Postural tremor and sexual chromosome aneuploidies: case report and review of literature.

PURPOSE: To examine the link between tremor and sex chromosome abnormalities, emphasizing the necessity of comprehensive physical examination. CASE DESCRIPTION: An 18-year-old man exhibited an isolated action tremor in both hands. Despite having no familial history of tremors and no identifiable secondary causes, his tall stature and learning difficulties suggested a genetic origin. His karyotype confirmed the diagnosis of Jacob's syndrome (XYY syndrome). Therapies with primidone and propranolol were ineffective for his tremor. CONCLUSIONS: Tremor can be caused by various conditions, and aneuploidies might often be overlooked as a cause. They should be considered in young patients with concrete phenotypes and negative familiar history of tremors. Karyotyping is a cost-effective diagnostic tool crucial for genetic counselling. Common treatments for tremors often yield unsatisfactory results in these cases.

First patient with mosaic NOTCH3 gene pathogenic variant. Unrevealed mosaicisms and importance of their detection.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused predominantly by pathogenic variants in NOTCH3 gene. Neither germline nor somatic mosaicism has been previously published in NOTCH3 gene. CADASIL is inherited in an autosomal dominant manner; only rare cases have been associated with de novo pathogenic variants. Mosaicism is more common than previously thought because mosaic variants often stay unrevealed. An apparently de novo variant might actually be a consequence of a parental mosaicism undetectable with Sanger sequencing, especially in the case of low grade mosaicism. Parental testing by sensitive tools like deep targeted next-generation sequencing (NGS) analysis could detect cases of unrevealed medium or low level mosaicism in patients tested by Sanger sequencing. Here, we report the first patient with mosaic NOTCH3 gene pathogenic variant to our knowledge; the allelic fraction in the leucocyte DNA was low (13%); the pathogenic variant was inhered by his two daughters. The patient was diagnosed by deep targeted NGS analysis after studying his two affected daughters. This report highlights the importance of parental testing by sensitive tools like deep targeted NGS analysis. Detection of mosaicism is of great importance for diagnosis and adequate family genetic counseling.

Home calligraphic exercises as manual dexterity training in patients with Parkinson's disease: a pilot feasibility study.

PURPOSE: To assess the feasibility and effects on manual dexterity and the quality of life (QoL) of a 12-week home calligraphic training program in patients with Parkinson's disease (PD). METHODS: A pilot study with participants recruited from the Movement Disorders consultation at the Hospital 12 de Octubre (Madrid). The main outcome, manual dexterity, was assessed using the Purdue Pegboard Test (PPT). Secondary outcomes included clinical rating scales that contemplate aspects related to manual dexterity (DextQ-24, UPDRSII, UPDRSIII), and QoL (PDQ-39 and EuroQoL-5D). RESULTS: Thirty PD patients (57% males) with a mean age of 66.11 (9.76) years and 93% adherence rate. The PPT scores improved significantly (p < 0.0001) from T0 (start of the study) to T1 (after 24 weeks). No statistically significant change was found in DextQ-24, UPDRS-II and UPDRS-III, but a clear improvement was observed in the QoL measurement: EuroQoL-5D (p < 0.0001), PDQ-39 (p < 0.0001) and modified PDQ-39 (p = 0.022). CONCLUSIONS: This is the first study to demonstrate the feasibility and improvement in hand dexterity assessed by the PPT for patients diagnosed with PD after a 12-week home calligraphic training program. A significant improvement was noted in the QoL measurements, such as the PDQ-39, modified PDQ-39, and EuroQoL-5D.Implications for RehabilitationMost patients with Parkinson's disease suffer from impaired manual dexterity, making it difficult to perform activities of daily living such as eating, buttoning, or shaving.A 12-week home calligraphic training program could improve hand dexterity in these patients.The advantage of this home calligraphic trainingis is that it is an easy-to-perform, low-cost and no side effects.This training also improves their quality of life.

COVID19-associated new-onset movement disorders: a follow-up study.

BACKGROUND: Neurological symptoms are common manifestation in acute COVID-19. This includes hyper- and hypokinetic movement disorders. Data on their outcome, however, is limited. METHODS: Cases with new-onset COVID-19-associated movement disorders were identified by searching the literature. Authors were contacted for outcome data which were reviewed and analyzed. RESULTS: Movement disorders began 12.6 days on average after the initial onset of COVID-19. 92% of patients required hospital admission (mean duration 23 days). In a fraction of patients (6 of 27; 22%; 4 males/2 females, mean age 66.8 years) the movement disorder (ataxia, myoclonus, tremor, parkinsonism) was still present after a follow-up period of 7.5 ± 3 weeks. Severe COVID-19 in general and development of encephalopathy were risk factors, albeit not strong predictors, for the persistence. CONCLUSIONS: The prognosis of new-onset COVID-19-associated movement disorder appears to be generally good. The majority recovered without residual symptoms within several weeks or months. Permanent cases may be due to unmasking of a previous subclinical movement disorder or due to vascular/demyelinating damage. Given the relatively low response rate of one third only and the heterogeneity of mechanisms firm conclusions on the (long-term) outome cannot, however, be drawn.

