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Introduction: Scrub typhus is a potentially life-threatening but curable disease that can produce multi-organ failure. Neurological manifestations in scrub typhus have gained attention recently, where the entire neural axis except the myoneural junction can be involved. Although the pathogenesis of neurological involvement has not been established, immune-mediated mechanisms are suspected. This article reports the clinicopathological features of scrub typhus cases presenting several rare neurological and neuropsychiatric manifestations. Methods: Three hundred fifty-four serologically confirmed scrub typhus cases were admitted to the Department of General Medicine of Burdwan Medical College and Hospital (West Bengal, India) between May 2018 and May 2022. There were 50 patients who had predominantly neurological manifestations. Of these 50 cases, ten patients presented with extremely rare neurological manifestations. Results: We report 10 cases of scrub typhus (four men and six women) who presented with complex neurological pictures (posterior reversible encephalopathy syndrome, Opalski syndrome, parkinsonism, cerebellitis, isolated opsoclonus, acute transverse myelitis, myositis, polyradiculoneuropathy with cranial neuropathy, acute transient behavioral changes, and fibromyalgia). Immune-mediated mechanisms might have mediated the pathogenesis of most cases following scrub typhus infection. Conclusion: From a clinicopathological point of view, each case was unique in its presentation and treatment response. In any acute onset neurological disorders associated with febrile illness in the tropics or subtropics, scrub typhus infection should be included in the differential diagnosis, despite the absence of eschar and unremarkable neuroimaging findings. This otherwise curable disease may result in multi-organ dysfunction syndrome and death if the diagnosis is delayed. Resumen: Introducción: El tifus de los matorrales es una enfermedad potencialmente mortal pero curable que puede producir fallo multiorgánico. Las manifestaciones neurológicas en el tifus de los matorrales han cobrado fuerza recientemente, donde todo el neuroeje excepto la unión mioneural puede estar involucrado. Aunque no se ha establecido la patogenia de la afectación neurológica, se sospechan mecanismos inmunomediados. En este artículo se describen las características clinicopatológicas de casos de tifus de los matorrales que presentan varias manifestaciones neurológicas y neuropsiquiátricas raras. Métodos: Trescientos cincuenta y cuatro casos de tifus de los matorrales confirmados serológicamente fueron admitidos en el Departamento de Medicina General del Burdwan Medical College and Hospital, Bengala Occidental (India) entre mayo de 2018 y mayo de 2022. Hubo 50 pacientes con manifestaciones neurológicas predominantes. De estos 50, diez presentaron manifestaciones neurológicas extremadamente raras. Resultados: Presentamos 10 casos de tifus de los matorrales (cuatro hombres y seis mujeres) que presentaron cuadros neurológicos complejos (síndrome de encefalopatía posterior reversible, síndrome de Opalski, parkinsonismo, cerebelitis, opsoclono aislado, mielitis transversa aguda, miositis, polirradiculoneuropatía con neuropatía craneal, cambios transitorios de comportamiento y fibromialgia). Los mecanismos inmunomediados mediaron la patogenia de la mayoría de los casos después del tifus de los matorrales. Conclusión: Desde el punto de vista clinicopatológico, cada caso fue único en su presentación y respuesta al tratamiento. En cualquier trastorno neurológico de inicio agudo asociado con enfermedad febril en los trópicos o subtrópicos, la infección por tifus de los matorrales debe incluirse en el diagnóstico diferencial, a pesar de la ausencia de escaras y de neuroimágenes normales. Esta enfermedad, por lo demás curable, puede provocar un síndrome de disfunción multiorgánica y la muerte si se retrasa el diagnóstico.

Introduction Fatigue is one of the most disabling symptoms of multiple sclerosis (MS), and effective treatments are lacking. Amantadine is one of the most used treatments, although its efficacy is under debate. Transcranial magnetic stimulation (TMS) is a promising intervention that has shown positive effects in some preliminary investigations. We aim to investigate the effect of 6 weeks of amantadine and/or TMS in fatigue due to MS.Methods and analysis The study is a national, multicentre, phase 3, randomised, double-blind, cross-over, placebo-controlled and sham-controlled clinical trial. Adult patients with relapsing-remitting MS, Expanded Disability Status Scale score of 1.5–4.5 and Fatigue Severity Score>4 are eligible for the trial. Participants will be randomised to one of the sequences of the study. Each sequence consists of four periods of 6 weeks of treatment and three washout periods of 12–18 weeks. All patients will receive all the combinations of therapies. The primary outcome is the Modified Fatigue Impact Scale. The secondary outcomes are the Symbol Digit Modalities Test (cognition), Beck Depression Inventory-II (depressive symptoms) and Short-Survey 12 (quality of life). Safety and cost-effectiveness will also be evaluated. An exploratory substudy including MRI and blood biomarkers will be conducted.Ethics and dissemination The study is approved by the Ethics Committee of the Hospital Clinico San Carlos and the Spanish Agency of Medications and Medical Devices. All study findings will be published in scientific peer-reviewed journals and presented at relevant scientific conferences.Trial registration number EudraCT 2021-004868-95; NCT05809414.

