Essential Tremor: Update of Therapeutic Strategies. / Temblor esencial: actualización de las estrategias terapéuticas.

In the last decades there has been progress in the treatment of essential tremor (TE) especially in the surgical field and to a lesser extent in the pharmacological field. We carry out a review of the currently available treatments. The first intervention is the use of non-pharmacological and non-surgical strategies (general advice, occupational therapy, speech therapy, psychotherapy). With discrete advances, the pharmacological treatment is not very satisfactory. Only 30-60% of patients have a positive response, and in these the anti-tremor effectiveness is 40-60%. The first-line drugs are still propranolol and primidone. In cases with severe tremor we will consider a surgical option, the method of choice being thalamotomy using high-intensity focused ultrasound. In the future we must continue to study the pathophysiology of TE, develop drugs specifically designed for TE and improve the technology of available invasive techniques.

Non-Persistence of Tremorolytic Effect of Perampanel in Essential Tremor: Real-World Experience with 50 Patients.

Background: We describe our experience of using perampanel to treat essential tremor (ET) over 12 months. Methods: We enrolled 50 ET patients in an open-label trial. Perampanel was titrated to 4 mg/day as adjuvant therapy. The main outcome measures were baseline, +1, +3, +6, and + 12 month scores of the Tremor Clinical Rating Scale (TCRS) and the Glass scale (GS). Results: Twenty patients withdrew because of adverse effects. At +1 month, 27 of 30 patients improved: 68% reduction in both TCRS 1 + 2 (P < 0.001) and TCRS 3 (P < 0.001); TCRS 4 + 1.8 and GS 1.1 point reduction. By +12 months non-persistence of therapeutic effect occurred in 70% of patients: the mean reduction in TCRS 1 + 2 was 33% (P = 0.03), TCRS 3 (0.04), TCRS 4 + 0.8, GS 0.2 points reduction. Conclusions: We report important peramapanel acute tremorolytic effects, but poor tolerance to adverse effects and a non-sustained therapeutic effect in most patients.

Comparison of the Results of a Parkinson's Holter Monitor With Patient Diaries, in Real Conditions of Use: A Sub-analysis of the MoMoPa-EC Clinical Trial.

Background: For specialists in charge of Parkinson's disease (PD), one of the most time-consuming tasks of the consultations is the assessment of symptoms and motor fluctuations. This task is complex and is usually based on the information provided by the patients themselves, which in most cases is complex and biased. In recent times, different tools have appeared on the market that allow automatic ambulatory monitoring. The MoMoPa-EC clinical trial (NCT04176302) investigates the effect of one of these tools-Sense4Care's STAT-ON-can have on routine clinical practice. In this sub-analysis the agreement between the Hauser diaries and the STAT-ON sensor is analyzed. Methods: Eighty four patients from MoMoPa-EC cohort were included in this sub-analysis. The intraclass correlation coefficient was calculated between the patient diary entries and the sensor data. Results: The intraclass correlation coefficient of both methods was 0.57 (95% CI: 0.3-0.73) for the OFF time (%), 0.48 (95% CI: 0.17-0.68) for the time in ON (%), and 0.65 (95% CI%: 0.44-0.78) for the time with dyskinesias (%). Furthermore, the Spearman correlations with the UPDRS scale have been analyzed for different parameters of the two methods. The maximum correlation found was -0.63 (p < 0.001) between Mean Fluidity (one of the variables offered by the STAT-dON) and factor 1 of the UPDRS. Conclusion: This sub-analysis shows a moderate concordance between the two tools, it is clearly appreciated that the correlation between the different UPDRS indices is better with the STAT-ON than with the Hauser diary. Trial Registration: https://clinicaltrials.gov/show/NCT04176302 (NCT04176302).

Is essential tremor a disorder of primary GABA dysfunction? Yes.

