tremor. Various neuroimaging, neuropathological, and physiological studies in human tremor disorders have been performed to further our knowledge of tremor. But, the causal relationship between these observations and tremor is usually difficult to establish and detailed mechanisms are not sufficiently studied. To overcome these obstacles, animal models can provide an important means to look into human tremor disorders. In this manuscript, we will discuss the use of different species of animals (mice, rats, fruit flies, pigs, and monkeys) to model human tremor disorders. Several ways to manipulate the brain circuitry and physiology in these animal models (pharmacology, genetics, and lesioning) will also be discussed. Finally, we will discuss how these animal models can help us to gain knowledge of the pathophysiology of human tremor disorders, which could serve as a platform towards developing novel therapies for tremor.

Low-intensity repetitive transcranial magnetic stimulation over prefrontal cortex in an animal model alters activity in the auditory thalamus but does not affect behavioural measures of tinnitus.

Tinnitus, a phantom auditory percept, is strongly associated with cochlear trauma. The latter leads to central changes in auditory pathways such as increased spontaneous activity and this may be involved in tinnitus generation. As not all people with cochlear trauma develop tinnitus, recent studies argue that non-auditory structures, such as prefrontal cortex (PFC), play an important role in tinnitus development. As part of sensory gating circuitry, PFC may modify activity in auditory thalamus and consequently in auditory cortex. Human studies suggest that repetitive transcranial magnetic stimulation (rTMS), a non-invasive tool for neurostimulation, can alter tinnitus perception. This study used a guinea pig model of hearing loss and tinnitus to investigate effects of low-intensity rTMS (LI-rTMS) over PFC on tinnitus and spontaneous activity in auditory thalamus. In addition, immunohistochemistry for calbindin and parvalbumin in PFC was used to investigate the possible mechanism of action of LI-rTMS. Three treatment groups were compared: sham treatment, LI, low frequency (1 Hz) or LI, high frequency (10 Hz) rTMS (10 min/day, 2 weeks, weekdays only). None of the treatments affected the behavioural measures of tinnitus but spontaneous activity was significantly increased in auditory thalamus after 1 Hz and 10 Hz treatment. Immunostaining showed significant effects of rTMS on the density of calcium-binding protein expressing neurons in the dorsal regions of the PFC suggesting that rTMS treatment evoked plasticity in cortex. In addition, calbindin-positive neuron density in the superficial region of PFC was negatively correlated with spontaneous activity in auditory thalamus suggesting a possible mechanism for change in activity observed.

Phenotypic Characterization of Genetically Distinct Phytophthora cinnamomi Isolates from Avocado.

Phytophthora cinnamomi, the causal agent of Phytophthora root rot (PRR), is the most destructive disease of avocado worldwide. A previous study identified two genetically distinct clades of A2 mating type avocado isolates in California; however, the phenotypic variation among them was not assessed. This study described the phenotype of a subset of isolates from these groups regarding growth rate, growth temperature, virulence, and fungicide sensitivity. Isolates corresponding to the A2 clade I group exhibited higher mycelial growth rate and sensitivity to higher temperatures than other isolates. Among the fungicides tested, potassium phosphite had the highest 50% effective concentration for mycelial growth inhibition and oxathiapiprolin had the lowest. Mycelial growth rate and potassium phosphite sensitivity phenotypes correlate with specific groups of isolates, suggesting that these traits could be a group characteristic. Moreover, isolates that are more virulent in avocado and less sensitive to potassium phosphite were identified. A detached-leaf P. cinnamomi inoculation method using Nicotiana benthamiana was developed and validated, providing an alternative method for assessing the virulence of a large number of isolates. This information will help avocado PRR management and assist breeding programs for the selection of rootstocks resistant against a more diverse pathogen population.

New Oomycota Fungicides With Activity Against Phytophthora cinnamomi and Their Potential Use for Managing Avocado Root Rot in California.