Abstract Whether cumulative smoking exposure is associated with cognitive decline among older adults remains unresolved. To address this question, we used data from the Neurological Disorders in Central Spain (NEDICES) cohort study, in which 2624 older adults were evaluated at two-time points separated by three years. A 37-item version of the Mini-Mental State Examination (MMSE-37) was administered at two visits to assess cognitive change. Regarding smoking exposure, we calculated an individual baseline score based on pack-years (i.e., packs of cigarettes smoked per day multiplied by years of smoking) in current and former smokers. Thus, smoking exposure was categorized into tertiles (low: 47.0). We used multivariable generalized estimating equation models to assess associations between pack-years and smoking status with 37-MMSE total score change from baseline to follow-up. The MMSE-37 total score had a decline of 1.05 points (confidence interval [CI] 95% 0.62 to 1.48) in the lower tertile of pack-years, 1.16 (CI 95% 0.70 to 1.62) in the middle tertile and 1.17 (CI 95% 0.70 to 1.65) in the higher tertile compared to never smokers, after adjusting for several demographic and clinical variables. The same occurred with smoking status, i.e., a decline of 1.33 (CI 95% 0.87 to 1.79) in current smokers and 1.01 (CI 95% 0.63 to 1.40) in former smokers. Our study provides evidence of the cumulative effect of smoking on cognition in older adults. Using a prospective population-based design, we demonstrated that cumulative smoking exposure was associated with cognitive decline in non-demented older adults. More population-based evidence is required to elucidate this association in older adults without dementia.

Brain tumors have long been considered one of the most prevalent causes of potentially reversible cognitive impairment. An accurate underlying cause of cognitive impairment due to brain tumor needs to be evaluated pragmatically. Patterns of cognitive impairment associated with brain tumors depend mainly on their location, lateralization, pathological classification and secondary effects of the treatment, as well as the structural plasticity and diaschisis. Hence, it is not rare that lesions with different locations and histologies may manifest with a similar pattern of cognitive impairment due to the complex interplay of determinants. We herein report 3 patients with brain tumors affecting different locations and with differing histologies, who shared a similar presentation as “frontal dysexecutive syndrome” masqueraded as psychiatric conditions. Detailed examination of saccades and pursuit along with eye movements and conventional motor examinations were essential not only to diagnose brain tumor as the potential cause of cognitive impairment, but also to rule out other coexisting etiologies with completely different underlying pathological mechanisms (i.e., Huntington’s disease in 1 of the cases). A detailed neurological examination, including eye movement assessment, in patients with psychiatric symptoms provides not only important clues to delineate the underlying anatomical substrate involved, but also helps clinicians to make an accurate diagnosis and to select appropriate therapeutic options.

Cerebral manifestations in Japanese B encephalitis are well known. However, there are very few studies focusing on extra-cerebral manifestations, among which focal anterior horn cell involvement is exceedingly rare. We herein report a case of Japanese B encephalitis with focal anterior horn cell involvement and unfurl how stepwise clinical approach and targeted investigations helped to solve the diagnostic conundrum. A 27-year-old female was admitted with fever, headache, altered sensorium, and convulsions. She tested positive for Japanese B encephalitis-IgM. Following conservative management, she regained consciousness after 5 days when neurological examination revealed marked cognitive impairment, medial convergence of eyeballs, upward gaze restriction, upper limbs dystonia with brisk tendon jerks, and flaccid paraparesis. A repeat neurological examination, on day 15 of admission, showed marked wasting and intermittent fasciculation in both lower limbs. Brain magnetic resonance imaging showed asymmetrical (right > left) bilateral thalamic and midbrain lesions, hyperintense on T2 and T2-fluid-attenuated inversion recovery (FLAIR)-weighted imaging with mild diffusion restriction on diffusion-weighted imaging and apparent diffusion coefficient map, suggestive of encephalitis . Nerve conduction study revealed decreased compound muscle action potentials exclusively in lower limbs with intact sensory nerve action potentials. Electromyogram showed chronic denervation potentials and presence of spontaneous activity in lower limbs, but not in upper limbs, indicative of focal anterior horn cell involvement. Prognosis of Japanese B encephalitis does not only depend on cerebral sequelae. Anterior horn cell involvement can dictate poor outcome and can easily be missed if not carefully dealt with.

Abstract Objective Orthostatic tremor (OT) is an extremely rare, misdiagnosed, and underdiagnosed disorder affecting adults in midlife. There is debate as to whether it is a different condition or a variant of essential tremor (ET), or even, if both conditions coexist. Our objective was to use data mining classification methods, using magnetic resonance imaging (MRI)‐derived brain volume and cortical thickness data, to identify morphometric measures that help to discriminate OT patients from those with ET. Methods MRI‐derived brain volume and cortical thickness were obtained from 14 OT patients and 15 age‐, sex‐, and education‐matched ET patients. Feature selection and machine learning methods were subsequently applied. Results Four MRI features alone distinguished the two, OT from ET, with 100% diagnostic accuracy. More specifically, left thalamus proper volume (normalized by the total intracranial volume), right superior parietal volume, right superior parietal thickness, and right inferior parietal roughness (i.e., the standard deviation of cortical thickness) were shown to play a key role in OT and ET characterization. Finally, the left caudal anterior cingulate thickness and the left caudal middle frontal roughness allowed us to separate with 100% diagnostic accuracy subgroups of OT patients (primary and those with mild parkinsonian signs). Conclusions A data mining approach applied to MRI‐derived brain volume and cortical thickness data may differentiate between these two types of tremor with an accuracy of 100%. Our results suggest that OT and ET are distinct conditions.

Abstract Craniocerebral metastases as the initial spread of supraglottic squamous cell carcinoma (SCC) are exceptional. The presence of several months' history of dysphagia, dyspnea, cachexia, tobacco/alcohol abuse, and seizure(s) is suspicious of craniocerebral metastases from an advanced‐stage supraglottic SCC. Physicians should be aware since early diagnosis and treatment may increase patient survival.

The elderly population is a sensitive and delicate cohort of society who is being compelled to bear the significant smoulders of disruptive social behavior of humankind amidst the COVID-19 pandemic. Our aim for this review was (1) to find out the root of disruption of societal integrity and self-centeredness by analyzing the spokes of HEXACO; (2) to delineate their possible relationships with the formation of Neuroticism and eventually Psychopathy, which have endangered human civilization the most in this pandemic; and (3) to search for the potential ways to get rid of these dark times. The constellation of different negative human behaviors probably originate from the negative deflection of components of the HEXACO model of personality towards the genesis of the dark triad. COVID-19 pandemic and upsurge of the dark triad in the form of Neuroticism, Narcissism and Machiavellianism potentially portend major mental health threats. Cultivation and practice of positive emotions and triumph of honesty, humility and humanity are imperative to save the mankind from the savagery of this pandemic.