Dysfunction in gamma-aminobutyric acid (GABA) neurotransmission has emerged as a prime suspect for the underlying neurochemical dysfunction in essential tremor (ET). This dysfunction has been termed the GABA hypothesis. We review findings to date supporting the 4 steps in this hypothesis in studies of cerebrospinal fluid, pathology, genetics, animal models, imaging, computational models, and human drugs, while not overlooking the evidence of negative studies and controversies. It remains to be elucidated whether reduced GABAergic tone is a primary contributing factor to ET pathophysiology, a consequence of altered Purkinje cell function, or even a result of Purkinje cell death. More studies are clearly needed to confirm both the neurodegenerative nature of ET and the reduction in GABA activity in the cerebellum. Also necessary is to test further therapies to enhance GABA transmission specifically focused on the cerebellar area.

Tipping the scales: how clinical assessment shapes the neural correlates of Parkinson's disease mild cognitive impairment.

Mild cognitive impairment in Parkinson's disease (PD-MCI) is associated with consistent structural and functional brain changes. Whether different approaches for diagnosing PD-MCI are equivalent in their neural correlates is presently unknown. We aimed to profile the neuroimaging changes associated with the two endorsed methods of diagnosing PD-MCI. We recruited 53 consecutive non-demented PD patients and classified them as PD-MCI according to comprehensive neuropsychological examination as operationalized by the Movement Disorders Task Force. Voxel-based morphometry, cortical thickness, functional connectivity and graph theoretical measures were obtained on a 3-Tesla MRI scanner. 18 patients (32%) were classified as PD-MCI with Level-II criteria, 19 (33%) with the Parkinson's disease Cognitive Rating Scale (PD-CRS) and 32 (60%) with the Montreal Cognitive Assessment (MoCA) scale. Though regions of atrophy differed across classifications, reduced gray matter in the precuneus was found using both Level-II and PD-CRS classifications in PD-MCI patients. Patients diagnosed with the PD-CRS also showed extensive changes in cortical thickness, concurring with the MoCA in regions of the cingulate cortex, and again with Level-II regarding cortical thinning in the precuneus. Functional connectivity analysis found higher coherence within salience network regions of interest, and decreased anticorrelations between salience/central executive and default-mode networks in the PD-CRS classification for PD-MCI patients. Graph theoretical metrics showed a widespread decrease in node degree for the three classifications in PD-MCI, whereas betweenness centrality was increased in select nodes of the default mode network (DMN). Clinical and neuroimaging commonalities between the endorsed methods of cognitive assessment suggest a corresponding set of neural correlates in PD-MCI: loss of structural integrity in DMN structures, mainly the precuneus, and a loss of weighted connections in the salience network that might be counterbalanced by increased centrality in the DMN. Furthermore, the similarity of the results between exhaustive Level-II and screening Level-I tools might have practical implications in the search for neuroimaging biomarkers of cognitive impairment in Parkinson's disease.

Exome-wide rare variant analysis in familial essential tremor.

INTRODUCTION: Essential tremor (ET) is one of the most common movement disorders. Despite its high prevalence and heritability, its genetic etiology remains elusive with only a few susceptibility genes identified and poorly replicated. Our aim was to find novel candidate genes involved in ET predisposition through whole exome sequencing. METHODS: We studied eight multigenerational families (N = 40 individuals) with an autosomal-dominant inheritance using a comprehensive strategy combining whole exome sequencing followed by case-control association testing of prioritized variants in a separate cohort comprising 521 ET cases and 596 controls. We further performed gene-based burden analyses in an additional dataset comprising 789 ET patients and 770 healthy individuals to investigate whether there was an enrichment of rare deleterious variants within our candidate genes. RESULTS: Fifteen variants co-segregated with disease status in at least one of the families, among which rs749875462 in CCDC183, rs535864157 in MMP10 and rs114285050 in GPR151 showed a nominal association with ET. However, we found no significant enrichment of rare variants within these genes in cases compared with controls. Interestingly, MMP10 protein is involved in the inflammatory response to neuronal damage and has been previously associated with other neurological disorders. CONCLUSIONS: We prioritized a set of promising genes, especially MMP10, for further genetic and functional studies in ET. Our study suggests that rare deleterious coding variants that markedly increase susceptibility to ET are likely to be found in many genes. Future studies are needed to replicate and further infer biological mechanisms and potential disease causality for our identified genes.