Phytophthora root rot (PRR), caused by Phytophthora cinnamomi, is the most destructive disease of avocado worldwide. In the United States, mefenoxam and phosphonate products are currently the only registered fungicides for managing avocado PRR. Four new Oomycota-specific and two registered fungicides, all with different modes of action, were evaluated. Seventy-one isolates of P. cinnamomi from avocado in California, most of them collected between 2009 to 2017, were tested for their in vitro sensitivity to the six fungicides. Baseline sensitivity ranges and mean values (in parentheses) of effective concentrations to inhibit mycelial growth by 50% (EC50) for the new fungicides ethaboxam, fluopicolide, mandipropamid, and oxathiapiprolin were 0.017 to 0.069 µg/ml (0.035), 0.046 to 0.330 µg/ml (0.133), 0.003 to 0.011 µg/ml (0.005), and 0.0002 to 0.0007 µg/ml (0.0004), respectively. In comparison, the EC50 value range (mean) was 0.023 to 0.138 µg/ml (0.061) for mefenoxam and 12.9 to 361.2 µg/ml (81.5) for potassium phosphite. Greenhouse soil inoculation trials with 8-month-old Zutano seedlings and 10-month-old Dusa and PS.54 clonal rootstocks were conducted to assess the efficacy of these fungicides for managing PRR. Mefenoxam and potassium phosphite were effective treatments; however, oxathiapiprolin, fluopicolide, and mandipropamid were more effective. Ethaboxam was effective in reducing PRR on the rootstocks evaluated. Oxathiapiprolin reduced PRR incidence and pathogen population size in the soil by >90%, and plant shoot growth and root dry weight were significantly increased compared with the control; thus, oxathiapiprolin was one of the best treatments overall. The high activity and performance of these new fungicides supports their registrations on avocado for use in rotation and mixture programs, including with previously registered compounds, to reduce the risk of development and spread of resistance in pathogen populations.

Participation in bowel screening among men attending abdominal aortic aneurysm screening.

BACKGROUND: Uptake of population-based screening for colorectal cancer in Scotland is around 55 per cent. Abdominal aortic aneurysm (AAA) screening has recently been introduced for men aged 65 years and the reported uptake is 78 per cent. The aim was to determine the impact of a brief intervention on bowel screening in men who attended AAA screening, but previously failed to complete bowel screening. METHODS: Men invited for AAA screening between September 2015 and March 2016 within NHS Tayside were included. Attendees who had not responded to their latest bowel screening invitation were seen by a colorectal cancer clinical nurse specialist. Reasons for not completing the faecal occult blood test (FOBT) were recorded; brief information on colorectal cancer screening was communicated, and participants were offered a further invitation to complete a FOBT. Those who responded positively were sent a further FOBT from the Scottish Bowel Screening Centre. Subsequent return of a completed FOBT within 6 months was recorded. RESULTS: A total of 556 men were invited for AAA screening, of whom 38·1 per cent had not completed a recent FOBT. The primary reason stated for not participating was the time taken to complete the test or forgetting it (35·1 per cent). Other reasons included: lack of motivation (23·4 per cent), confusion regarding the aim of screening (16·2 per cent), disgust (19·8 per cent), fear (6·3 per cent) and other health problems (9·9 per cent). Following discussion, 81·1 per cent agreed to complete the FOBT and 49 per cent subsequently returned the test. CONCLUSION: A substantial proportion of previous bowel screening non-responders subsequently returned a completed FOBT following a brief intervention with a nurse specialist. Attendance at non-bowel screening appointments may provide a valuable opportunity to improve bowel screening uptake.

Consensus Statement on the classification of tremors. from the task force on tremor of the International Parkinson and Movement Disorder Society.

BACKGROUND: Consensus criteria for classifying tremor disorders were published by the International Parkinson and Movement Disorder Society in 1998. Subsequent advances with regard to essential tremor, tremor associated with dystonia, and other monosymptomatic and indeterminate tremors make a significant revision necessary. OBJECTIVES: Convene an international panel of experienced investigators to review the definition and classification of tremor. METHODS: Computerized MEDLINE searches in January 2013 and 2015 were conducted using a combination of text words and MeSH terms: "tremor", "tremor disorders", "essential tremor", "dystonic tremor", and "classification" limited to human studies. Agreement was obtained using consensus development methodology during four in-person meetings, two teleconferences, and numerous manuscript reviews. RESULTS: Tremor is defined as an involuntary, rhythmic, oscillatory movement of a body part and is classified along two axes: Axis 1-clinical characteristics, including historical features (age at onset, family history, and temporal evolution), tremor characteristics (body distribution, activation condition), associated signs (systemic, neurological), and laboratory tests (electrophysiology, imaging); and Axis 2-etiology (acquired, genetic, or idiopathic). Tremor syndromes, consisting of either isolated tremor or tremor combined with other clinical features, are defined within Axis 1. This classification scheme retains the currently accepted tremor syndromes, including essential tremor, and provides a framework for defining new syndromes. CONCLUSIONS: This approach should be particularly useful in elucidating isolated tremor syndromes and syndromes consisting of tremor and other signs of uncertain significance. Consistently defined Axis 1 syndromes are needed to facilitate the elucidation of specific etiologies in Axis 2. © 2017 International Parkinson and Movement Disorder Society.