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

Despite the importance of cognitive function in multiple sclerosis, it is poorly represented in the Expanded Disability Status Scale (EDSS), the commonly used clinical measure to assess disability, suggesting that an analysis of eye movement, which is generated by an extensive and well-coordinated functional network that is engaged in cognitive function, could have the potential to extend and complement this more conventional measure. We aimed to measure the eye movement of a case series of MS patients with relapsing–remitting MS to assess their cognitive status using a conventional gaze tracker. A total of 41 relapsing–remitting MS patients and 43 age-matched healthy controls were recruited for this study. Overall, we could not find a clear common pattern in the eye motor abnormalities. Vertical eye movement was more impaired in MS patients than horizontal movement. Increased latencies were found in the prosaccades and reflexive saccades of antisaccade tests. The smooth pursuit was impaired with more corrections (backup and catchup movements, p<0.01). No correlation was found between eye movement variables and EDSS or disease duration. Despite significant alterations in the behavior of the eye movements in MS patients, which are compatible with altered cognitive status, there is no common pattern of these alterations. We interpret this as a consequence of the patchy, heterogeneous distribution of white matter involvement in MS that provokes multiple combinations of impairment at different points in the different networks involved in eye motor control. Further studies are therefore required.

Tremor is defined as a rhythmic, involuntary oscillatory movement of a body part. Although everyone exhibits a certain degree of tremor, some pathologies lead to very disabling tremors. These pathological tremors constitute the most prevalent movement disorder, and they imply severe difficulties in performing activities of daily living. Although tremors are currently managed through pharmacotherapy or surgery, these treatments present significant associated drawbacks: drugs often induce side effects and show decreased effectiveness over years of use, while surgery is a hazardous procedure for a very low percentage of eligible patients. In this context, recent research demonstrated the feasibility of managing upper limb tremors through wearable technologies that suppress tremors by modifying limb biomechanics or applying counteracting forces. Furthermore, recent experiments with transcutaneous afferent stimulation showed significant tremor attenuation. In this regard, this article reviews the devices developed following these tremor management paradigms, such as robotic exoskeletons, soft robotic exoskeletons, and transcutaneous neurostimulators. These works are presented, and their effectiveness is discussed. The article also evaluates the different metrics used for the validation of these devices and the lack of a standard validation procedure that allows the comparison among them.

Abstract Objective The pathogenesis of orthostatic tremor (OT) is unknown. We investigated OT‐related white matter changes and their correlations with scores from a neuropsychological testing battery. Methods Diffusion tensor imaging measures were compared between 14 OT patients and 14 age‐ and education‐matched healthy controls, using whole‐brain tract‐based spatial statistics analysis. Correlations between altered diffusion metrics and cognitive performance in OT group were assessed. Results In all cognitive domains (attention, executive function, visuospatial ability, verbal memory, visual memory, and language), OT patients’ cognitive performance was significantly worse than that of healthy controls. OT patients demonstrated altered diffusivity metrics not only in the posterior lobe of the cerebellum (left cerebellar lobule VI) and in its efferent cerebellar fibers (left superior cerebellar peduncle), but also in medial lemniscus bilaterally (pontine tegmentum), anterior limb of the internal capsule bilaterally, right posterior limb of the internal capsule, left anterior corona radiata, right insula, and the splenium of corpus callosum. No relationship was found between diffusion measures and disease duration in OT patients. Diffusion white matter changes, mainly those located in right anterior limb of the internal capsule, were correlated with poor performance on tests of executive function, visuospatial ability, verbal memory, and visual memory in OT patients. Interpretation White matter changes were preferentially located in the cerebellum, its efferent pathways, as well as in the pontine tegmentum and key components of the frontal–thalamic–cerebellar circuit. Further work needs to be done to understand the evolution of these white matter changes and their functional consequences.

Background: Article-level citation count is a hallmark indicating scientific impact. We aimed to pinpoint and evaluate the top 50 most-cited articles in orthostatic tremor (OT). Methods: The ISI Web of Knowledge database and 2017 Journal Citation Report Science Edition were used to retrieve the 50 top-cited OT articles published from 1984 to April 2019. Information was collected by the Analyze Tool on the Web of Science, including number of citations, publication title, journal name, publication year, and country and institution of origin. Supplementary analyses were undertaken to clarify authorship, study design, level of evidence, and category. Results: Up to 66% of manuscripts were recovered from five journals: Movement Disorders (n = 18), Brain (n = 4), Journal of Clinical Neurophysiology (n = 4), Neurology (n = 4), and Clinical Neurophysiology (n = 3). Articles were published between 1984 and 2018, with expert opinion as the predominant design (n = 22) and review as category (n = 17). Most articles had level 5 evidence (n = 26). According to their countries of origin, 34% of articles belonged to the United States (n = 17) leading the list, followed by United Kingdom (n = 15). University College London yielded the greater number of articles (n = 12), followed by the University of Kiel (n = 9). Most popular authors were G. Deuschl (n = 10), C.D. Marsden (n = 6), J. Jankovic (n = 5), P.D. Thompson (n = 5), J.C. Rothwell (n = 5), L.J. Findley (n = 4), and P. Brown (n = 4), who together accounted for 48% of them. All papers were in English. Discussion: Publishing high-cited OT articles could be facilitated by source journal, study design, category, publication language, and country and institution of origin.