Preservation of brain metabolism in recently diagnosed Parkinson's impulse control disorders.

BACKGROUND: Impulse control disorders (ICD) are a common and disrupting complication of Parkinson's disease (PD) treatment. Although their relationship with dopaminergic activity is well studied, their brain metabolic correlates are mostly unknown. METHODS: In this work we studied brain metabolism using brain 18F-FDG-PET. We performed a case-control study nested within a cohort of PD patients free of ICD at baseline to compare ICD patients right after ICD diagnosis and prior to any treatment modification with matched ICD-free patients. We also compared both PD groups with healthy controls. RESULTS: When compared with ICD-free PD patients, PD patients with recently diagnosed ICD showed higher glucose metabolism in widespread areas comprising prefrontal cortices, both amygdalae and default mode network hubs (p < 0.05, corrected). When compared to healthy controls, they did not show hypermetabolism, and the only hypometabolic region was the right caudate. In turn, ICD-free patients showed diffuse hypometabolism when compared to healthy controls. CONCLUSION: Our results suggest brain metabolism is more preserved in PD patients with ICD than patients without ICD. This metabolic preservation could be related to ICD development.

Primary Orthostatic Tremor: Experience of Perampanel Use in 20 Patients.

Background: Primary orthostatic tremor (POT) is a rare disorder for which current treatments are largely ineffective. Following up on our recent report of complete resolution of POT symptoms in a patient using low doses of perampanel, we describe our experience of perampanel in 20 patients. Methods: Twenty patients whose neurologists prescribed perampanel were recruited. Initial dose was 2 mg/day, which was increased to 4 mg/day after the first month. Treatment efficacy was self-scored from +3 to -3 at 1 and 3 months. Results: Eight patients withdrew due to adverse effects. Of the 12 patients who completed the study, 92% indicated that their POT symptoms had improved after 1 month, with 75% indicating moderate to marked improvement (mean score 1.9 ± 0.9). This improvement was not sustained by follow-up at 3 months (mean score 0.9 ± 1.3). A rebound of POT symptoms that lasted 2-6 weeks was observed in most patients who withdrew. Discussion: Our experience with this series of cases points to the potential of low-dose perampanel as a treatment for POT, although poor tolerance and the possibility of a non-persistent therapeutic benefit need to be considered. Controlled studies are needed to confirm these findings.

A divergent breakdown of neurocognitive networks in Parkinson's Disease mild cognitive impairment.

Cognitive decline is a major disabling feature in Parkinson's disease (PD). Multimodal imaging studies have shown functional disruption in neurocognitive networks related to cognitive impairment. However, it remains unknown whether these changes are related to gray matter loss, or whether they outline network vulnerability in the early stages of cognitive impairment. In this work, we intended to assess functional connectivity and graph theoretical measures and their relation to gray matter loss in Parkinson's disease with mild cognitive impairment (PD-MCI). We recruited 53 Parkinson's disease patients and classified them for cognitive impairment using Level-1 Movement Disorders Society-Task Force Criteria. Voxel-based morphometry, functional connectivity and graph theoretical measures were obtained on a 3-Tesla MRI scanner. Loss of gray matter was observed in the default mode network (bilateral precuneus), without a corresponding disruption of functional or graph theoretical properties. However, functional and graph theoretical changes appeared in salience network nodes, without evidence of gray matter loss. Global cognition and executive scores showed a correlation with node degree in the right anterior insula. We also found a correlation between visuospatial scores and right supramarginal gyrus node degree. Our findings highlight the loss of functional connectivity and topological features without structural damage in salience network regions in PD-MCI. They also underline the importance of multimodal hubs in the transition to mild cognitive impairment. This functional disruption in the absence of gray matter atrophy suggests that the salience network is a key vulnerable system at the onset of mild cognitive impairment in PD.

Parkinson's Disease: Impulsivity Does Not Cause Impulse Control Disorders but Boosts Their Severity.

