Seizures in children undergoing stem cell transplantation.

BACKGROUND: Neurological complications (NCs) are of major concern following hematological stem cell transplantation (HSCT), most of which present with seizures. PROCEDURES: We performed a retrospective study (2002-2018) of patients undergoing HSCT in order to analyze the incidence and aetiologies related to seizures. RESULTS: Of 155 children undergoing HSCT, 27 (17.4%) developed seizures at some point in 2 years of follow-up. The most frequent etiologies were central nervous system (CNS) infection (n = 10), drug toxicity (n = 8), and vascular disease (n = 5). A statistically significant association was found between seizure and the HSCT type (lower risk for a related identical donor, p = .010), prophylactic or therapeutic mycophenolate use (p = .043 and .046, respectively), steroid use (p = .023), selective CD45RA+ depletion (p = .002), pre-engraftment syndrome (p = .007), and chronic graft-versus-host disease (GVHD) severity (p = .030). Seizures predicted evolution to life-threatening complications and admission to intensive care (p < .001) and higher mortality (p = .023). A statistically significant association was also found between seizures and sequelae in survivors (p = .029). Children who developed seizures had a higher risk of CNS infection and vascular disease (odds ratio 37.25 [95% CI: 7.45-186.05] and 12.95 [95% CI 2.24-74.80], respectively). CONCLUSIONS: Neurological complications highly impact survival and outcomes and need to be addressed when facing an HSCT procedure.

The Sant Pau Initiative on Neurodegeneration (SPIN) cohort: A data set for biomarker discovery and validation in neurodegenerative disorders.

INTRODUCTION: The SPIN (Sant Pau Initiative on Neurodegeneration) cohort is a multimodal biomarker platform designed for neurodegenerative disease research following an integrative approach. METHODS: Participants of the SPIN cohort provide informed consent to donate blood and cerebrospinal fluid samples, receive detailed neurological and neuropsychological evaluations, and undergo a structural 3T brain MRI scan. A subset also undergoes other functional or imaging studies (video-polysomnogram, 18F-fluorodeoxyglucose PET, amyloid PET, Tau PET). Participants are followed annually for a minimum of 4 years, with repeated cerebrospinal fluid collection and imaging studies performed every other year, and brain donation is encouraged. RESULTS: The integration of clinical, neuropsychological, genetic, biochemical, imaging, and neuropathological information and the harmonization of protocols under the same umbrella allows the discovery and validation of key biomarkers across several neurodegenerative diseases. DISCUSSION: We describe our particular 10-year experience and how different research projects were unified under an umbrella biomarker program, which might be of help to other research teams pursuing similar approaches.

Different pattern of CSF glial markers between dementia with Lewy bodies and Alzheimer's disease.

The role of innate immunity in dementia with Lewy bodies (DLB) has been little studied. We investigated the levels in cerebrospinal fluid (CSF) of glial proteins YKL-40, soluble TREM2 (sTREM2) and progranulin in DLB and their relationship with Alzheimer's disease (AD) biomarkers. We included patients with DLB (n = 37), prodromal DLB (prodDLB, n = 23), AD dementia (n = 50), prodromal AD (prodAD, n = 53), and cognitively normal subjects (CN, n = 44). We measured levels of YKL-40, sTREM2, progranulin, Aß1-42, total tau (t-tau) and phosphorylated tau (p-tau) in CSF. We stratified the group DLB according to the ratio t-tau/Aß1-42 (≥0.52, indicative of AD pathology) and the A/T classification. YKL-40, sTREM2 and progranulin levels did not differ between DLB groups and CN. YKL-40 levels were higher in AD and prodAD compared to CN and to DLB and prodDLB. Patients with DLB with a CSF profile suggestive of AD copathology had higher levels of YKL-40, but not sTREM2 or PGRN, than those without. T+ DLB patients had also higher YKL-40 levels than T-. Of these glial markers, only YKL-40 correlated with t-tau and p-tau in DLB and in prodDLB. In contrast, in prodAD, sTREM2 and PGRN also correlated with t-tau and p-tau. In conclusion, sTREM2 and PGRN are not increased in the CSF of DLB patients. YKL-40 is only increased in DLB patients with an AD biomarker profile, suggesting that the increase is driven by AD-related neurodegeneration. These data suggest a differential glial activation between DLB and AD.

Clinical Subtypes of Dementia with Lewy Bodies Based on the Initial Clinical Presentation.