Abstract Introduction Bradyphrenia is a key cognitive feature in Parkinson's disease (PD). There is no consensus on whether information processing speed is impaired or not beyond motor performance. Objective This study aims to explore which perceptual, motor, or cognitive components of information processing are involved in the slowdown affecting cognitive performance. Methods The study included 48 patients with PD (age: 63, 3 ± 8, 18; HY I‐III; UPDRS 15,46 ± 7,76) and 53 healthy controls (age: 60,09 ± 12,83). Five reaction time (RT) tasks were administered to all participants. The average RT in each of the tasks and the percentage of correct answers were measured. Patients with PD were in "ON state" at the time of the evaluation. Perceptual, motor, and cognitive components were isolated by means of a series of ANCOVAs. Results As expected, the motor component was slowed down in patients with PD. Moreover, while patients with PD showed slower RT than controls in all tasks, differences between groups did not exponentially increase with the increasing task complexity. ANCOVA analyses also revealed that the perceptual and sustained alert component resulted to be slowed down, with no differences being found in any of the remaining isolated cognitive components (i.e., response strategy‐inhibition, decisional, visual search, or interference control). Conclusions The results revealed that slowness of information processing in PD was mainly associated with an impaired processing speed of the motor and perceptual‐alertness components analyzed. The results may help designing new neurorehabilitation strategies, focusing on the improvement of perceptual and alertness mechanisms.

Rhinosporidiosis, a chronic inflammatory disease, which is caused by the aquatic microorganism Rhinosporidium seeberi, is endemic in India and in many other regions of the tropics. It primarily infects mucocutaneous surfaces of nose, nasopharynx, and conjunctiva through transepithelial invasion. However, over the centuries, atypical involvement of other body parts, especially viscera, bone, subcutaneous layers, genitals, the tracheobronchial tree, and even the skull has been, though rarely, reported. This chronic granulomatous infection is notorious for its propensity for recurrence following autoinoculation and poor response to most of the anti-microbials except dapsone. Surgical excision followed by cauterization remains the treatment of choice when an operation is feasible. We herein report a case of an immunocompetent person with primary disseminated dermato-pulmonary rhinosporidiosis, which created significant diagnostic dilemma at the beginning, got complicated due to dapsone-induced direct anti-globulin test-positive autoimmune hemolytic anemia, and finally responded to prolonged multidrug therapy with liposomal amphotericin B, ketoconazole and cycloserine. This report establishes the importance of tissue diagnosis in rhinosporidiosis and even, in resource-poor set-ups, a simple histopathological diagnosis can promote an early and affordable accurate diagnosis, and subsequently, a proper therapeutic intervention.

There is much evidence pointing out eye movement alterations in several neurological diseases. To the best of our knowledge, this is the first video-oculography study describing potential alterations of eye movements in the post-COVID-19 condition. Visually guided saccades, memory-guided saccades, and antisaccades in horizontal axis were measured. In all visual tests, the stimulus was deployed with a gap condition. The duration of the test was between 5 and 7 min per participant. A group of n=9 patients with the post-COVID-19 condition was included in this study. Values were compared with a group (n=9) of healthy volunteers whom the SARS-CoV-2 virus had not infected. Features such as centripetal and centrifugal latencies, success rates in memory saccades, antisaccades, and blinks were computed. We found that patients with the post-COVID-19 condition had eye movement alterations mainly in centripetal latency in visually guided saccades, the success rate in memory-guided saccade test, latency in antisaccades, and its standard deviation, which suggests the involvement of frontoparietal networks. Further work is required to understand these eye movements’ alterations and their functional consequences.

Abstract Diffusion tensor imaging (DTI) studies have detected white matter microstructural changes in essential tremor (ET). However, it is still unclear whether these changes are related to cognitive deficits, which have been described in ET patients. DTI-derived fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity measures were compared between 23 ET patients and 23 age-, gender-, and education-matched healthy individuals, using whole-brain tract-based spatial statistics. Correlations of white matter changes with scores obtained from a detailed neuropsychological assessment were subsequently examined. ET patients demonstrated increases in MD in the bilateral posterior corona radiata, bilateral superior longitudinal fasciculus, bilateral fornix (cres)/stria terminalis, genu and splenium of the corpus callosum, bilateral anterior and posterior limbs of internal capsule, bilateral retrolenticular region part of internal capsule, and left posterior thalamic radiation. Except for the genu of the corpus callosum, an increase in AD values was also found in these same tracts. Furthermore, increased MD and AD values in different white matter areas was negatively correlated with performance on language and verbal memory and positively with visuospatial ability. These correlations suggest that white matter changes might be involved in the pathogenesis of cognitive deficits in ET.

Abstract Essential tremor (ET) is one of the most prevalent movement disorders. Being that it is a common disorder, its diagnosis is considered routine. However, misdiagnoses may occur regularly. Over the past decade, several studies have identified brain morphometric changes in ET, but these changes remain poorly understood. Here, we tested the informativeness of measuring cortical thickness for the purposes of ET diagnosis, applying feature selection and machine learning methods to a study sample of 18 patients with ET and 18 age- and sex-matched healthy control subjects. We found that cortical thickness features alone distinguished the two, ET from controls, with 81% diagnostic accuracy. More specifically, roughness (i.e., the standard deviation of cortical thickness) of the right inferior parietal and right fusiform areas was shown to play a key role in ET characterization. Moreover, these features allowed us to identify subgroups of ET patients as well as healthy subjects at risk for ET. Since treatment of tremors is disease specific, accurate and early diagnosis plays an important role in tremor management. Supporting the clinical diagnosis with novel computer approaches based on the objective evaluation of neuroimage data, like the one presented here, may represent a significant step in this direction.