The essential tremor syndromes.

PURPOSE OF REVIEW: Essential tremor has not been defined or used consistently in clinical diagnosis and research. Other monosymptomatic disorders are often referred to as essential tremor variants. RECENT FINDINGS: There is now solid evidence that essential tremor, however defined, is a syndrome with multiple causes. SUMMARY: A new tremor classification scheme is being developed by the International Parkinson and Movement Disorder Society Task Force on Tremor. In this scheme, tremor in the absence of other neurological signs is called isolated tremor, and tremor in combination with other signs is called combined tremor. Many isolated and combined tremor syndromes can be defined on the basis of commonly recurring or unique clinical symptoms and signs, including historical features (age at onset, family history, and temporal evolution) and tremor characteristics (body distribution, activation condition, associated features). Essential tremor, however defined, is simply a syndrome and not a specific disease. Essential tremor should be defined and used consistently, or this term should be abandoned. As essential tremor is an arbitrarily defined syndrome, it makes no sense to refer to other tremors as variants of essential tremor or essential tremor syndromes.

Transducer-based evaluation of tremor.

The International Parkinson and Movement Disorder Society established a task force on tremor that reviewed the use of transducer-based measures in the quantification and characterization of tremor. Studies of accelerometry, electromyography, activity monitoring, gyroscopy, digitizing tablet-based measures, vocal acoustic analysis, and several other transducer-based methods were identified by searching PubMed.gov. The availability, use, acceptability, reliability, validity, and responsiveness were reviewed for each measure using the following criteria: (1) used in the assessment of tremor; (2) used in published studies by people other than the developers; and (3) adequate clinimetric testing. Accelerometry, gyroscopy, electromyography, and digitizing tablet-based measures fulfilled all three criteria. Compared to rating scales, transducers are far more sensitive to changes in tremor amplitude and frequency, but they do not appear to be more capable of detecting a change that exceeds random variability in tremor amplitude (minimum detectable change). The use of transducer-based measures requires careful attention to their limitations and validity in a particular clinical or research setting. © 2016 International Parkinson and Movement Disorder Society.

Surgical Approach, Findings, and Eight-Year Follow-Up in a Twenty-Nine Year Old Female With Freeman-Sheldon Syndrome Presenting With Blepharophimosis Causing Near-Complete Visual Obstruction.

The authors describe the surgical approach, findings, and 8-year follow-up in a 29-year-old woman, with severe Freeman-Sheldon syndrome, presenting with congenital blepharophimosis of both upper eyelids resulting in near-complete functional visual obstruction. To avoid possible Freeman-Sheldon syndrome-associated complications of malignant hyperthermia, difficult vascular access, and challenging endotracheal intubation, the surgery was completed under local anesthesia without sedation, and anatomical and functional correction was immediate and remained stable at 8-year follow-up. Unlike many congenital craniofacial syndromes, which frequently involve life-long impairments, important implications exist for plastic surgeons to facilitate opportunities for patients to overcome functional limitations.

What does low-intensity rTMS do to the cerebellum?