BACKGROUND: Dementia with Lewy bodies (DLB) is a heterogeneous disease in which clinical presentation, symptoms, and evolution widely varies between patients. OBJECTIVE: To investigate the existence of clinical subtypes in DLB based on the initial clinical presentation. METHODS: 81 patients with a clinical diagnosis of probable DLB were consecutively included. All patients underwent a neurological evaluation including a structured questionnaire about neuropsychiatric symptoms and sleep, an assessment of motor impairment (Unified Parkinson Disease Rating Scale subscale III), and a formal neuropsychological evaluation. Onset of core symptoms (hallucinations, parkinsonism, and fluctuations) and dementia were systematically reviewed from medical records. We applied a K-means clustering method based on the initial clinical presentation. RESULTS: Cluster analysis yielded three different groups. Patients in cluster I (cognitive-predominant, n = 46) presented more frequently with cognitive symptoms (95.7%, n = 44, p < 0.001), and showed a longer duration from onset to DLB diagnosis (p < 0.001) than the other clusters. Patients in cluster II (neuropsychiatric-predominant, n = 22) were older at disease onset (78.1±5 versus 73.6±6.1 and 73.6±4.2 in clusters I and III, respectively, both p < 0.01), presented more frequently with psychotic symptoms (77.3%, n = 17), and had a shorter duration until the onset of hallucinations (p < 0.001). Patients in cluster III (parkinsonism-predominant, n = 13) showed a shorter time from onset to presence of parkinsonism (p < 0.001) and dementia (0.008). CONCLUSIONS: Three clinical subtypes of DLB can be defined when considering the differential initial presentations. The proposed subtypes have distinct clinical profiles and progression patterns.

Cortical microstructural changes along the Alzheimer's disease continuum.

INTRODUCTION: Cortical mean diffusivity (MD) and free water fraction (FW) changes are proposed biomarkers for Alzheimer's disease (AD). METHODS: We included healthy control subjects (N = 254), mild cognitive impairment (N = 41), and AD dementia (N = 31) patients. Participants underwent a lumbar puncture and a 3 T magnetic resonance imaging. Healthy control subjects were classified following National Institute on Aging-Alzheimer's Association stages (stage 0, N = 220; stage 1, N = 25; and stage 2/3, N = 9). We assessed the cortical MD, cortical FW, and cortical thickness (CTh) changes along the AD continuum. RESULTS: Microstructural and macrostructural changes show a biphasic trajectory. Stage 1 subjects showed increased CTh and decreased MD and FW with respect the stage 0 subjects. Stage 2/3 subjects showed decreased CTh and increased cortical MD and FW, changes that were more widespread in symptomatic stages. DISCUSSION: These results support a biphasic model of changes in AD, which could affect the selection of patients for clinical trials and the use of magnetic resonance imaging as a surrogate marker of disease modification.

Cerebral amyloid angiopathy in Down syndrome and sporadic and autosomal-dominant Alzheimer's disease.

INTRODUCTION: We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer's disease (AD) (early-onset AD [EOAD]). METHODS: Neuroimaging features of CAA, apolipoprotein (APOE), and cerebrospinal fluid amyloid ß (Aß) 40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68). RESULTS: CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE ε4 genotype was borderline significantly associated with CAA in sporadic EOAD (P = .06) but not with DS or ADAD. There were no differences in Aß040 levels between groups or between subjects with and without CAA. DISCUSSION: CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid Aß40 levels are not a useful biomarker for CAA in AD.

Diagnostic and Prognostic Value of the Combination of Two Measures of Verbal Memory in Mild Cognitive Impairment due to Alzheimer's Disease.

BACKGROUND: Episodic memory impairment is the core feature of typical Alzheimer's disease. OBJECTIVE: To evaluate the performance of two commonly used verbal memory tests to detect mild cognitive impairment due to Alzheimer's disease (MCI-AD) and to predict progression to Alzheimer's disease dementia (AD-d). METHODS: Prospective study of MCI patients in a tertiary memory disorder unit. Patients underwent an extensive neuropsychological battery including two tests of declarative verbal memory: The Free and Cued Selective Reminding Test (FCSRT) and the word list learning task from the Consortium to Establish a Registry for Alzheimer's disease (CERAD-WL). Cerebrospinal fluid (CSF) was obtained from all patients and MCI-AD was defined by means of the t-Tau/Aß1-42 ratio. Logistic regression analyses tested whether the combination of FCSRT and CERAD-WL measures significantly improved the prediction of MCI-AD. Progression to AD-d was analyzed in a Cox regression model. RESULTS: A total of 202 MCI patients with a mean follow-up of 34.2±24.2 months were included and 98 (48.5%) met the criteria for MCI-AD. The combination of FCSRT and CERAD-WL measures improved MCI-AD classification accuracy based on CSF biomarkers. Both tests yielded similar global predictive values (59.9-65.3% and 59.4-62.8% for FCSRT and CERAD-WL, respectively). MCI-AD patients with deficits in both FCSRT and CERAD-WL had a faster progression to AD-d than patients with deficits in only one test. CONCLUSIONS: The combination of FCSRT and CERAD-WL improves the classification of MCI-AD and defines different prognostic profiles. These findings have important implications for clinical practice and the design of clinical trials.

