Impact of Switching From Immediate- or Prolonged-Release to Once-Daily Extended-Release Tacrolimus (LCPT) on Tremor in Stable Kidney Transplant Recipients: The Observational ELIT Study.

Once-daily extended-release tacrolimus (LCPT) exhibits increased bioavailability versus immediate-release (IR-TAC) and prolonged release (PR-TAC) tacrolimus. Improvements in tremor were previously reported in a limited number of kidney transplant patients who switched to LCPT. We conducted a non-interventional, non-randomized, uncontrolled, longitudinal, prospective, multicenter study to assess the impact of switching to LCPT on tremor and quality of life (QoL) in a larger population of stable kidney transplant patients. The primary endpoint was change in The Essential Tremor Rating Assessment Scale (TETRAS) score; secondary endpoints included 12-item Short Form Survey (SF-12) scores, tacrolimus trough concentrations, neurologic symptoms, and safety assessments. Subgroup analyses were conducted to assess change in TETRAS score and tacrolimus trough concentration/dose (C0/D) ratio by prior tacrolimus formulation and tacrolimus metabolizer status. Among 221 patients, the mean decrease of TETRAS score after switch to LCPT was statistically significant (p < 0.0001 vs. baseline). There was no statistically significant difference in change in TETRAS score after switch to LCPT between patients who had received IR-TAC and those who had received PR-TAC before switch, or between fast and slow metabolizers of tacrolimus. The overall increase of C0/D ratio post-switch to LCPT was statistically significant (p < 0.0001) and from baseline to either M1 or M3 (both p < 0.0001) in the mITT population and in all subgroups. In the fast metabolizers group, the C0/D ratio crossed over the threshold of 1.05 ng/mL/mg after the switch to LCPT. Other neurologic symptoms tended to improve, and the SF-12 mental component summary score improved significantly. No new safety concerns were evident. In this observational study, all patients had a significant improvement of tremor, QoL and C0/D ratio post-switch to LCPT irrespective of the previous tacrolimus formulation administered (IR-TAC or PR-TAC) and irrespective from their metabolism status (fast or slow metabolizers).

Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson's disease.

Prasinezumab, a monoclonal antibody that binds aggregated α-synuclein, is being investigated as a potential disease-modifying therapy in early-stage Parkinson's disease. Although in the PASADENA phase 2 study, the primary endpoint (Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) sum of Parts I + II + III) was not met, prasinezumab-treated individuals exhibited slower progression of motor signs than placebo-treated participants (MDS-UPDRS Part III). We report here an exploratory analysis assessing whether prasinezumab showed greater benefits on motor signs progression in prespecified subgroups with faster motor progression. Prasinezumab's potential effects on disease progression were assessed in four prespecified and six exploratory subpopulations of PASADENA: use of monoamine oxidase B inhibitors at baseline (yes versus no); Hoehn and Yahr stage (2 versus 1); rapid eye movement sleep behavior disorder (yes versus no); data-driven subphenotypes (diffuse malignant versus nondiffuse malignant); age at baseline (≥60 years versus <60 years); sex (male versus female); disease duration (>12 months versus <12 months); age at diagnosis (≥60 years versus <60 years); motor subphenotypes (akinetic-rigid versus tremor-dominant); and motor subphenotypes (postural instability gait dysfunction versus tremor-dominant). In these subpopulations, the effect of prasinezumab on slowing motor signs progression (MDS-UPDRS Part III) was greater in the rapidly progressing subpopulations (for example, participants who were diffuse malignant or taking monoamine oxidase B inhibitors at baseline). This exploratory analysis suggests that, in a trial of 1-year duration, prasinezumab might reduce motor progression to a greater extent in individuals with more rapidly progressing Parkinson's disease. However, because this was a post hoc analysis, additional randomized clinical trials are needed to validate these findings.

Cortico-cortical connectivity is influenced by levodopa in tremor-dominant Parkinson's disease.

