Publications by authors named "José Berciano"

202 Publications

Re-evaluating the accuracy of optimized electrodiagnostic criteria in very early Guillain-Barré syndrome: a sequential study.

Acta Neurol Belg 2021 Feb 18. Epub 2021 Feb 18.

Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.

Using recent optimized electrodiagnostic criteria sets, we aimed at verifying the accuracy of initial nerve conduction studies (NCS) in classic very early Guillain-Barré syndrome (VEGBS), ≤ 4 days after onset, compared with the results of serial NCS. This is a retrospective study based on unreported and consecutive VEGBS patients admitted to two university hospitals between 2015 and 2019. Each patient had serial NCS in at least four nerves. Initial NCS studies were done within 4 days after onset, and serial ones from days 20 to 94. Electrophysiological recordings were blinded evaluated by four of the authors, GBS subtype being established accordingly. Seven adult classic VEGBS patients were identified with a median age of 58 years. At first NCS, GBS subtyping was only possible in 1 case that exhibited an axonal pattern, the remaining patterns being equivocal in 3, and mixed (combining axonal and demyelinating criteria) in the remaining 3. Upon serial NSC there was a rather intricate evolution of electrophysiological GBS patterns, 3 of them being classified as axonal or demyelinating, and the remaining 4 as equivocal or mixed. NCS in VEGBS systematically allows detection of changes suggestive of peripheral neuropathy, though even after serial studies accurate GBS subtyping was only possible in 43% of cases. We provide new pathophysiological insights for better understanding of the observed electrophysiological changes.
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http://dx.doi.org/10.1007/s13760-021-01603-7DOI Listing
February 2021

LRSAM1 and the RING domain: Charcot-Marie-Tooth disease and beyond.

Orphanet J Rare Dis 2021 Feb 10;16(1):74. Epub 2021 Feb 10.

Molecular Neurogenomics Group, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.

In the past decade, mutations in LRSAM1 were identified as the genetic cause of both dominant and recessive forms of axonal CMT type 2P (CMT2P). Despite demonstrating different inheritance patterns, dominant CMT2P is usually characterized by relatively mild, slowly progressive axonal neuropathy, mainly involving lower limbs, with age of onset between the second and fifth decades of life. Asymptomatic individuals were identified in several pedigrees exemplifying the strong phenotypic variability of these patients requiring serial clinical evaluation to establish correct diagnosis; in this respect, magnetic resonance imaging of lower-limb musculature showing fatty atrophy might be helpful in detecting subclinical gene mutation carriers. LRSAM1 is a universally expressed RING-type E3 ubiquitin protein ligase catalysing the final step in the ubiquitination cascade. Strikingly, TSG101 remains the only known ubiquitination target hampering our mechanistic understanding of the role of LRSAM1 in the cell. The recessive CMT mutations lead to complete loss of LRSAM1, contrary to the heterozygous dominant variants. These tightly cluster in the C-terminal RING domain highlighting its importance in governing the CMT disease. The domain is crucial for the ubiquitination function of LRSAM1 and CMT mutations disrupt its function, however it remains unknown how this leads to the peripheral neuropathy. Additionally, recent studies have linked LRSAM1 with other neurodegenerative diseases of peripheral and central nervous systems. In this review we share our experience with the challenging clinical diagnosis of CMT2P and summarize the mechanistic insights about the LRSAM1 dysfunction that might be helpful for the neurodegenerative field at large.
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http://dx.doi.org/10.1186/s13023-020-01654-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874611PMC
February 2021

Hans Joachim Scherer (1906-1945).

Authors:
José Berciano

J Neurol 2020 Nov 11. Epub 2020 Nov 11.

Professor Emeritus of Neurology, Service of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", University of Cantabria and "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)", Santander, Spain.

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http://dx.doi.org/10.1007/s00415-020-10301-yDOI Listing
November 2020

Serum neurofilament light chain predicts long-term prognosis in Guillain-Barré syndrome patients.

J Neurol Neurosurg Psychiatry 2020 Nov 5. Epub 2020 Nov 5.

Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

Objective: To study baseline serum neurofilament light chain (sNfL) levels as a prognostic biomarker in Guillain-Barré syndrome (GBS).