Introduction: Impulse control disorders (ICDs) are a common complication of Parkinson's disease (PD) receiving dopamine agonist (DAA) Impulsivity is considered an underlying mechanism but evidence of this relationship is scarce. To explore the relationship between impulsivity and the presence and severity of ICD in PD. Methods: Prospective cross-sectional study of consecutive PD outpatients. Patients with dementia or previously known ICDs were excluded. Two measures of impulsivity were assessed: Barratt Impulsiveness Scale (BIS-11) for impulsiveness trait (main exposure) and commission errors in the Continuous Performance Test (CE) for motor inhibition. Main outcomes were diagnosis of ICD based on a comprehensive clinical interview and severity of ICD based on the Questionnaire for Impulsive-Compulsive Disorders. Results: Of 100 patients (mean [SD] age, 67.2 [8.8], 54 male), 31 had ICD. Patients with ICDs were 5.3 years younger (p = 0.01), used more frequently dopamine agonist (p = 0.02), alcohol (p = 0.009) and tobacco (p = 0.02). They were not more impulsive on BIS-11 (56 vs. 58, p = 0.23, adjusted p = 0.46) and CE (p = 0.96). No relationship was found between dopaminergic medications and impulsivity or ICD severity. Among patients with ICD, impulsivity was correlated with ICD severity (BIS-11 r = 0.33, p = 0.001, adjusted p = 0.002, CE r = 0.53, p = 0.006). Multivariate regression analysis confirmed the independent predictive role of both measures. Conclusions: Impulsivity is not associated with increased prevalence of ICD in PD but it is strongly linked to ICD severity. When considering dopamine replacement therapy, assessment of impulsivity may be a useful approach to detect those patients at risk of severe forms of ICD.

Tremor Types in Parkinson Disease: A Descriptive Study Using a New Classification.

BACKGROUND: The current classification of tremor types in Parkinson disease (PD) is potentially confusing, particularly for mixed tremor, and there is no label for pure resting tremor. With a view to better defining the clinical phenomenological classification of these tremors, our group relabeled the different types as follows: pure resting tremor (type I); mixed resting and action tremor with similar frequencies (type II) divided, according to action tremor presentation, into II-R when there is a time lag and II-C otherwise; pure action tremor (type III); and mixed resting and action tremor with differing frequencies (type IV). We performed a descriptive study to determine prevalence and clinical correlates for this new tremor classification. PATIENT/METHODS: A total of 315 consecutively recruited patients with PD and tremor were clinically evaluated. X 2 tests were used to assess tremor type associations with categorical variables, namely, sex, family history of PD, motor fluctuations, and anticholinergic and beta-blocker use. With tremor type as the independent variable, ANOVA was performed to study the relationship between dependent quantitative variables, namely, age, age at PD diagnosis, disease duration, and UPDRS scores for rigidity. RESULTS: The studied patients had tremor types as follows: type I, 30%; type II, 50% (II-R, 25% and II-C, 25%); type III, 19%; and type IV, 1%. No significant association was found between the studied clinical variables and tremor types. CONCLUSIONS: Mixed tremor was the most common tremor type in our series of patients with PD according to our proposed classification, which we hope will enhance understanding of the broad clinical phenomenology of PD.

Complete Resolution of Symptoms of Primary Orthostatic Tremor with Perampanel.

Background: Primary orthostatic tremor (POT) is an infrequent disorder whose physiopathology is unknown. Current medication is largely ineffective or only offers mild benefits. Case Report: A 75-year-old female with refractory POT treated with 4 mg/day of perampanel achieved complete symptom resolution. Owing to adverse effects, the patient reduced intake to 2 mg/day, but even at this lower dose the benefit was maintained. Discussion: We report the complete resolution of POT symptoms using low doses of perampanel, an antiepileptic drug that blocks glutamate-mediated post-synaptic excitation. Further controlled studies are necessary to confirm this finding.

Isolated Propriospinal Myoclonus as a Presentation of Cervical Myelopathy.