Resting tremor is the most common presenting motor symptom in Parkinson's disease (PD). The supplementary motor area (SMA) is a main target of the basal-ganglia-thalamo-cortical circuit and has direct, facilitatory connections with the primary motor cortex (M1), which is important for the execution of voluntary movement. Dopamine potentially modulates SMA and M1 activity, and both regions have been implicated in resting tremor. This study investigated SMA-M1 connectivity in individuals with PD ON and OFF dopamine medication, and whether SMA-M1 connectivity is implicated in resting tremor. Dual-site transcranial magnetic stimulation was used to measure SMA-M1 connectivity in PD participants ON and OFF levodopa. Resting tremor was measured using electromyography and accelerometry. Stimulating SMA inhibited M1 excitability OFF levodopa, and facilitated M1 excitability ON levodopa. ON medication, SMA-M1 facilitation was significantly associated with smaller tremor than SMA-M1 inhibition. The current findings contribute to our understanding of the neural networks involved in PD which are altered by levodopa medication and provide a neurophysiological basis for the development of interventions to treat resting tremor.

[Tremor-dominant form of Parkinson's disease]. / Tremor-dominantnaya forma bolezni Parkinsona.

The article is of a review nature and is devoted to tremor, one of the maladaptive and difficult-to-treat symptoms of Parkinson's disease (PD). Along with the classic rest tremor, patients with PD may experience tremor of other modalities: postural tremor, kinetic tremor, which reflects a multimodal mechanism of tremor formation involving multiple neurotransmitter systems. The unpredictable response to therapeutic options, the ambiguous response to levodopa, also reflects the role of multiple underlying pathophysiological processes. Among the drug methods of tremor correction, preference is given to dopamine receptor agonists - due to the spectrum of their pharmaceutical action, high efficiency in relation to all leading motor and a number of non-motor manifestations. The evidence for advanced neurosurgical, non-invasive modalities is mixed, and there are insufficient comparative studies to assess their efficacy in patients with tremor-dominant forms of PD.

Mitochondrial dysfunction in Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome: prospect use of antioxidants and mitochondrial nutrients.

Fragile X syndrome (FXS) is a genetic disorder characterized by mutation in the FMR1 gene, leading to the absence or reduced levels of fragile X Messenger Ribonucleoprotein 1 (FMRP). This results in neurodevelopmental deficits, including autistic spectrum conditions. On the other hand, Fragile X-associated tremor/ataxia syndrome (FXTAS) is a distinct disorder caused by the premutation in the FMR1 gene. FXTAS is associated with elevated levels of FMR1 mRNA, leading to neurodegenerative manifestations such as tremors and ataxia.Mounting evidence suggests a link between both syndromes and mitochondrial dysfunction (MDF). In this minireview, we critically examine the intricate relationship between FXS, FXTAS, and MDF, focusing on potential therapeutic avenues to counteract or mitigate their adverse effects. Specifically, we explore the role of mitochondrial cofactors and antioxidants, with a particular emphasis on alpha-lipoic acid (ALA), carnitine (CARN) and Coenzyme Q10 (CoQ10). Findings from this review will contribute to a deeper understanding of these disorders and foster novel therapeutic strategies to enhance patient outcomes.

Resolution of Wing-Beating Tremor and Magnetic Resonance Imaging Lesions in Wilson's Disease Following Penicillamine.

Background: The wing-beating tremor, characteristic of Wilson's disease (WD), is a disabling symptom that can be resistant to anti-copper and anti-tremor medications. Phenomenology Shown: This video illustrates severe bilateral wing-beating tremor, moderate head and lower limb tremors, mild cervical dystonia, and subtle cerebellar ataxia, with nearly resolution after penicillamine treatment. Educational Value: This case highlights a typical aspect of WD, emphasizing the importance of early detection and treatment, and its correlation with MRI findings. Highlights: This case highlights the typical wing-beating tremor in Wilson's disease and its correlation with the involvement of the dentato-rubro-thalamic pathway. The early diagnosis and initiation of treatment with penicillamine resulted in an excellent clinical and radiological response.

Abdominal Tremor in Idiopathic Parkinson's Disease: A Case Report.