Progranulin Protein Levels in Cerebrospinal Fluid in Primary Neurodegenerative Dementias.

BACKGROUND: Progranulin is implicated in frontotemporal dementia (FTD), but its role in other neurodegenerative disorders is unknown. OBJECTIVE: To investigate the levels of progranulin (PGRN) in cerebrospinal fluid (CSF) in different neurodegenerative dementias and their correlation with levels in plasma in cognitively normal subjects. METHODS: We measured PGRN in CSF in 229 patients with amnestic mild cognitive impairment, Alzheimer's disease dementia, sporadic FTD, dementia with Lewy bodies, corticobasal syndrome, or progressive supranuclear palsy. We also measured PGRN in CSF and plasma in 74 cognitively normal individuals. We examined the correlation between PGRN levels in CSF and diagnosis, cortical thickness, genetic factors and other CSF biomarkers. We also investigated the correlation between plasma and CSF levels of PGRN in cognitively normal individuals. RESULTS: CSF levels did not differ across diagnoses or correlate with cortical thickness. Polymorphism rs5848 in GRN influenced CSF PGRN levels, but APOEɛ4 allele did not. Amyloid-ß42, t-tau, p-tau, and YKL-40 levels correlated weakly with PGRN in CSF. We found a weak correlation (r = 0.362) between plasma and CSF PGRN levels in cognitively normal individuals. CONCLUSIONS: Our findings do not support a diagnostic value of CSF PGRN in neurodegenerative diseases. Our data confirm that levels of PGRN in plasma do not reflect accurately levels in CSF in cognitively normal controls. These data should be considered in clinical trials aiming to increase PGRN.

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.

Severity stages in essential tremor: a long-term retrospective study using the glass scale.

BACKGROUND: Few prospective studies have attempted to estimate the rate of decline of essential tremor (ET) and these were over a relatively short time period (less than 10 years). We performed a long-term study of severity stages in ET using the Glass Scale scoring system. METHODS: Fifty consecutive patients with severe ET were included. We retrospectively obtained Glass Scale scores throughout the patient's life. Common milestone events were used to help recall changes in tremor severity. RESULTS: According to the Glass Scale, the age distributions were as follows: score I, 40±17 years, score II, 55±12 years, score III, 64±9 years, and score IV, 69±7 years. A significant negative correlation between age at first symptom and rate of progression was found (r = -0.669, p<0.001). The rate of progression was significantly different (p<0.001) when the first symptom appeared at a younger age (under 40 years of age) compared with older age (40 years or older). DISCUSSION: Our results support the progressive nature of ET. Age at onset was a prognostic factor. The Glass Scale may be a useful tool to determine severity stages during the course of ET in a manner similar to the Hoehn and Yahr Scale for Parkinson's disease.

Measuring functional impact of cognitive impairment: validation of the Parkinson's disease cognitive functional rating scale.

BACKGROUND: Little is known on the impact of cognitive impairment on instrumental activities of daily living (IADL) in pre-dementia stages of Parkinson's disease (PD). OBJECTIVE: To investigate the clinimetric properties, applicability and responsiveness of a brief questionnaire (twelve-item; maximum score = 24) for rating functional abnormalities associated to cognitive impairment in non-demented PD patients (ND-PD). METHODS: Two studies were carried-out: (1) a clinimetric study validated the Parkinson's Disease-Cognitive Functional Rating Scale (PD-CFRS) against the Older Americans Resource Survey (OARS-IADL) in 53 ND-PD patients and 53 matched controls; (2) A prospective multicenter 6-month responsiveness study involving 120 ND-PD patients explored sensitivity to change. RESULTS: In the clinimetric study the PD-CFRS showed intermediate concurrent validity (ICC = 0.50), high test-retest (ICC = 0.82), inter-rater reliability (ICC = 0.80) and internal consistency (Cronbach's α = 0.79), and higher coefficient of variation to detect dysfunction in ND-PD patients (PD-CFRS 86.6% vs. OARS-IADL 8.1%). There was a strong relationship between the PD-CFRS and the global cognitive status determined with the PD-Cognitive Rating Scale (r = -0.72, p < 0.0001). The responsiveness study recruited 63 patients with normal cognition and 57 with mild cognitive impairment (MCI); an increase of 2 points in the PD-CFRS after 6 months was associated with a clinically significant worsening of the cognitive functional status. According to a discriminant analysis a PD-CFRS cut-off score of ≥3 was found to be optimal for detecting functional impairment in PD-MCI patients. CONCLUSIONS: Cognitive impairment exerts measurable impact on IADL in ND-PD patients that can be reliable measured with the PD-CFRS, a PD-validated instrument that can be useful in clinical and research settings.

