Publications by authors named "Beatriz De la Casa-Fages"

12 Publications

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Neurological complications of COVID-19 in hospitalized patients: The registry of a neurology department in the first wave of the pandemic.

Eur J Neurol 2021 Jan 21. Epub 2021 Jan 21.

Department of Neurology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Objective: To describe the spectrum of neurological complications observed in a hospital-based cohort of COVID-19 patients who required a neurological assessment.

Methods: We conducted an observational, monocentric, prospective study of patients with a COVID-19 diagnosis hospitalized during the 3-month period of the first wave of the COVID-19 pandemic in a tertiary hospital in Madrid (Spain). We describe the neurological diagnoses that arose after the onset of COVID-19 symptoms. These diagnoses could be divided into different groups.

Results: Only 71 (2.6%) of 2750 hospitalized patients suffered at least one neurological complication (77 different neurological diagnoses in total) during the timeframe of the study. The most common diagnoses were neuromuscular disorders (33.7%), cerebrovascular diseases (CVDs) (27.3%), acute encephalopathy (19.4%), seizures (7.8%), and miscellanea (11.6%) comprising hiccups, myoclonic tremor, Horner syndrome and transverse myelitis. CVDs and encephalopathy were common in the early phase of the COVID-19 pandemic compared to neuromuscular disorders, which usually appeared later on (p = 0.005). Cerebrospinal fluid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction was negative in 15/15 samples. The mortality was higher in the CVD group (38.1% vs. 8.9%; p = 0.05).

Conclusions: The prevalence of neurological complications is low in patients hospitalized for COVID-19. Different mechanisms appear to be involved in these complications, and there was no evidence of direct invasion of the nervous system in our cohort. Some of the neurological complications can be classified into early and late neurological complications of COVID-19, as they occurred at different times following the onset of COVID-19 symptoms.
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http://dx.doi.org/10.1111/ene.14748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013314PMC
January 2021

Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia.

Neurobiol Aging 2021 Mar 2;99:99.e15-99.e22. Epub 2020 Sep 2.

Instituto de Investigación Sanitaria del Principado de Asturias - ISPA, Oviedo, Spain; Servicio de Neurología, Hospital Universitario Central de Asturias, Oviedo, Spain.

Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.08.018DOI Listing
March 2021

Serotonin syndrome in two COVID-19 patients treated with lopinavir/ritonavir.

J Neurol Sci 2020 08 27;415:116944. Epub 2020 May 27.

Movement Disorders Unit, Neurology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

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http://dx.doi.org/10.1016/j.jns.2020.116944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255189PMC
August 2020

Role for ATXN1, ATXN2, and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease.

Neurobiol Aging 2020 03 1;87:139.e1-139.e7. Epub 2019 Nov 1.

Instituto de Investigación Sanitaria del Principado de Asturias -ISPA, Oviedo, Spain; Servicio de Neurología, Hospital Universitario Central de Asturias, Oviedo, Spain.

We analyzed the frequency of intermediate alleles (IAs) in the ATXN1, ATXN2, and HTT genes in several neurodegenerative diseases. The study included 1126 patients with Alzheimer's disease (AD), 440 patients with frontotemporal dementia (FTD), and 610 patients with Parkinson's disease. In all cohorts, we genotyped ATXN1 and ATXN2 CAG repeats. In addition, in the FTD cohort, we determined the number of HTT CAG repeats. The frequency of HTT IAs was higher in patients with FTD (6.9%) versus controls (2.9%) and in the C9orf72 expansion noncarriers (7.2%) versus controls (2.9%), although the difference was nonsignificant after correction for multiple testing. Compared with controls, progressive nonfluent aphasia (PNFA) groups showed a significantly higher frequency of HTT IAs (13.6% vs. 2.9% controls). For the ATXN2 gene, we observed an increase in IA frequency in AD cases (AD 4.1% vs. controls 1.8%) and in the behavioral FTD group (4.8% vs. 1.8%). For the ATXN1 gene, we found a significant increase of IAs in patients with PNFA (18.6%) versus controls (6.7%). In conclusion, our work suggests that the HTT and ATXN1 IAS may contribute to PNFA pathogenesis and point to a link between ATXN2 IAS and AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.10.017DOI Listing
March 2020

Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism.

Mov Disord 2019 10 21;34(10):1547-1561. Epub 2019 Aug 21.

Department of Neurology, Hospital Universitario Donostia, San Sebastian, Spain.