Background: Tremor in Parkinson's disease (PD) is commonly seen in the upper extremities and can involve the lower extremities and mouth. We present a case of a patient with idiopathic PD who presented with abdominal tremor. Case Report: A 40-year-old man with a 2-year history of subjective weakness and stiffness in the right arm and leg, followed by emergence of a right hand tremor, subsequently developed abdominal tremor. Patient experienced marked improvement of both abdominal and hand tremor and mobility of the right limbs with levodopa. Discussion: Our case report serves as the second only published report of abdominal tremor in an idiopathic PD patient. Highlights: Tremor in Parkinson's disease (PD) commonly affects the upper and lower extremities and mouth. We describe a 40-year-old man with PD who developed abdominal tremor which was brought under control with levodopa. This case is one of only two published reports of abdominal tremor in PD.

Botulinum toxin treatment in parkinsonism.

Botulinum toxin (BoNT) was approved by the United States Food and Drug Administration (FDA) in 1989 for facial movement disorders and strabismus, but since that time its indications have been expanding beyond neurologic and ophthalmologic disorders. This article is a narrative review of the therapeutic use of BoNT in tremors, dystonia, sialorrhea, bladder and other autonomic symptoms, levodopa-induced dyskinesia and other problems occuring in the setting of parkinsonism. Though FDA approval is lacking for some of these indications, expert experiences have shown that BoNT is often beneficial in this group of patients.

The association between tacrolimus exposure and tremor, headache and insomnia in adult kidney transplant recipients: A systematic review.

PURPOSE: Tremor, headache and insomnia have been linked to the immunosuppressant, tacrolimus. The aim of this systematic review was to determine if there is a correlation between tacrolimus exposure and new-onset tremor, headache and insomnia experienced by adult kidney transplant recipients. METHODS: PubMed, Embase, Cochrane Library and CINAHL databases were searched up to 11 April 2023 for published studies which reported on tacrolimus exposure in adult kidney transplant recipients, alongside information on treatment-emergent neurologic manifestations, including tremor, headache and insomnia. Review articles, case studies, conference abstracts and articles not published in English in peer-reviewed journals were excluded. The Physiotherapy Evidence Database and Newcastle-Ottawa Quality Assessment Scales were used to assess risk of bias. Extracted data was analysed via a narrative synthesis. RESULTS: Eighteen studies involving 4030 patients in total were included in the final analysis. These comprised five randomised control trials and thirteen observational studies. Studies failed to find significant association between tacrolimus trough concentrations in whole blood and the incidence of neurologic side effects such as tremor, headache and insomnia; however, in one study the incidence of toxicity requiring a dose reduction increased with increasing, supratherapeutic targeted levels. Females, especially Black females, and older age were positively associated with the prevalence of neurologic adverse effects. Results were conflicting regarding whether extended-release formulations were associated with fewer neurologic complications than immediate-release formulations. CONCLUSION: The varied study designs and criteria for reporting tremor, headache and insomnia impacted on the quality of the data for exploring the relationship between tacrolimus exposure and the onset of neurologic manifestations experienced after kidney transplantation. Studies that examine defined neurologic complications as the primary outcome, and that consider novel markers of tacrolimus exposure while assessing the potential contribution of multiple covariate factors, are required.

Dopaminergic versus anticholinergic treatment effects on physiologic complexity of hand tremor in Parkinson's disease: A randomized crossover study.

AIMS: Parkinsonian tremor (PT) is regulated by numerous neurophysiological components across multiple temporospatial scales. The dynamics of tremor fluctuation are thus highly complex. This study aimed to explore the effects of different medications on tremor complexity, and how the underlying factors contribute to such tremor complexity. METHODS: In this study, 66 participants received a 2-mg dose of benzhexol or a pre-determined dose of levodopa at two study visits in a randomized order. Before and after taking the medications, tremor fluctuation was recorded using surface electromyography electrodes and accelerometers in resting, posture, and weighting conditions with and without a concurrent cognitive task. Tremor complexity was quantified using multiscale entropy. RESULTS: Tremor complexity in resting (p = 0.002) and postural condition (p < 0.0001) was lower when participants were performing a cognitive task compared to a task-free condition. After taking levodopa and benzhexol, participants had increased (p = 0.02-0.03) and decreased (p = 0.03) tremor complexity compared to pre-medication state, respectively. Tremor complexity and its changes as induced by medications were significantly correlated with clinical ratings and their changes (ß = -0.23 to -0.39; p = 0.002-0.04), respectively. CONCLUSION: Tremor complexity may be a promising marker to capture the pathophysiology underlying the development of PT, aiding the characterization of the effects medications have on PT regulation.