Objetivo: Analizar las sentencias condenatorias por responsabilidad derivada de pérdida de oportunidad asistencial, dictadas por la Jurisdicción Contencioso Administrativa (es decir, en la medicina pública), en las que tanto el origen de la patología a tratar como las secuelas fueron procesos neurológicos. Métodos: Se han analizado las 90 sentencias relacionadas con patologías neurológicas que hacían referencia al concepto de pérdida de oportunidad asistencial y que fueron dictadas en España desde 2003 (año de la primera sentencia) hasta mayo de 2014. Resultados: De las 90 sentencias, 52 (57,8%) fueron dictadas por error diagnóstico y 30 por tratamiento inadecuado (33,3%). Desde el año 2009 se han producido 72 (80,0%) sentencias, lo que supone más de un 300% de aumento con respecto a las 18 (20,0%) dictadas en los primeros 6 años del estudio (2003 a 2008). La mayoría de los pacientes fueron hombres (66,7%) que tuvieron secuelas (61,1%), siendo las patologías que con más frecuencia originaron la condena la encefalopatía neonatal hipóxico-isquémica (14,4%) y las lesiones medulares (14,4%). Conclusiones: La actividad litigante por pérdida de oportunidad asistencial en patologías neurológicas, en la medicina pública española, ha aumentado de manera significativa estos últimos años. Las sentencias fueron dictadas fundamentalmente por error diagnóstico o por tratamiento inadecuado.

Landolfi's sign, alternating systolic constriction and diastolic dilatation of pupils, is a clinical hallmark of aortic regurgitation. It is thought to stem from exacerbation of physiological circulatory hippus in the vessels of iris due to a wide pulse pressure in a backdrop of severe aortic valvular incompetence. Degenerative and rheumatic heart diseases are exquisitely common in rural India and often these patients turn up late with complications to the primary care physicians. Herein, the authors report a 34-year-old pregnant female who presented with acute heart failure, and on examination, Landolfi's sign was found. It was immediately followed by Doppler echocardiography to stamp it as a case of severe aortic regurgitation. The patient was stabilized with anti-failure medications and feto-maternal health was closely monitored. The authors want to conclude claiming that bedside clinical training in cardiology will forever remain important, more so, while dealing patients at non-sophisticated primary health-care facilities. Besides, they also argue that basic tool supports like an echocardiography should be made available at those centers.

Parkinson's disease (PD) is a common debilitating neurodegenerative disease caused by a loss of dopamine neurons in the substantia nigra within the central nervous system (CNS). The process leading to this neuronal loss is poorly understood. Seborrheic dermatitis (SD) is a common benign inflammatory condition of the skin which mainly affects lipid-rich regions of the head and trunk. SD is caused by over proliferation of the lipophilic fungus Malassezia. PD and SD are strongly associated. The increased PD risk following an SD diagnosis (OR = 1.69, 95% CI 1.36, 2.1; p < 0.001) reported by Tanner and colleagues remains unexplained. Malassezia were historically considered commensals confined to the skin. However, many recent studies report finding Malassezia in internal organs, including the CNS. This raises the possibility that Malassezia might be directly contributing to PD. Several lines of evidence support this hypothesis. AIDS is causally associated with both parkinsonism and SD, suggesting that weak T cell-mediated control of commensal microbes such as Malassezia might contribute to both. Genetic polymorphisms associated with PD (LRRK2, GBA, PINK1, SPG11, SNCA) increase availability of lipids within human cells, providing a suitable environment for Malassezia. Four LRRK2 polymorphisms which increase PD risk also increase Crohn's disease risk; Crohn's disease is strongly associated with an immune response against fungi, particularly Malassezia. Finally, Malassezia hypha formation and melanin synthesis are stimulated by L-DOPA, which could promote Malassezia invasiveness of dopamine neurons, and contribute to the accumulation of melanin in these neurons. Although Malassezia's presence in the substantia nigra remains to be confirmed, if Malassezia play a role in PD etiology, antifungal drugs should be tested as a possible therapeutic intervention.

Alzheimer disease (AD) mortality risk in a large cohort of subjects treated or not with non-steroidal anti-inflammatory drugs (NSAIDs) is unknown. Our objective was to determine whether NSAIDs use is associated with decreased risk of AD mortality. In this prospective, population-based study (Neurological Disorders in Central Spain [NEDICES]) of 5,072 people without AD (aged 65 years and older), sociodemographic, comorbidity factors, and current medications were recorded at baseline. Community-dwelling older adults were followed for a median of 12.7 years, after which the death certificates of deceased participants were examined. 2,672 (52.7%) of 5,072 participants died, including 504 (18.9%) NSAIDs users and 2,168 (81.1%) non-users. Of the 2,672 deceased participants, 113 (4.2%) had AD as a cause of death (8 [1.6%] among NSAIDs users and 105 [4.8%] among non-users, chi-square = 10.70, p = 0.001). In an unadjusted Cox model, risk of AD mortality was decreased in NSAIDs users (hazard ratio [HR] for AD mortality = 0.35, 95% confidence interval [CI] 0.17-0.72, p = 0.004) when compared to non-users. After adjusting for numerous demographic factors and co-morbidities, the HR for AD mortality in NSAIDs users was 0.29, 95% CI 0.12-0.73, p = 0.009. Stratified analyses showed a significantly decreased risk of AD mortality with aspirin, whereas non-aspirin NSAIDs only showed a statistical trend toward significance in the adjusted Cox regression models. NSAIDs use was associated with 71% decreased risk of AD mortality in older adults. Our results support the hypothesis that NSAIDs use is a protective factor of developing AD.