Non-invasive stimulation of the human cerebellum, such as by transcranial magnetic stimulation (TMS), is increasingly used to investigate cerebellar function and identify potential treatment for cerebellar dysfunction. However, the effects of TMS on cerebellar neurons remain poorly defined. We applied low-intensity repetitive TMS (LI-rTMS) to the mouse cerebellum in vivo and in vitro and examined the cellular and molecular sequelae. In normal C57/Bl6 mice, 4 weeks of LI-rTMS using a complex biomimetic high-frequency stimulation (BHFS) alters Purkinje cell (PC) dendritic and spine morphology; the effects persist 4 weeks after the end of stimulation. We then evaluated whether LI-rTMS could induce climbing fibre (CF) reinnervation to denervated PCs. After unilateral pedunculotomy in adult mice and 2 weeks sham or BHFS stimulation, VGLUT2 immunohistochemistry was used to quantify CF reinnervation. In contrast to sham, LI-rTMS induced CF reinnervation to the denervated hemicerebellum. To examine potential mechanisms underlying the LI-rTMS effect, we verified that BHFS could induce CF reinnervation using our in vitro olivocerebellar explants in which denervated cerebellar tissue is co-cultured adjacent to intact cerebella and treated with brain-derived neurotrophic factor (BDNF) (as a positive control), sham or LI-rTMS for 2 weeks. Compared with sham, BDNF and BHFS LI-rTMS significantly increased CF reinnervation, without additive effect. To identify potential underlying mechanisms, we examined intracellular calcium flux during the 10-min stimulation. Complex high-frequency stimulation increased intracellular calcium by release from intracellular stores. Thus, even at low intensity, rTMS modifies PC structure and induces CF reinnervation.

Selfing ability and dispersal are positively related, but not affected by range position: a multispecies study on southern African Asteraceae.

Dispersal and breeding system traits are thought to affect colonization success. As species have attained their present distribution ranges through colonization, these traits may vary geographically. Although several theories predict associations between dispersal ability, selfing ability and the relative position of a population within its geographic range, there is little theoretical or empirical consensus on exactly how these three variables are related. We investigated relationships between dispersal ability, selfing ability and range position across 28 populations of 13 annual, wind-dispersed Asteraceae species from the Namaqualand region of South Africa. Controlling for phylogeny, relative dispersal ability--assessed from vertical fall time of fruits--was positively related to an index of autofertility--determined from hand-pollination experiments. These findings support the existence of two discrete syndromes: high selfing ability associated with good dispersal and obligate outcrossing associated with lower dispersal ability. This is consistent with the hypothesis that selection for colonization success drives the evolution of an association between these traits. However, no general effect of range position on dispersal or breeding system traits was evident. This suggests selection on both breeding system and dispersal traits acts consistently across distribution ranges.

Static magnetic stimulation induces structural plasticity at the axon initial segment of inhibitory cortical neurons.

Static magnetic stimulation (SMS) is a form of non-invasive brain stimulation that alters neural activity and induces neural plasticity that outlasts the period of stimulation. This can modify corticospinal excitability or motor behaviours, suggesting that SMS may alter the intrinsic excitability of neurons. In mammalian neurons, the axon initial segment (AIS) is the site of action potential initiation and undergoes structural plasticity (changes in length and position from the soma) as a homeostatic mechanism to counteract chronic changes in neuronal activity. We investigated whether the chronic application of SMS (6 and 48 h, 0.5 T) induces structural AIS plasticity in postnatally derived primary cortical neurons. Following 6 h of SMS, we observed a shortening in mean AIS length compared to control, that persisted 24 h post stimulation. In contrast, 48 h of SMS induced an immediate distal shift that persisted 24 h post-stimulation. Pharmacological blockade of voltage gated L/T-type calcium channels during stimulation did not prevent SMS-induced AIS structural plasticity. Our findings provide the foundation to expand the use of chronic SMS as a non-invasive method to promote AIS plasticity.

Associations Among Tremor Amplitude, Activities of Daily Living, and Quality of Life in Patients with Essential Tremor.