Differences in Striatal Metabolism in [18F]FDG PET in Parkinson's Disease and Atypical Parkinsonism.

Neurodegenerative parkinsonisms affect mainly cognitive and motor functions and are syndromes of overlapping symptoms and clinical manifestations such as tremor, rigidness, and bradykinesia. These include idiopathic Parkinson's disease (PD) and the atypical parkinsonisms, namely progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple system atrophy (MSA) and dementia with Lewy body (DLB). Differences in the striatal metabolism among these syndromes are evaluated using [18F]FDG PET, caused by alterations to the dopaminergic activity and neuronal loss. A study cohort of three patients with PD, 29 with atypical parkinsonism (10 PSP, 6 CBD, 2 MSA, 7 DLB, and 4 non-classifiable), and a control group of 25 patients with normal striatal metabolism is available. Standardized uptake value ratios (SUVR) are extracted from the striatum, and the caudate and the putamen separately. SUVRs are compared among the study groups. In addition, hemispherical and caudate-putamen differences are evaluated in atypical parkinsonisms. Striatal hypermetabolism is detected in patients with PD, while atypical parkinsonisms show hypometabolism, compared to the control group. Hemispherical differences are observed in CBD, MSA and DLB, with the latter also showing statistically significant caudate-putamen asymmetry (p = 0.018). These results indicate disease-specific metabolic uptake patterns in the striatum that can support the differential diagnosis.

Physical activity and risk of Parkinson's disease and parkinsonism in a prospective population-based study (NEDICES).

To investigate whether physical activity (PA) is a protective factor for the incidence of Parkinson's disease (PD) and parkinsonism after three years of follow-up. All participants of this study were obtained from the Neurological Disorders in Central Spain (NEDICES), a prospective population-based cohort survey of older subjects (≥65 years) that comprised 5278 census-based participants at baseline (1994-1995). A modified version of Rosow-Breslau questionnaire was applied to categorize PA into active versus sedentary group. The final diagnosis of PD and parkinsonism was made by an expert neurologist. Cox regression models (CRM) adjusted for several covariates (sex, age, education, alcohol consumption, tobacco, stroke, hypertension and body mass index) were used to calculate the association between PA (active group vs. sedentary) and risk of PD and parkinsonism after three years. 22 incident PD and 25 incident parkinsonism cases were identified among 2943 participants with available PA information (57.1% female; mean age = 73.28 ± 6.24 years) after three years of follow-up. The CRM showed that the active group (vs. sedentary) showed a lower risk of parkinsonism (Hazard ratio (HR) = 0.18; 95% CI [0.07-0.51]; p = 0.0001). However, this effect was restricted to men (HR = 0.34; 95% CI [0.11-0.99], p < 0.05) for incident PD. PA may be a protective factor for incident parkinsonism, whereas this effect was only significant for men in the case of PD. The mechanisms implicated for brain maintenance in active individuals and the neurophysiological differences behind the role of sex on PD are discussed.

Expanding the clinical and genetic spectrum of SQSTM1-related disorders in family with personality disorder and frontotemporal dementia.

Objective:SQSTM1-variants associated with frontotemporal lobar degeneration have been described recently. In this study, we investigated a heterozygous in-frame duplication c.436_462dup p. (Pro146_Cys154dup) in the SQSTM1 gene in a family with a new phenotype characterized by a personality disorder and behavioral variant frontotemporal dementia (bvFTD). We review the literature on frontotemporal dementia (FTD) associated with SQSTM1. Methods: The index case and relatives were described, and a genetic study through Whole Exome Sequencing was performed. The literature was reviewed using Medline and Web of Science. Case reports, case series, and cohort studies were included if they provided information on SQSTM1 mutations associated with FTD. Results: Our patient is a 70-year-old man with a personality disorder since youth, familial history of dementia, and personality disorders with a 10-year history of cognitive decline and behavioral disturbances. A diagnosis of probable bvFTD was established, and the in-frame duplication c.436_462dup in the SQSTM1 gene was identified. Segregation analysis in the family confirmed that both affected sons with personality disorder were heterozygous carriers, but not his healthy 65-year-old brother. A total of 14 publications about 57 patients with SQSTM1-related FTD were reviewed, in which the bvFTD subtype was the main phenotype described (66.6%), with a predominance in men (63%) and positive family history in 61.4% of the cases. Conclusions: We describe a heterozygous in-frame duplication c.436_462dup p.(Pro146_Cys154dup) in the SQSTM1 gene, which affects the zinc-finger domain of p62, in a family with a personality disorder and bvFTD, expanding the genetics and clinical phenotype related to SQSTM1.