Methods: We measured NfL in serum (98 samples) and cerebrospinal fluid (CSF) (24 samples) of patients with GBS prospectively included in the International GBS Outcome Study (IGOS) in Spain using single-molecule array (SiMoA) and compared them with 53 healthy controls (HCs). We performed multivariable regression to analyse the association between sNfL levels and functional outcome at 1 year.

Results: Patients with GBS had higher NfL levels than HC in serum (55.49 pg/mL vs 9.83 pg/mL, p<0.0001) and CSF (1308.5 pg/mL vs 440.24 pg/mL, p=0.034). Patients with preceding diarrhoea had higher sNfL than patients with respiratory symptoms or no preceding infection (134.90 pg/mL vs 47.86 pg/mL vs 38.02 pg/mL, p=0.016). sNfL levels correlated with Guillain-Barré Syndrome Disability Score and Inflammatory Rasch-built Overall Disability Scale (I-RODS) at every timepoint. Patients with pure motor variant and Miller Fisher syndrome showed higher sNfL levels than patients with sensorimotor GBS (162.18 pg/mL vs 95.50 pg/mL vs 38.02 pg/mL, p=0.025). Patients with acute motor axonal neuropathy cute motor axonal neuropathy had higher sNfL levels than other variants (190.55 pg/mL vs 46.79 pg/mL, p=0.013). sNfL returned to normal levels at 1 year. High baseline sNfL levels were associated with inability to run (OR=1.65, 95% CI 1.14 to 2.40, p=0.009) and lower I-RODS (β -2.60, 95% CI -4.66 to -0.54, p=0.014) at 1 year. Cut-off points predicting clinically relevant outcomes at 1 year with high specificity were calculated: inability to walk independently (>319 pg/mL), inability to run (>248 pg/mL) and ability to run (<34 pg/mL).

Conclusion: Baseline sNfL levels are increased in patients with GBS, are associated with disease severity and axonal variants and have an independent prognostic value in patients with GBS.
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http://dx.doi.org/10.1136/jnnp-2020-323899DOI Listing
November 2020

Spinal nerve pathology in Guillain-Barré syndrome associated with COVID-19 infection.

Muscle Nerve 2020 11 11;62(5):E74-E75. Epub 2020 Aug 11.

Service of Radiology, University Hospital "Marqués de Valdecilla (IDIVAL)", University of Cantabria, "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas", Santander, Spain.

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http://dx.doi.org/10.1002/mus.27031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405080PMC
November 2020

Ultrasonography of cervical nerve roots: cross-sectional reference values according to age.

Neurol Sci 2021 Jan 2;42(1):215-223. Epub 2020 Jul 2.

Service of Radiology, University Hospital "Marqués de Valdecilla (IDIVAL)", University of Cantabria and "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)", Santander, Spain.

Introduction: The aim of this study is to describe the normal cross-sectional area (CSA) and appearance of cervical nerve roots in ultrasound, correlating it to age and other patient somatic parameters.

Methods: One hundred healthy volunteers were included. We aimed to achieve uniform representation throughout all age groups. Ultrasound of the cervical nerve roots was performed bilaterally. CSA and margins description were obtained.

Results: C5 nerve, 8.32 ± 2.30; C6 nerve, 11.88 ± 3.36; C7 nerve, 12.79 ± 3.85; C8 nerve, 11.20 ± 3.45. Significant correlation between CSA and age was demonstrated, but not for body mass index. Blurred margins were present in up to 23.71% cervical nerves, more frequently in older individuals and in C7 nerve.

Discussion: If ultrasound morphology of cervical nerve roots is used as a diagnostic parameter, the normal range of CSA values and percentage of blurred margins according to age should be considered.
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http://dx.doi.org/10.1007/s10072-020-04551-xDOI Listing
January 2021

Axonal degeneration in Guillain-Barré syndrome: a reappraisal.

Authors:
José Berciano

J Neurol 2020 Jun 30. Epub 2020 Jun 30.

Professor Emeritus of Neurology, Service of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)", University of Cantabria, Santander, Spain.