Resumen: Objetivo: La pérdida de oportunidad asistencial se ha introducido con mucha fuerza en las resoluciones judiciales dictadas en los últimos años. Nuestro objetivo fue analizar las sentencias condenatorias por responsabilidad derivada de pérdida de oportunidad asistencial, dictadas por la Jurisdicción Contencioso Administrativa (es decir, en la medicina pública), en las que tanto el origen de la patología a tratar como las secuelas fueron procesos oncológicos. Método: Se han analizado las 137 sentencias judiciales, relacionadas con patologías oncológicas, en el ámbito de la Jurisdicción Contencioso Administrativa, que hacían referencia al concepto de pérdida de oportunidad asistencial y que fueron dictadas en España hasta mayo de 2014. Resultados: De las 137 sentencias, 119 (86,9%) fueron dictadas por error diagnóstico y 14 (10,2%) por un tratamiento inadecuado. Desde el año 2010 se han producido 100 (73,0%) sentencias, lo que supone más de un 170% de aumento con respecto a las 37 (27,0%) dictadas en los primeros 6 años del estudio (2004 a 2009). La mayoría de los pacientes (68,6%) fallecieron, siendo las de mama y de órganos genitales femeninos (24,1%), así como las digestivas (21,1%), las neoplasias malignas que con más frecuencia originaron la condena. Conclusiones: La actividad litigante por pérdida de oportunidad asistencial en patologías oncológicas en la medicina pública española ha aumentado de manera significativa estos últimos años. Las sentencias fueron dictadas fundamentalmente por error diagnóstico o tratamiento inadecuado. Abstract: Objective: The loss of chance in healthcare has been forcibly introduced in the adjudications pronounced in recent years. Our objective was to analyse the verdicts of guilt resulting from the loss of chance ordered by the Contentious-Administrative Court (i.e., in the public healthcare system), in which both the origin of the disease to be treated and the sequelae were oncological processes. Method: We analysed 137 cancer-related court judgments from the Contentious-Administrative Court, which referred to the concept of loss of chance, issued in Spain up to May 2014. Results: Of the 137 sentences, 119 (86.9%), were pronounced due to diagnostic error and 14 (10.2%) due to inadequate treatment. Since 2010, 100 sentences have been passed (73.0%), representing an increase of more than 170% with respect to the 37 (27.0%) ordered in the first six years of the study (from 2004 to 2009). Most of the patients (68.6%) died, predominantly from breast cancer and gynaecological cancer (24.1%), and gastrointestinal cancers (21.1%). These malignancies were the ones most often involved in the sentences. Conclusions: The litigant activity due to loss of chance in oncological processes in the public health care has significantly increased in the last years. The judgments were mainly given because of diagnostic error or inadequate treatment. Palabras clave: Pérdida de oportunidad, Jurisprudencia, Compensación, Oncología, Keywords: Loss of chance, Jurisprudence, Compensation, Oncology

La depresión es una enfermedad que tiene un impacto especialmente preocupante en la vejez por el incremento de factores precipitantes de enfermedades en esta etapa de la vida. En México, aún hay pocos estudios poblacionales que estudien la depresión en la senectud. Los objetivos de nuestro estudio son: 1) estimar la prevalencia de síntomas depresivos en el adulto mayor; 2) analizar la asociación entre síntomas depresivos y diferentes factores favorecedores de la depresión; y 3) reflexionar en qué sentido los resultados de este trabajo pueden contribuir a la mejora de las políticas de salud en México. La investigación es poblacional y transversal y se realizó en Ciudad Victoria, Tamaulipas. Se estudió a 1.126 personas mayores (455 hombres y 671 mujeres), que suponían aproximadamente el 5,1% de toda la población mayor de Ciudad Victoria en el momento de realización del estudio. La depresión fue medida mediante la escala Geriatric Depression Scale. Los resultados indican que: 1) la prevalencia de síntomas depresivos se sitúa en un 29%; y 2) los factores favorecedores de la depresión fueron la dependencia en actividades de la vida diaria, el deterioro cognitivo, la falta de apoyo social, la edad, el sexo, la soledad, la pobreza, los eventos estresantes y la percepción subjetiva de salud. La reducción de la depresión no sólo está vinculada a la mejora de aspectos relacionados con la salud, sino a la mejora de las condiciones de vida de los ancianos.

Background: Traditional studies on the neural mechanisms of tremor use coherence analysis to investigate the relationship between cortical and muscle activity, measured by electroencephalograms (EEG) and electromyograms (EMG). This methodology is limited by the need of relatively long signal recordings, and it is sensitive to EEG artifacts. Here, we analytically derive and experimentally validate a new method for automatic extraction of the tremor-related EEG component in pathological tremor patients that aims to overcome these limitations.Methods: We exploit the coupling between the tremor-related cortical activity and motor unit population firings to build a linear minimum mean square error estimator of the tremor component in EEG. We estimated the motor unit population activity by decomposing surface EMG signals into constituent motor unit spike trains, which we summed up into a cumulative spike train (CST). We used this CST to initialize our tremor-related EEG component estimate, which we optimized using a novel approach proposed here.Results: Tests on simulated signals demonstrate that our new method is robust to both noise and motor unit firing variability, and that it performs well across a wide range of spectral characteristics of the tremor. Results on 9 essential (ET) and 9 Parkinson's disease (PD) patients show a ~2-fold increase in amplitude of the coherence between the estimated EEG component and the CST, compared to the classical EEG-EMG coherence analysis.Conclusions: We have developed a novel method that allows for more precise and robust estimation of the tremor-related EEG component. This method does not require artifact removal, provides reliable results in relatively short datasets, and tracks changes in the tremor-related cortical activity over time.