Miller Fisher syndrome and polyneuritis cranialis in COVID-19.

OBJECTIVE: To report 2 patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who presented acutely with Miller Fisher syndrome and polyneuritis cranialis, respectively. METHODS: Patient data were obtained from medical records from the University Hospital "Príncipe de Asturias," Alcalá de Henares, and the University Hospital "12 de Octubre," Madrid, Spain. RESULTS: A 50-year-old man presented with anosmia, ageusia, right internuclear ophthalmoparesis, right fascicular oculomotor palsy, ataxia, areflexia, albuminocytologic dissociation, and positive testing for anti-GD1b-immunoglobulin G antibody. Five days previously, he had developed a cough, malaise, headache, low back pain, and fever. A 39-year-old man presented with ageusia, bilateral abducens palsy, areflexia, and albuminocytologic dissociation. Three days previously, he had developed diarrhea, a low-grade fever, and poor general condition. Oropharyngeal swab test for SARS-CoV-2 by qualitative real-time reverse transcriptase PCR assay was positive in both patients and negative in the CSF. The first patient was treated with IV immunoglobulin and the second with acetaminophen. Two weeks later, both patients made a complete neurologic recovery, except for residual anosmia and ageusia in the first case. CONCLUSIONS: Our 2 cases highlight the rare occurrence of Miller Fisher syndrome and polyneuritis cranialis during the coronavirus disease 2019 (COVID-19) pandemic. These neurologic manifestations may occur because of an aberrant immune response to COVID-19. The full clinical spectrum of neurologic symptoms in patients with COVID-19 remains to be characterized.

Generalized myoclonus in COVID-19.

OBJECTIVE: To report 3 patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who developed generalized myoclonus. METHODS: Patient data were obtained from medical records from the University Hospital "12 de Octubre," Madrid, Spain. RESULTS: Three patients (2 men and 1 woman, aged 63-88 years) presented with mild hypersomnia and generalized myoclonus following the onset of the so-called inflammatory phase of coronavirus disease 2019 (COVID-19). All of them had presented previously with anosmia. Myoclonus was generalized with both positive and negative jerks, predominantly involving the facial, trapezius, sternocleidomastoid, and upper extremities muscles. These myoclonic jerks occurred spontaneously and were extremely sensitive to multisensory stimuli (auditive and tactile) or voluntary movements, with an exaggerated startle response. Other causes of myoclonus were ruled out, and none of the patients had undergone respiratory arrest or significant prolonged hypoxia. All of them improved, at least partially, with immunotherapy. CONCLUSIONS: Our 3 cases highlight the occurrence of myoclonus during the COVID-19 pandemic as a post- or para-infectious immune-mediated disorder. However, we cannot rule out that SARS-CoV-2 may spread transneuronally to first- and second-order structures connected with the olfactory bulb. Further investigation is required to clarify the full clinical spectrum of neurologic symptoms and optimal treatment.

Acute hypokinetic-rigid syndrome following SARS-CoV-2 infection.

OBJECTIVE: To report a case of a patient infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who acutely developed a hypokinetic-rigid syndrome. METHODS: Patient data were obtained from medical records from the Hospital Universitario 12 de Octubre in Madrid, Spain. [123I]-ioflupane dopamine transporter (DaT) SPECT images were acquired 4 hours after a single dose of 185 MBq of 123I-FP-CIT. Quantitative analysis was performed with DaTQUANT software providing the specific binding ratio and z score values of the striatum. RESULTS: We report a previously healthy 58-year-old man who developed hyposmia, generalized myoclonus, fluctuating and transient changes in level of consciousness, opsoclonus, and an asymmetric hypokinetic-rigid syndrome with ocular abnormalities after a severe SARS-CoV-2 infection. DaT-SPECT confirmed a bilateral decrease in presynaptic dopamine uptake asymmetrically involving both putamina. Significant improvement in the parkinsonian symptoms was observed without any specific treatment. CONCLUSION: This case study provides clinical and functional neuroimaging evidence to support that SARS-CoV-2 can gain access to the CNS, affecting midbrain structures and leading to neurologic signs and symptoms.

Mechanical vibration does not systematically reduce the tremor in essential tremor patients.