Background: Pathogenic variants in the spastic paraplegia type 7 gene cause a complicated hereditary spastic paraplegia phenotype associated with classical features of mitochondrial diseases, including ataxia, progressive external ophthalmoplegia, and deletions of mitochondrial DNA.

Objectives: To better characterize spastic paraplegia type 7 disease with a clinical, genetic, and functional analysis of a Spanish cohort of spastic paraplegia type 7 patients.

Methods: Genetic analysis was performed in patients suspecting hereditary spastic paraplegia and in 1 patient with parkinsonism and Pisa syndrome, through next-generation sequencing, whole-exome sequencing, targeted Sanger sequencing, and multiplex ligation-dependent probe analysis, and blood mitochondrial DNA levels determined by quantitative polymerase chain reaction.

Results: Thirty-five patients were found to carry homozygous or compound heterozygous pathogenic variants in the spastic paraplegia type 7 gene. Mean age at onset was 40 years (range, 12-63); 63% of spastic paraplegia type 7 patients were male, and three-quarters of all patients had at least one allele with the c.1529C>T (p.Ala510Val) mutation. Eighty percent of the cohort showed a complicated phenotype, combining ataxia and progressive external ophthalmoplegia (65% and 26%, respectively). Parkinsonism was observed in 21% of cases. Analysis of blood mitochondrial DNA indicated that both patients and carriers of spastic paraplegia type 7 pathogenic variants had markedly lower levels of mitochondrial DNA than control subjects (228 per haploid nuclear DNA vs. 176 vs. 573, respectively; P < 0.001).

Conclusions: Parkinsonism is a frequent finding in spastic paraplegia type 7 patients. Spastic paraplegia type 7 pathogenic variants impair mitochondrial DNA homeostasis irrespective of the number of mutant alleles, type of variant, and patient or carrier status. Thus, spastic paraplegia type 7 supports mitochondrial DNA maintenance, and variants in the gene may cause parkinsonism owing to mitochondrial DNA abnormalities. Moreover, mitochondrial DNA blood analysis could be a useful biomarker to detect at risk families. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27812DOI Listing
October 2019

Effect of subthalamic nucleus deep brain stimulation on balance in Parkinson's disease: A static posturographic analysis.

Gait Posture 2017 02 29;52:374-380. Epub 2016 Dec 29.

Movement Disorders Unit, Neurology Department, Hospital General Universitario Gregorio Marañón, Calle Doctor Esquerdo n°46, 28007, Madrid, Spain. Electronic address:

Background: The effect of subthalamic deep brain stimulation on balance in Parkinson's disease remains unclear.

Objective: To evaluate the effect of subthalamic nucleus stimulation on balance in Parkinson's disease using posturography.

Methods: 16 patients (9 women) who underwent subthalamic deep brain stimulation [mean age 59.6 years (46-70); mean disease duration 15.6 years (7-25); mean duration of subthalamic stimulation 32.1 months (3.0-69.6)] and 13 healthy age-matched controls were evaluated using a static posturography analysis. Patients were assessed under four conditions: 1) off medication/off stimulation; 2) off medication/on stimulation; 3) on medication/off stimulation and 4) on medication/on stimulation in ten experimental paradigms, some reproducing common situations of daily living. The displacement of the centre of pressure was analyzed using 14 posturographic parameters. The Mann-Whitney test was used to compare patients with controls. The Wilcoxon signed rank test was used to compare patients under different clinical conditions.

Results: Patients off medication/off stimulation showed larger and more rapid displacements of the centre of pressure than controls in most paradigms (p<0.05), particularly when performing a dual task. Subthalamic stimulation alone reduced the lateral excursion and anterior-posterior velocity of the centre of pressure in quite stance paradigms (p<0.05). Subthalamic stimulation combined with antiparkinsonian medication did not induce statistically significant changes in posturagraphic measures in any experimental paradigm.

Conclusions: Although subthalamic stimulation alone may induce some positive effect on balance, subthalamic stimulation in addition to antiparkinsonian medication, which is the usual treatment in clinical practice, did not modify balance as assessed by static posturography in patients with Parkinson's disease.
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http://dx.doi.org/10.1016/j.gaitpost.2016.12.025DOI Listing
February 2017

Long-term Thalamic Deep Brain Stimulation for Essential Tremor: Clinical Outcome and Stimulation Parameters.

Mov Disord Clin Pract 2016 Nov-Dec;3(6):567-572. Epub 2016 Mar 1.

Movement Disorders Deep Brain Stimulation Group Hospital General Universitario Gregorio Marañón Madrid Spain.