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system. Infectious triggers of MS are being actively investigated. Substantial evidence supports the involvement of the Epstein-Barr virus (EBV), though other viruses, bacteria, protists, and fungi are also being considered. Many links between fungi and diseases involving chronic inflammation have been found recently. Evidence linking MS and fungi is reviewed here. The HLA-DRB1*15 allele group is the most important genetic risk factor of MS, and is a risk factor in several other conditions linked to fungal infections. Many biomarkers of MS are consistent with fungal infections, such as IL-17, chitotriosidase, and antibodies against fungi. Dimethyl fumarate (DMF), first used as an industrial fungicide, was recently repurposed to reduce MS symptoms. Its mechanisms of action in MS have not been firmly established. The low risk of MS during childhood and its moderate association with herpes simplex virus type 2 suggest genital exposure to microbes (including fungi) should be investigated as a possible trigger. Molecular and epidemiological evidence support a role for infections such as EBV in MS. Though fungal infections have not been widely studied in MS, many lines of evidence are consistent with a fungal etiology. Future microbiome and serological studies should consider fungi as a possible risk factor for MS, and future clinical studies should consider the effect of fungicides other than DMF on MS symptoms.

Background: Essential tremor (ET) and Parkinson’s disease (PD) are two of the most common movement disorders. Leaving aside their motor features, these two conditions share several non-motor features, including cognitive dysfunction and personality changes. However, there are few data comparing the cognitive and personality profiles of ET with PD. Here we compare the cognitive and personality profiles of the two diseases.Methods: Thirty-two consecutive non-demented ET patients (13 females and 19 males) (67.7±9.8 years), 32 non-demented PD patients (13 females and 19 males) (67.7±9.5 years), and 32 healthy matched controls (14 females and 18 males) (67.9±10.1 years) underwent a neuropsychological test battery, including a global cognitive assessment and tests of attention, executive function, memory, language, and visuospatial function, as well as the Personality Assessment Inventory. Multivariable linear regression analyses were performed, adjusted for age, sex, years of education, medications that potentially affect cognitive function, number of medications, and the 17-item Hamilton Depression Rating Scale Total Score.Results: Neuropsychological scores were similar in PD and ET patients, but patients with disease performed more poorly than control subjects in cognitive tasks such as attention, executive function, memory, and naming.Discussion: ET and PD exhibited similar deficits in specific aspects of neuropsychological functioning, particularly those thought to rely on the integrity of the prefrontal cortex, and this suggests involvement of frontocerebellar circuits. These findings further challenge the traditional view of ET as a benign and monosymptomatic disorder.

Background: Orthostatic tremor (OT) remains among the most intriguing and poorly understood of movement disorders. Compared to Parkinson’s disease or even essential tremor, there are very few articles addressing more basic science issues. In this review, we will discuss the findings of main case series on OT, including data on etiology, pathophysiology, diagnostic approach, treatment strategies, and outcome.Methods: Data for this review were identified by searching PUBMED (January 1966 to August 2016) for the terms “orthostatic tremor” or “shaky leg syndrome,” which yielded 219 entries. We did not exclude papers on the basis of language, country, or publication date. The electronic database searches were supplemented by articles in the authors’ files that pertained to this topic.Results: Owing to its rarity, the current understanding of OT is limited and is mostly based on small case series or case reports. Despite this, a growing body of evidence indicates that OT might be a progressive condition that is clinically heterogeneous (primary vs. secondary cases) with a broader spectrum of clinical features, mainly cerebellar signs, and possible cognitive impairment and personality disturbances. Along with this, advanced neuroimaging techniques are now demonstrating distinct anatomical and functional changes, some of which are consistent with neuronal loss.Discussion: OT might be a family of diseases, unified by the presence of leg tremor, but further characterized by etiological and clinical heterogeneity. More work is needed to understand the pathogenesis of this condition.

Background: Our aim was to assess the diagnostic agreement among the neurologists in the Neurological Disorders in Central Spain 2 (NEDICES‐2) study; these neurologists were assigning diagnoses of essential tremor (ET) vs. no ET.Methods: Clinical histories and standardized video‐taped neurological examinations of 26 individuals (11 ET, seven Parkinson’s disease, three diagnostically unclear, four normal, one with a tremor disorder other than ET) were provided to seven consultant neurologists, six neurology residents, and five neurology research fellows (18 neurologists total). For each of the 26 individuals, neurologists were asked to assign a diagnosis of “ET” or “no ET” using diagnostic criteria proposed by the Movement Disorders Society (MDS). Inter‐rater agreement was assessed both with percent concordance and non‐weighted Κ statistics. Results: Overall Κ was 0.61 (substantial agreement), with no differences between consultant neurologists (Κ = 0.60), neurology residents (Κ = 0.61), and neurology research fellows (Κ = 0.66) in subgroup analyses. Subanalyses of agreement only among those 15 subjects with a previous diagnosis of ET (11 patients) and those with a previous diagnosis of being normal (four individuals) showed an overall Κ of 0.51 (moderate agreement). Discussion In a population‐based epidemiological study, substantial agreement was demonstrated for the diagnosis of ET among neurologists of different levels of expertise. However, agreement was lower than that previously reported using the Washington Heights–Inwood Genetic Study of Essential Tremor criteria, and a head‐to‐head comparison is needed to assess which is the tool of choice in epidemiological research in ET.