Essential tremor (ET) is a major cause of disability and is not effectively managed in half of the patients. We investigated whether mechanical vibration could reduce tremor in ET by selectively recruiting afferent pathways. We used piezoelectric actuators to deliver vibratory stimuli to the hand and forearm during long trials (4 min), while we monitored the tremor using inertial sensors. We analyzed the effect of four stimulation strategies, including different constant and variable vibration frequencies, in 18 ET patients. Although there was not a clear homogeneous response to vibration across patients and strategies, in most cases (50-72%) mechanical vibration was associated with an increase in the amplitude of their tremor. In contrast, the tremor was reduced in 5-22% of the patients, depending on the strategy. However, these results are hard to interpret given the intrinsic variability of the tremor: during equally long trials without vibration, the tremor changed significantly in 67% of the patients (increased in 45%; decreased in 22%). We conclude that mechanical vibration of the limb does not have a systematic effect on tremor in ET. Moreover, the observed intrinsic variability of the tremor should be taken into account when designing future experiments to assess tremor in ET and how it responds to any intervention.

Smartwatch for the analysis of rest tremor in patients with Parkinson's disease.

Wearable technology used in Parkinson's disease (PD) research has become an increasing focus of interest in this field. Our group assessed the feasibility, clinical correlation, reliability, and acceptance of smartwatches in order to quantify arm resting tremors in PD patients. An Android application on a smartwatch was used to obtain raw data from the smartwatch's gyroscopes. Twenty-two PD patients were consecutively recruited and followed for 1 year. Arm rest tremors were video filmed and scored by two independent raters using the motor subscale of the Unified Parkinson's Disease Rating Scale (UPDRS-III). The tremor intensity parameter was defined by the root mean square of the angular speed measured by the smartwatch at the wrist. Sixty-four smartwatch evaluations were completed. The Spearman coefficient among the mean of the resting tremor (UPDRS-III) scores and smartwatch measurements for tremor intensity was 0.81 (p < .001); smartwatch reliability to quantify tremors was checked by intraclass reliability coefficient with a resting tremor = 0.89, minimum detectable change = 59.03%. Good acceptance of the system was shown. Smartwatch use for PD tremor analysis is possible, reliable, well-correlated with clinical scores, and well-accepted by patients for clinical follow-up. The results from these experiments suggest that this commodity hardware has the potential to quantify PD patients' tremors objectively in a consulting-room.

Improvement of mouse controlling in Essential tremor by a tremor filter: A case report.

The interaction with electronic devices is crucial in our technological society. Hand kinetic tremor complicates mouse driving in Essential tremor patients. To solve this issue some technological solutions are available and accessible online. We present a 71-year-old patient with prominent mouse controlling tremor who improved with one of these systems.

Essential tremor quantification based on the combined use of a smartphone and a smartwatch: The NetMD study.

BACKGROUND: The use of wearable technology is an emerging field of research in movement disorders. This paper introduces a clinical study to evaluate the feasibility, clinical correlation and reliability of using a system based in smartwatches to quantify tremor in essential tremor (ET) patients and check its acceptance as clinical monitoring tool. NEW METHOD: The system is based on a commercial smartwatch and an Android smartphone. An investigational Android application controls the process of recording raw data from the smartwatch three-dimensional gyroscopes. Thirty-four ET patients were consecutively enrolled in the experiments and assessed along one year. Arm tremor was videofilmed and scored using the Fahn-Tolosa-Marin Tremor Rating Scale (FTM-TRS). Tremor intensity was quantified with the root mean square of angular velocity measured in the patients' wrists. RESULTS: Eighty-two assessments with smartwatches were performed. Spearman's correlation coefficients (ρ) between clinical tremor (FTM-TRS) scores and smartwatch measures for tremor intensity were 0.590 at rest; ρ = 0.738 in steady posture; ρ = 0.189 in finger-to-nose maneuvers; and ρ = 0.652 in pouring water task. Smartwatch reliability was checked by intraclass realiability coefficients: 0.85, 0.95, 0.91, 0.95 respectively. Most of patients showed good acceptance of the system. COMPARISON WITH EXISTING METHOD(S): This commodity hardware contributes to quantify tremor objectively in a consulting-room by customized Android smart devices as clinical monitoring tool. CONCLUSIONS: The NetMD system for tremor analysis is feasible, well-correlated with clinical scores, reliable and well-accepted by patients to tremor follow-up. Therefore, it could be an option to objectively quantify tremor in ET patients during their regular follow-up.

Drug-Related Eyelid Nystagmus: Two Cases of a Rare Clinical Phenomenon Related to Carbamazepine and Derivatives.

BACKGROUND: Eyelid nystagmus is a rare clinical phenomenon described mostly related to brainstem or cerebellum lesions. The mechanism of this phenomenon is incompletely understood. PATIENTS AND METHODS: We report 2 cases of eyelid nystagmus induced by carbamazepine and oxcarbazepine intoxication. CONCLUSIONS: Carbamazepine and derivatives may induce eyelid nystagmus in the setting of acute intoxication. To the best of our knowledge, these are the first cases of drug-related eyelid nystagmus.