Background: Propriospinal myoclonus is an infrequent type of hyperkinetic movement that can be commonly idiopathic but also may occur after spinal cord lesions. Phenomenology Shown: We describe an 8-year-old female showing repetitive flexor and extensor arrhythmic brief jerks of the trunk, compatible with propriospinal myoclonus secondary to cervical myelopathy. Educational Value: Isolated propriospinal myoclonus may be the clinical sign that leads to the diagnosis of incipient myelopathy.

Ethosuximide for Essential Tremor: An Open-Label Trial.

BACKGROUND: T-type calcium channel activation has been postulated to underlie rhythmicity in the olivo-cerebellar system that is implicated in ET. Ethosuximide reduces T-type calcium currents and can suppress tremor in two animal models of ET. We explored the effects of ethosuximide in subjects with ET in an open-label trial using both clinical scales and accelerometric recordings measures. We initially planned to conduct the trial with 15 patients, but due to lack of efficacy and a high incidence of adverse effects, the trial was stopped after seven patients had participated. METHODS: Seven patients diagnosed with ET were included in the study. The ethosuximide dose was 500 mg daily (BID). The main outcome measures were: 1) tremor clinical rating scale (TCRS) score, 2) accelerometric recordings, and 3) self-reported disability scale score. RESULTS: Five patients completed the study, and two dropped out due to adverse effects. There were no significant changes in clinical scores in motor task performance (TCRS 1+2), daily living activities (TCRS 3), or in the patients' subjective assessment (TCRS 4) and global appraisal. There were no differences observed for accelerometry data or disability scale scores. Anxiety, nervousness, headache, and dizziness were reported by two patients while on ethosuximide, causing them to stop the trial. No patient preferred to continue ethosuximide treatment. DISCUSSION: The results of our exploratory study suggest that ethosuximide is not an effective treatment for ET.

La esencia del temblor esencial: bases neuroquímicas / The essence of essential tremor: neurochemical bases

Introducción. El temblor esencial es el trastorno del movimiento más frecuente en el adulto. Se ha considerado una enfermedad benigna, pero puede ocasionar una importante discapacidad física y psicosocial. El tratamiento farmacológico sigue siendo poco satisfactorio. Su etiología, fisiopatología y anatomía siguen sin conocerse del todo. Objetivo. El conocimiento de las bases neuroquímicas es fundamental para el desarrollo de terapias más eficaces. Se revisan los conocimientos actuales en este campo a fin de incentivar nuevas investigaciones e ideas que permitan mejorar la comprensión de la enfermedad y que fomenten el desarrollo de nuevas terapias farmacológicas. Desarrollo. Se revisan los trabajos realizados hasta la fecha en humanos y en modelos animales de neurotransmisores (ácido gamma-aminobutírico, glutamato, noradrenalina, serotonina, adenosina), proteínas y otros fenómenos neuroquí- micos, como los canales de calcio de tipo T en el temblor esencial. Conclusiones. Se han descrito cuatro disfunciones neuroquímicas que acontecerían básicamente en el cerebelo y el núcleo olivar inferior: alteración del sistema gabérgico, aumento del rebote postinhibitorio mediante corrientes de calcio de tipo T, disminución de los mecanismos de inhibición neuronal y aumento de la actividad de los neurotransmisores excitatorios. Estas disfunciones neuroquímicas comportarían un aumento de la actividad de las neuronas profundas cerebelosas con actividad oscilatoria, que se trasladaría al núcleo del tálamo y a la corteza motora, y comportarían la aparición del temblor. Son necesarios nuevos estudios para poder confirmar estas hipótesis y seguir avanzando para conseguir tratamientos farmacológicos más eficaces para los pacientes con temblor esencial (AU)