Open-Label Sulforaphane Trial in FMR1 Premutation Carriers with Fragile-X-Associated Tremor and Ataxia Syndrome (FXTAS).

Fragile X (FMR1) premutation is a common mutation that affects about 1 in 200 females and 1 in 450 males and can lead to the development of fragile-X-associated tremor/ataxia syndrome (FXTAS). Although there is no targeted, proven treatment for FXTAS, research suggests that sulforaphane, an antioxidant present in cruciferous vegetables, can enhance mitochondrial function and maintain redox balance in the dermal fibroblasts of individuals with FXTAS, potentially leading to improved cognitive function. In a 24-week open-label trial involving 15 adults aged 60-88 with FXTAS, 11 participants successfully completed the study, demonstrating the safety and tolerability of sulforaphane. Clinical outcomes and biomarkers were measured to elucidate the effects of sulforaphane. While there were nominal improvements in multiple clinical measures, they were not significantly different after correction for multiple comparisons. PBMC energetic measures showed that the level of citrate synthase was higher after sulforaphane treatment, resulting in lower ATP production. The ratio of complex I to complex II showed positive correlations with the MoCA and BDS scores. Several mitochondrial biomarkers showed increased activity and quantity and were correlated with clinical improvements.

Trial of Botulinum Toxin for Isolated or Essential Head Tremor.

BACKGROUND: Local injections of botulinum toxin type A have been used to treat essential head tremor but have not been extensively studied in randomized trials. METHODS: In a multicenter, double-blind, randomized trial, we assigned, in a 1:1 ratio, adult patients with essential or isolated head tremor to receive botulinum toxin type A or placebo. Botulinum toxin or placebo was injected under electromyographic guidance into each splenius capitis muscle on the day of randomization (day 0) and during week 12. The primary outcome was improvement by at least 2 points on the Clinical Global Impression of Change (CGI) scale at week 6 after the second injection (week 18 after randomization). The CGI scale was used to record the patient's assessment of the degree of improvement or worsening of head tremor since baseline; scores range from 3 (very much improved) to -3 (very much worse). Secondary outcomes included changes in tremor characteristics from baseline to weeks 6, 12, and 24. RESULTS: A total of 120 patients were enrolled; 3 patients were excluded during screening, and 117 patients were randomly assigned to receive botulinum toxin (62 patients) or placebo (55 patients) and were included in the intention-to-treat analysis. Twelve patients in the botulinum toxin group and 2 patients in the placebo group did not receive injections during week 12. The primary outcome - improvement by at least 2 points on the CGI scale at week 18 - was met by 31% of the patients in the botulinum toxin group as compared with 9% of those in the placebo group (relative risk, 3.37; 95% confidence interval, 1.35 to 8.42; P = 0.009). Analyses of secondary outcomes at 6 and 12 weeks but not at 24 weeks were generally supportive of the primary-outcome analysis. Adverse events occurred in approximately half the patients in the botulinum toxin group and included head and neck pain, posterior cervical weakness, and dysphagia. CONCLUSIONS: Injection of botulinum toxin into each splenius capitis muscle on day 0 and during week 12 was more effective than placebo in reducing the severity of isolated or essential head tremor at 18 weeks but not at 24 weeks, when the effects of injection might be expected to wane, and was associated with adverse events. (Funded by the French Ministry of Health; Btx-HT ClinicalTrials.gov number, NCT02555982.).

Delayed-Onset Psychosis Secondary to Tacrolimus Neurotoxicity After Lung Transplant: A Case Report and Systematic Review.