Temblor esencial y enfermedad de Parkinson: ¿existe una asociación? / No disponible

No disponible

[Descriptive analysis of the activity in a movement disorder unit in a tertiary hospital in Catalonia]. / Análisis descriptivo de la actividad de una unidad de trastornos del movimiento en un hospital terciario de Cataluña.

INTRODUCTION: Movement disorders are an important part of the activity of a Neurology service, but there are few studies examining their health care demand. AIMS: To analyze the first visits of the Movement Disorders Unit of the Hospital de la Santa Creu i Sant Pau in Barcelona and to compare the results with those of previous studies. PATIENTS AND METHODS: Prospective study of the first neurological assessments carried out during 2010. Demographic variables of patients were collected and diagnoses were reviewed 12 months later. RESULTS: 423 first visits were done (application rate of 1.41 per 1000 inhabitants-year): 54% females, median age 68.8 ± 14.2 years-old. 74.3% of referrals came from the family doctor. The most frequent reasons for consultation were tremor (40%) and parkinsonism-motor clumsiness (26%). The most prevalent diagnoses were Parkinson's disease (36%) and essential tremor (19%). After the first assessment, 84% of patients continued controls in the Unit. One year later, in the 8% of cases there was a change in the initial diagnosis. Taking into account the incidence of each disorder, the number of patients seen was fewer compared to the estimated (19.5 times lower), especially marked in cases of restless legs syndrome, essential tremor and Tourette syndrome. CONCLUSIONS: In our Unit the most frequent reason for consultation is tremor and the most prevalent diagnosis is Parkinson's disease. The number of patients treated is clearly lower than the estimated according to the incidence of the diseases in the population.

Análisis descriptivo de la actividad de una unidad de trastornos del movimiento en un hospital terciario de Cataluña / Descriptive analysis of the activity in a movement disorder unit in a tertiary hospital in Catalonia

Introducción. Los trastornos del movimiento constituyen una parte importante de la actividad de un servicio de neurología, pero hay pocos estudios que examinen su demanda asistencial. Objetivos. Analizar las primeras visitas de la Unidad de Trastornos del Movimiento del Hospital de la Santa Creu i Sant Pau de Barcelona y comparar los resultados con los de estudios previos. Pacientes y métodos. Estudio prospectivo de las primeras valoraciones realizadas durante el año 2010. Se recogieron las variables demográficas y se hizo una revisión diagnóstica a los 12 meses. Resultados. Se realizaron 423 primeras visitas (índice de solicitudes 1,41/1.000 habitantes-año): el 54,4% eran mujeres y la edad media era de 68,8 ± 14,2 años. El 74,3% de las derivaciones procedía del médico de familia. Los motivos deconsulta más frecuentes fueron temblor (40%) y parkinsonismo-torpeza motora (26%). Los diagnósticos más prevalentesfueron enfermedad de Parkinson (36%) y temblor esencial (19%). Tras la primera valoración, el 84% de los pacientes siguió controles en la unidad. Al año, en el 8% de los casos hubo un cambio en la orientación diagnóstica. El número de pacientes atendidos fue menor al estimado según la incidencia de las patologías en nuestra población (19,5 veces inferior),especialmente en los casos de síndrome de piernas inquietas, temblor esencial y síndrome de Tourette. Conclusiones. En nuestra unidad, el motivo de consulta más frecuente es el temblor, y el diagnóstico más prevalente, laenfermedad de Parkinson. El número de pacientes atendidos es claramente inferior al estimado según la incidencia de laspatologías en la población (AU)

Introduction. Movement disorders are an important part of the activity of a Neurology service, but there are few studies examining their health care demand. Aims. To analyze the first visits of the Movement Disorders Unit of the Hospital de la Santa Creu i Sant Pau in Barcelona and to compare the results with those of previous studies. Patients and methods. Prospective study of the first neurological assessments carried out during 2010. Demographicvariables of patients were collected and diagnoses were reviewed 12 months later. Results. 423 first visits were done (application rate of 1.41 per 1000 inhabitants-year): 54% females, median age 68.8 ±14.2 years-old. 74.3% of referrals came from the family doctor. The most frequent reasons for consultation were tremor (40%) and parkinsonism-motor clumsiness (26%). The most prevalent diagnoses were Parkinson’s disease (36%) and essential tremor (19%). After the first assessment, 84% of patients continued controls in the Unit. One year later, in the8% of cases there was a change in the initial diagnosis. Taking into account the incidence of each disorder, the number of patients seen was fewer compared to the estimated (19,5 times lower), especially marked in cases of restless legs syndrome, essential tremor and Tourette syndrome. Conclusions. In our Unit the most frequent reason for consultation is tremor and the most prevalent diagnosis is Parkinson’s disease. The number of patients treated is clearly lower than the estimated according to the incidence of the diseases in the population (AU)