Introduction. Essential tremor is the most frequent movement disorder in adults. It has been considered a benign disease, but can result in significant physical and psychosocial disability. Pharmacological treatment is still not very satisfactory. Its causation, pathophysiology and anatomy remain only partially understood. Aims. An understanding of its neurochemical basis is essential to be able to develop more efficient therapies. We review what is currently known in this field in order to motivate further research and ideas that allow an enhanced understanding of the disease and which foster the development of new pharmacological therapies. Development. We review the studies conducted to date in humans and in animal models of neurotransmitters (gammaaminobutyric acid, glutamate, noradrenalin, serotonin, adenosine), proteins and other neurochemical phenomena, such as T-type calcium channels, in essential tremor. Conclusions. Four neurochemical dysfunctions have been described that basically occur in the cerebellum and the inferior olivary nucleus: alteration of the GABAergic system, increased post-inhibitory rebound via T-type calcium currents, decreased neuronal inhibition mechanisms and an increase in excitatory neurotransmitter activity. These neurochemical dysfunctions would involve an increase in the activity of the deep neurons of the cerebellum with an oscillatory activity that would shift to the thalamic nucleus and the motor cortex, which in turn would lead to the appearance of tremor. Further research is needed to be able to confirm these hypotheses and to continue to advance towards achieving more efficient pharmacological treatments for patients with essential tremor (AU)

Linking Essential Tremor to the Cerebellum: Neurochemical Evidence.

The pathophysiology and the exact anatomy of essential tremor (ET) is not well known. One of the pillars that support the cerebellum as the main anatomical locus in ET is neurochemistry. This review examines the link between neurochemical abnormalities found in ET and cerebellum. The review is based on published data about neurochemical abnormalities described in ET both in human and in animal studies. We try to link those findings with cerebellum. γ-aminobutyric acid (GABA) is the main neurotransmitter involved in the pathophysiology of ET. There are several studies about GABA that clearly points to a main role of the cerebellum. There are few data about other neurochemical abnormalities in ET. These include studies with noradrenaline, glutamate, adenosine, proteins, and T-type calcium channels. One single study reveals high levels of noradrenaline in the cerebellar cortex. Another study about serotonin neurotransmitter results negative for cerebellum involvement. Finally, studies on T-type calcium channels yield positive results linking the rhythmicity of ET and cerebellum. Neurochemistry supports the cerebellum as the main anatomical locus in ET. The main neurotransmitter involved is GABA, and the GABA hypothesis remains the most robust pathophysiological theory of ET to date. However, this hypothesis does not rule out other mechanisms and may be seen as the main scaffold to support findings in other systems. We clearly need to perform more studies about neurochemistry in ET to better understand the relations among the diverse systems implied in ET. This is mandatory to develop more effective pharmacological therapies.

Minor hallucinations occur in drug-naive Parkinson's disease patients, even from the premotor phase.

OBJECTIVES: The description of minor hallucinatory phenomena (presence, passage hallucinations) has widened the spectrum of psychosis in Parkinson's disease (PD). Minor hallucinatory phenomena seem to antedate the development of more severe hallucinations. Early detection of minor hallucinations may be useful for screening patients with more severe endophenotypes. Motivated by the observation of "de novo," drug-naive PD patients reporting minor hallucinations, we aimed to prospectively identify "de novo" untreated PD patients experiencing hallucinatory phenomena, and to compare their clinico-demographic characteristics with those of untreated PD patients without hallucinations and healthy controls. METHODS: Screening and description of psychosis was assessed by the Movement Disorders Society Unified Parkinson's Disease Rating Scale-Part I and a structured interview covering all types of psychotic phenomena reported in PD. Clinical, neuropsychological, and demographic data of PD patients with and without psychotic phenomena were compared with those of age- and education-matched healthy controls. RESULTS: Fifty drug-naive, "de novo" PD patients and 100 controls were prospectively included. Minor hallucinations were experienced in 42% (21 of 50) PD patients and 5% controls (P < 0.0001). Coexistence of passage and presence hallucinations was the most common finding. Unexpectedly, 33.3% of patients with minor hallucinations manifested these as a pre-motor symptom, starting 7 months to 8 years before first parkinsonian motor symptoms. The presence of minor hallucinations was significantly associated with presence of rapid eye movement sleep behavior disorder. CONCLUSIONS: In this first study to prospectively analyze the frequency of minor hallucinatory phenomena in incident, untreated PD patients, hallucinations appeared as a frequent early non-motor symptom that may even predate the onset of parkinsonism.