BACKGROUND: Tacrolimus is the most common immunosuppressant used after transplant, yet it can result in moderate-to-severe neurotoxicity in up to 32% of patients. Signs of neurotoxicity can vary from mild (tremor or headache) to severe (posterior reversible encephalopathy syndrome or psychosis. Prompt recognition and management is needed to lead to symptom resolution. OBJECTIVE: The objective of this study is to describe the clinical presentation of tacrolimus-induced psychosis, a type of tacrolimus-inducted neurotoxicity, and distinguish it from other central nervous system disturbances, including delirium. METHODS AND RESULTS: We present a case of delayed onset tacrolimus-induced psychosis with focus on unique clinical features and management strategies. We conducted a systematic review of cases of tacrolimus-induced psychosis using the PubMed database and included 15 manuscripts in our review. CONCLUSIONS: Tacrolimus-induced psychosis is a unique presentation of tacrolimus-related neurotoxicity and can present without the cardinal symptoms of delirium. The data on isolated psychotic symptoms are limited with current literature focusing on more common presentations of tacrolimus-induced neurotoxicity, such as delirium and tremor. Development of psychosis can occur later in the treatment course and at normal tacrolimus serum levels. It can improve with antipsychotic therapies, but primary management should include cross-titration to an alternate immunosuppressant regimen.

Amantadine for Refractory Tremor in Parkinson Disease and Other Indications: A Chart Review With Long-Term Follow-up.

OBJECTIVES: The aim of this study was to determine how amantadine was used in a movement disorders clinic and how effective it was. METHODS: A chart review over a 2-month period in 2022 of all patients in a movement disorders clinic who had ever taken amantadine was undertaken. RESULTS: One hundred six charts were included. Amantadine was initiated primarily for tremor and secondly for l -dopa-induced dyskinesias (LIDs). Sixty-two percent of tremor patients improved and tolerated amantadine; 74% of those with LID improved and tolerated the drug. Hallucinations occurred in 23%. Initiating amantadine as a syrup allowed a more conservative titration than other formulations, which is attractive given the high percentage of hallucinations that may occur. Patients who tolerated drug initiation were generally kept on the drug for many years. CONCLUSIONS: Amantadine should be considered as adjunctive therapy in Parkinson disease patients with refractory tremor as well as for LIDs.

Effectiveness of Botulinum Toxin on Hand Tremor Intensity and Upper Limb Function in Patients with Parkinson's Disease: Results of a Systematic Review.

Background: Hand tremor is a common symptom of Parkinson's disease (PD). Tremors may be resistant to drug treatments. Therefore, Botulinum toxin (BoNT) could be a good alternative. This study aimed to review and analyze studies on the efficacy and safety of BoNT injection in hand tremor intensity and upper limb function in patients with idiopathic PD. Methods: A comprehensive search was conducted for studies on the effect of local BoNT injections on tremors in PD patients from 1990 to December 2021. Electronic databases such as Cochrane Central Control Records, PubMed, Scopus, Web of Science, EMBASE, Google Scholar, Clinicaltrial.gov, ProQuest, Science Direct, CINAHL, and Psychoinfo were searched systematically. Results: Ten studies, comprising one double-blinded randomized clinical trial and nine pilot open-labeled studies with 131 participants, met eligibility criteria. The reported tremor intensity ranged from 1 to 3, and the average tremor duration of 5.93 ± 2.08 years. The injectable dose was 68-100 units of onabotulinum-toxin-A in each upper limb muscle, mostly wrist flexors. The results showed a decrease in unified Parkinson's disease rating scale (UPDRS)_20 and UPDRS_21 indices by 1.22 ± 1.1 and 1.20 ± 0.9, respectively, without causing severe side effects. The BoNT relative effectiveness in the forearm and arm muscles was reported 6-16 weeks after injection. Discussion: The kinematic, electromyography-guided, and electrical stimulation evaluations allow for accurate muscle localization and minimize the possibility of BoNT diffusion and antibody formation. More extensive randomized clinical trials with uniform measurement criteria are recommended to reduce bias and provide more accurate conclusions. Highlight: Tremor treatment in Parkinson's-disease (PD) is challenging. Drugs effect is temporary, and surgery is critical management. This study reviews the Botulinum-toxin injection efficacy in hand tremor intensity and upper limb function. The results showed a decrease in unified Parkinson's disease rating scale (UPDRS)_20 and UPDRS_21 by 1.22 ± 1.1 and 1.20 ± 0.9, respectively, 6-16 weeks after injection.