Background: The reasons underlying the loss of efficacy of deep brain stimulation (DBS) of the thalamic nucleus ventralis intermedius (VIM-DBS) over time in patients with essential tremor are not well understood.

Methods: Long-term clinical outcome and stimulation parameters were evaluated in 14 patients with essential tremor who underwent VIM-DBS. The mean ± standard deviation postoperative follow-up was 7.7 ± 3.8 years. At each visit (every 3-6 months), tremor was assessed using the Fahn-Tolosa-Marin tremor rating scale (FTM-TRS) and stimulation parameters were recorded (contacts, voltage, frequency, pulse width, and total electrical energy delivered by the internal generator [TEED ]).

Results: The mean reduction in FTM-TRS score was 73.4% at 6 months after VIM-DBS surgery ( < 0.001) and 50.1% at the last visit ( < 0.001). The gradual worsening of FTM-TRS scores over time fit a linear regression model (coefficient of determination [R] = 0.887; < 0.001). Stimulation adjustments to optimize tremor control required a statistically significant increase in voltage ( = 0.01), pulse width ( = 0.01), frequency ( = 0.02), and TEED ( = 0.008). TEED fit a third-order polynomial curve model throughout the follow-up period (R = 0.966; < 0.001). The initial exponential increase (first 4 years of VIM-DBS) was followed by a plateau and a further increase from the seventh year onward.

Conclusions: The current findings suggest that the waning effect of VIM-DBS over time in patients with essential tremor may be the consequence of a combination of factors. Superimposed on the progression of the disease, tolerance can occur during the early years of stimulation.
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http://dx.doi.org/10.1002/mdc3.12337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178759PMC
March 2016

Paroxysmal Kinesigenic Dystonia in a Lesch-Nyhan Disease Variant.

Mov Disord Clin Pract 2014 Jun 23;1(2):123-124. Epub 2014 May 23.

Movement Disorders Unit Hospital General Universitario Gregorio Marañón Madrid Spain.

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http://dx.doi.org/10.1002/mdc3.12034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6183184PMC
June 2014

Dopamine dysregulation syndrome and deep brain stimulation of the subthalamic nucleus in Parkinson's disease.

Neurol Res Int 2011 2;2011:759895. Epub 2011 Nov 2.

Movement Disorders Research Unit, Hospital Universitario Gregorio Marañón, 28007 Madrid, Spain.

Dopamine dysregulation syndrome is a complication of the dopaminergic treatment in Parkinson's disease that may be very disabling due to the negative impact that compulsive medication use may have on patients' social, psychological, and physical functioning. The relationship between subthalamic nucleus deep brain stimulation and dopamine dysregulation syndrome in patients with Parkinson's disease remains unclear. Deep brain stimulation may improve, worsen, or have no effect on preoperative dopamine dysregulation syndrome. Moreover, dopamine dysregulation syndrome may appear for the first time after deep brain stimulation of the subthalamic nucleus. The outcome of postoperative dopamine dysregulation syndrome is poor despite stimulation and medication adjustments. Here we review the phenomenology and neurobiology of this disorder, discuss possible mechanisms that may underlie the diverse outcomes of dopamine dysregulation syndrome after subthalamic nucleus deep brain stimulation, and propose management strategies.
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http://dx.doi.org/10.1155/2011/759895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3216377PMC
August 2012

Dopamine dysregulation syndrome after deep brain stimulation of the subthalamic nucleus in Parkinson's disease.

J Neurol Sci 2012 Jan 27;312(1-2):191-3. Epub 2011 Aug 27.

Movement Disorders Research Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Dopamine dysregulation syndrome is a complication of the dopaminergic treatment for Parkinson's disease, probably related to sensitization of the mesolimbic dopamine system. The relationship between dopamine dysregulation syndrome and deep brain stimulation of the subthalamic nucleus remains unclear. We report three patients with Parkinson's disease who developed de novo dopamine dysregulation syndrome after deep brain stimulation of the subthalamic nucleus. We hypothesized that the combined effect of dopaminergic replacement therapy and deep brain stimulation on the limbic territory of the subthalamic nucleus could have precipitated the dopamine dysregulation syndrome in these patients, by inducing hyperstimulation of the mesolimbic dopamine system. The outcome of postoperative dopamine dysregulation syndrome is poor despite deep brain stimulation adjustments, attempts to reduce the dose of dopaminergic drugs and the addition of quetiapine or antidepressants.
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http://dx.doi.org/10.1016/j.jns.2011.08.014DOI Listing
January 2012