Background: Essential tremor (ET) is a disabling syndrome consisting of tremor, primarily in the upper limbs. We assessed the correlation of The Essential Tremor Rating Assessment Scale (TETRAS) Performance Item 4 ratings of upper limb tremor with the TETRAS activities of daily living (ADL) subscale and with 2 quality of life (QoL) scales. Methods: This noninterventional, cross-sectional, point-in-time survey of neurologists(n = 60), primary care physicians (n = 38), and their patients with ET (n = 1,003) used real-world data collected through the Adelphi ET Disease Specific Programme™. Physician-reported measures (TETRAS Performance Item 4 and TETRAS ADL total) and patient-reported QoL measures (generic EuroQol-5 Dimension 5 Level [EQ-5D-5 L] and ET-specific Quality of Life in Essential Tremor Questionnaire (QUEST)) were assessed with bivariate and multivariable analyses. Sensitivity analyses were also conducted. Results: The bivariate association between TETRAS Performance Item 4 score and TETRAS ADL total score was high (Pearson r = 0.761, P < 0.001). The bivariate associations between TETRAS Performance Item 4 score and EQ-5D-5 L index score (r = -0.410, P < 0.001) and between TETRAS ADL total score and EQ-5D-5 L index score (r = -0.543, P < 0.001) were moderate. The bivariate associations between TETRAS Performance Item 4 score and QUEST total score (r = 0.457, P < 0.001), and between TETRAS ADL total score and QUEST total score (r = 0.630, P < 0.001) were also moderate. These associations were unaltered by the inclusion of covariates. Discussion: This study showed that greater tremor severity (TETRAS Performance Item 4) was positively correlated with ADL impairment (TETRAS ADL) and negatively associated with QoL (EQ-5D-5 L and QUEST). TETRAS Performance Item 4 score is a robust predictor of TETRAS ADL total score, and TETRAS Performance Item 4 and TETRAS ADL total scores were robust predictors of the 2 QoL scales. The results demonstrate the value of TETRAS scores as valid endpoints for future clinical trials. Highlights: This real-world study assessed TETRAS scores as predictors of impaired QoL in ET. TETRAS Performance Item 4 and ADL were associated with EQ-5D-5 L and QUEST. TETRAS scores may serve as valid endpoints for future clinical trials.

Validation of a New Patient-Reported Outcome Measure of the Functional Impact of Essential Tremor on Activities of Daily Living.

Background: The Essential Tremor Rating Assessment Scale (TETRAS) is a popular scale for essential tremor (ET), but its activities of daily living (ADL) and performance (P) subscales are based on a structured interview and physical exam. No patient-reported outcome (PRO) scale for ET has been developed according to US regulatory guidelines. Objective: Develop and validate a TETRAS PRO subscale. Methods: Fourteen items, rated 0-4, were derived from TETRAS ADL and structured cognitive interviews of 18 ET patients. Convergent validity analyses of TETRAS PRO versus TETRAS ADL, TETRAS-P, and the Quality of Life in Essential Tremor Questionnaire (QUEST) were computed for 67 adults with ET or ET plus. Test-retest reliability was computed at intervals of 1 and 30 days. The influence of mood (Hospital Anxiety and Depression Scale, HADS) and coping behaviors (Essen Coping Questionnaire, ECQ) was examined with multiple linear regression. Results: TETRAS PRO was strongly correlated (r > 0.7) with TETRAS ADL, TETRAS-P, and QUEST and exhibited good to excellent reliability (Cronbach alpha 95%CI = 0.853-0.926; 30-day test-retest intraclass correlation 95%CI = 0.814-0.921). The 30-day estimate of minimum detectable change (MDC) was 6.6 (95%CI 5.2-8.0). TETRAS-P (rsemipartial = 0.607), HADS depression (rsemipartial = 0.384), and the coping strategy of information seeking and exchange of experiences (rsemipartial = 0.176) contributed statistically to TETRAS PRO in a multiple linear regression (R2 = 0.67). Conclusions: TETRAS PRO is a valid and reliable scale that is influenced strongly by tremor severity, moderately by mood (depression), and minimally by coping skills. The MDC for TETRAS PRO is probably sufficient to detect clinically important change.

Tremor disorders.

PURPOSE OF REVIEW: The pathophysiology of tremor disorders is reviewed in the context of pharmacologic and surgical treatment. RECENT FINDINGS: The anatomical origin and pathophysiologic mechanism of tremorogenic oscillation are unknown for all tremor disorders. Except for Parkinson tremor and rhythmic cortical myoclonus, the discovery of drugs for tremor disorders has been largely serendipitous. The cerebellothalamocortical pathway is involved in essentially all pathologic tremors, and stereotactic destruction or deep brain stimulation of the ventrolateral thalamus has been efficacious in all tremor disorders, despite widely varying tremor pathophysiology. The ventrolateral thalamocortical loop appears to amplify all forms of tremor deleteriously, regardless of origin. SUMMARY: A better understanding of pathophysiology of the thalamocortical loop in tremorogenesis could lead to better pharmacotherapy for most or all forms of pathologic tremor.