Tremor Induced by Cyclosporine, Tacrolimus, Sirolimus, or Everolimus: A Review of the Literature.

Calcineurin inhibitors such as cyclosporine and tacrolimus are immunosuppressant drugs that are known to induce tremors. Non-calcineurin inhibitors such as sirolimus and everolimus have also reportedly been accompanied by tremors, albeit less likely. However, the prevalence rates reported in the literature are notably wide, and the risk profiles for these drug-induced tremors are less understood. We searched PubMed to extract data on the risk of tremors with these drugs when prescribed for various transplant and non-transplant indications. We ascertained whether the risk of drug-induced tremor is influenced by the underlying diagnosis, dosing formulations, drug concentrations, and blood monitoring. We extracted data on treatment strategies and outcomes for tremors. Articles were primarily screened based on English language publications, abstracts, and studies with n ≥ 5, which included case series, retrospective studies, case-controlled studies, and prospective studies. We found 81 eligible studies comprising 33 cyclosporine, 43 tacrolimus, 6 sirolimus, and 1 everolimus that discussed tremor as an adverse event. In the pooled analysis of studies with n > 100, the incidence of tremor was 17% with cyclosporine, 21.5% with tacrolimus, and 7.8% with sirolimus and everolimus together. Regarding the underlying diagnosis, tremor was more frequently reported in kidney transplant (cyclosporine 28%, tacrolimus 30.1%) and bone marrow transplant (cyclosporine 40%, tacrolimus 41.9%) patients compared with liver transplant (cyclosporine 9%, tacrolimus 11.5%) and nontransplant indications (cyclosporine 21.5%, tacrolimus 11.3%). Most studies did not report whether the risk of tremors correlated with drug concentrations in the blood. The prevalence of tremors when using the twice-daily formulation of tacrolimus was nearly the same as the once-daily formulation (17% vs 18%). Data on individual-level risk factors for tremors were lacking. Except for three studies that found some benefit to maintaining magnesium levels, there were minimal data on treatments and outcomes. A large body of data supports a substantive and wide prevalence of tremor resulting from tacrolimus use followed by cyclosporine, especially in patients receiving a kidney transplant. However, there is little reporting on the patient-related risk factors for tremor, risk relationship with drug concentrations, treatment strategies, and outcomes.

Mapping Pharmacologically Evoked Neurovascular Activation and Its Suppression in a Rat Model of Tremor Using Functional Ultrasound: A Feasibility Study.

Functional ultrasound (fUS), an emerging hemodynamic-based functional neuroimaging technique, is especially suited to probe brain activity and primarily used in animal models. Increasing use of pharmacological models for essential tremor extends new research to the utilization of fUS imaging in such models. Harmaline-induced tremor is an easily provoked model for the development of new therapies for essential tremor (ET). Furthermore, harmaline-induced tremor can be suppressed by the same classic medications used for essential tremor, which leads to the utilization of this model for preclinical testing. However, changes in local cerebral activities under the effect of tremorgenic doses of harmaline have not been completely investigated. In this study, we explored the feasibility of fUS imaging for visualization of cerebral activation and deactivation associated with harmaline-induced tremor and tremor-suppressing effects of propranolol. The spatial resolution of fUS using a high frame rate imaging enabled us to visualize time-locked and site-specific changes in cerebral blood flow associated with harmaline-evoked tremor. Intraperitoneal administration of harmaline generated significant neural activity changes in the primary motor cortex and ventrolateral thalamus (VL Thal) regions during tremor and then gradually returned to baseline level as tremor subsided with time. To the best of our knowledge, this is the first functional ultrasound study to show the neurovascular activation of harmaline-induced tremor and the therapeutic suppression in a rat model. Thus, fUS can be considered a noninvasive imaging method for studying neuronal activities involved in the ET model and its treatment.