BACKGROUND: Essential tremor (ET) is characterised by postural and action tremors with a frequency of 4-12 Hz. Previous studies suggest that the tremor activity originates in the cerebello-thalamocortical pathways. Alprazolam is a short-acting benzodiazepine that attenuates tremors in ET. The mechanisms that mediate the therapeutic action of alprazolam are unknown; however, in healthy subjects, benzodiazepines increase cortical beta activity. In this study, we investigated the effect of alprazolam both on beta and tremor-related cortical activity and on alterations in tremor presentation in ET patients. Therefore, we characterised the dynamics of tremor and cortical activity in ET patients after alprazolam intake. METHODS: We recorded hand tremors and contralateral cortical activity in four recordings before and after a single dose of alprazolam. We then computed the changes in tremors, cortico-muscular coherence, and cortical activity at the tremor frequency and in the beta band. RESULTS: Alprazolam significantly attenuated tremors (EMG: 76.2 ± 22.68%), decreased cortical activity in the tremor frequency range and increased cortical beta activity in all patients (P

BACKGROUND: Some epidemiological, genetic, and experimental data suggest a possible role of vitamin D in the pathogenesis of multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis. Data on the possible contribution of several single nucleotide polymorphisms (SNP) in the vitamin D receptor (VDR) gene to the risk for MS are controversial. Several studies suggested an interaction between some SNPs in the VDR gene and HLADRB1*1501 in the risk for MS. OBJECTIVES: The aim of this study was to investigate a possible influence of the SNPs rs2228570 and rs731236 in the VDR gene in the risk for MS. A secondary objective was to address the possible interactions between VDR genes and HLADRB1*1501. METHODS: We analyzed the allelic and genotype frequency of VDR rs2228570, rs731236, and HLADRB1*1501 (rs3135388) in 303 patients with MS and 310 healthy controls, using TaqMan Assays. We also conducted a meta-analysis, that was carried out by using the software Meta-Disc 1.1.1 (http://www.hrc.es/investigacion/metadisc.html; Unit of Clinical Statistics, Hospital Ramón y Cajal, Madrid, Spain). Heterogeneity between studies in terms of degree of association was tested using the Q-statistic. RESULTS: VDR rs2228570 and rs731236 allelic and genotype frequencies did not differ significantly between MS patients and controls, and were unrelated with the age of onset of MS, gender, and course of MS. HLADRB1*1501 showed a high association with the risk of developing MS 4.76(95% C.I. = 3.14-7.27; p

Background: Tremor is the most common movement disorder and strongly increases in incidence and prevalence with aging. Although not life threatening, upper-limb tremors hamper the independence of 65% of people suffering from them affected persons, greatly impacting their quality of life. Current treatments include pharmacotherapy and surgery (thalamotomy and deep brain stimulation). However, these options are not sufficient for approximately 25% of patients. Therefore, further research and new therapeutic options are required to effectively manage pathological tremor.Methods: This paper presents findings of two research projects in which two different wearable robots for tremor management were developed based on force loading and validated. The first consisted of a robotic exoskeleton that applied forces to tremulous limbs and consistently attenuated mild and severe tremors. The second was a neuroprosthesis based on transcutaneous neurostimulation. A total of 22 patients suffering from parkinsonian or essential tremor (ET) of different severities were recruited for experimental validation, and both systems were evaluated using standard tasks employed for neurological examination. The inclusion criterion was a postural and/or kinetic pathological upper-limb tremor resistant to medication.Results: The results demonstrate that both approaches effectively suppressed tremor in most patients, although further research is required. The work presented here is based on clinical evidence from a small number of patients (n = 10 for robotic exoskeleton and n = 12 for the neuroprosthesis), but most had a positive response to the approaches. In summary, biomechanical loading is non-invasive and painless. It may be effective in patients who are insufficiently responsive (or have adverse reactions) to drugs or in whom surgery is contraindicated.Discussion: This paper identifies and evaluates biomechanical loading approaches to tremor management and discusses their potential.Erratum published March 14, 2013

The most frequent MAPT H1 haplotype is associated with the risk for developing progressive supranuclear palsy and other neurodegenerative diseases such as Parkinson's disease. A recent report suggests that the MAPT H1 is associated with the risk for developing essential tremor. We wanted to confirm this association in a different population. We analyzed the distribution of allelic and genotype frequencies of rs1052553, which is an H1/H2 SNP, in 200 subjects with familial ET and 291 healthy controls. rs1052553 genotype and allelic frequencies did not differ significantly between subjects with ET and controls and were unrelated with the age at onset of tremor or gender, and with the presence of head, voice, chin, and tongue tremor. Our study suggests that the MAPT H1 rs1052553 is not associated with the risk for developing familial ET in the Spanish population.

The TNF-related apoptosis inducing ligand (TRAIL)/TRAIL receptor system participates in crucial steps in immune cell activation or differentiation. It is able to inhibit proliferation and activation of T cells and to induce apoptosis of neurons and oligodendrocytes, and seems to be implicated in autoimmune diseases. Thus, TRAIL and TRAIL receptor genes are potential candidates for involvement in susceptibility to multiple sclerosis (MS). To test whether single-nucleotide polymorphisms (SNPs) in the human genes encoding TRAIL, TRAILR-1, TRAILR-2, TRAILR-3 and TRAILR-4 are associated with MS susceptibility, we performed a candidate gene case-control study in the Spanish population. 59 SNPs in the TRAIL and TRAIL receptor genes were analysed in 628 MS patients and 660 controls, and validated in an additional cohort of 295 MS patients and 233 controls. Despite none of the SNPs withstood the highly conservative Bonferroni correction, three SNPs showing uncorrected p values

ABSTRACT High education has been associated with faster cognitive decline after diagnosis of Alzheimer's disease (AD), but it is unclear whether these findings extend to other dementia subtypes. OBJECTIVE: We investigated whether educational attainment influences the cognitive trajectories of older adults with different dementia subtypes. METHODS: All participants were selected from NEDICES, a prospective population-based cohort study of Spanish older adults. A total sample of 53 individuals with dementia completed the MMSE-37 at Times 1 and 2 (mean follow-up=2.8±0.5 years) to assess cognitive decline. RESULTS: At follow-up, MMSE-37 scores had decreased by 3.34±4.98 points in low-educated individuals with dementia versus 7.90±4.88 points in high-educated subjects (effect size (r)=0.32, p=0.02). CONCLUSION: Educational level influenced the cognitive trajectories of patients with dementia assessed by the MMSE-37.