The aim of this review was to analyse the pathophysiology of axonal degeneration in Guillain-Barré syndrome (GBS) with emphasis on early stages (≤ 10 days after onset). An overview of experimental autoimmune neuritis (EAN) models is provided. Originally GBS and acute inflammatory demyelinating polyneuropathy were equated, presence of axonal degeneration being attributed to a "bystander" effect. Afterwards, primary axonal GBS forms were reported, designated as acute motor axonal neuropathy/acute motor-sensory axonal neuropathy. Revision of the first pathological description of axonal GBS indicates the coexistence of active axonal degeneration and demyelination in spinal roots, and pure Wallerian-like degeneration in peripheral nerve trunks. Nerve conduction studies are essential for syndrome subtyping, though their sensitivity is scanty in early GBS. Serum markers of axonal degeneration include increased levels of neurofilament light chain and presence of anti-ganglioside reactivity. According to nerve ultrasonographic features and autopsy studies, ventral rami of spinal nerves are a hotspot in early GBS. In P-induced EAN models, the initial pathogenic change is inflammatory oedema of spinal roots and sciatic nerve, which is followed by demyelination, and Wallerian-like degeneration in nerve trunks possessing epi-perineurium; a critical elevation of endoneurial fluid pressure is a pre-requisite for inducing ischemic axonal degeneration. Similar lesion topography may occur in GBS. The repairing role of adaxonal Schwann cytoplasm in axonal degeneration is analysed. A novel pathophysiological mechanism for nerve trunk pain in GBS, including pure motor forms, is provided. The potential therapeutic role of intravenous boluses of methylprednisolone for early severe GBS and intractable pain is argued.
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http://dx.doi.org/10.1007/s00415-020-10034-yDOI Listing
June 2020

Inflammatory oedema of nerve trunks may be pathogenic in very early Guillain-Barré syndrome.

Authors:
José Berciano

Acta Neurol Belg 2020 Oct 18;120(5):1061-1065. Epub 2020 Jun 18.

Service of Neurology, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), University Hospital "Marqués de Valdecilla (IDIVAL)", University of Cantabria, Santander, Spain.

The aim of this paper is to analyse the pathological background of very early Guillain-Barré (VEGBS) (≤ 4 days after onset) comparing it with initial stages of experimental autoimmune neuritis (EAN). The pathological hallmark of VEGBS is inflammatory oedema predominating in proximal nerve trunks. In EAN inflammatory oedema precedes the development of demyelination or axonal degeneration; such oedema may increase endoneurial fluid pressure (EFP) stretching the perineurium and constricting the transperineurial microcirculation. Centrofascicular or wedge-shaped areas of nerve ischemia have been reported in GBS and EAN. Additional support for proximal VEGBS pathology comes from electrophysiology showing alterations in late responses as the most frequent features, and ultrasonography illustrating that main changes rely on ventral rami of spinal nerves. Selective inefficiency of the blood-nerve barrier would explain the topography of changes in VEGBS. Increased serum neurofilament light chain concentration has recently been reported in VEGBS, with no difference between demyelinating and axonal subtypes. This is a marker of axonal damage, which could be correlated with endoneurial ischemia caused by increased EFP. Inflammatory oedema of proximal nerve trunks may be pathogenic in VEGBS, and consequently there is a pressing need for therapeutic strategies to stop its rapid impact on the axons.
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http://dx.doi.org/10.1007/s13760-020-01413-3DOI Listing
October 2020

Contributions to the study of spinocerebellar ataxia type 38 (SCA38).

J Neurol 2020 Aug 20;267(8):2288-2295. Epub 2020 Apr 20.

Department of Neurology, CIBERNED, Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander, Spain.

Objective: To report clinical and ancillary findings in a kindred with spinocerebellar ataxia 38 (SCA38).

Patients And Methods: Five family members spanning two generations developed gait ataxia and intermittent diplopia. On examination, a cerebellar syndrome accompanied by downbeat nystagmus and a saccadic head impulse test (HIT) were found.

Results: Whole-exome sequencing demonstrated a heterozygous variant in ELOVL5, c.779A > G (p.Tyr260Cys), in four tested patients. Intermittent concomitant esotropia and hypertropia caused transient diplopia in one individual each. Saccadic HIT responses were found in four subjects. Sensorineural hypoacusis was present in every case. Electrophysiological studies demonstrated a sensory neuronopathy in patients from the first generation, with prolonged disease duration. Baseline serum docosahexaenoic acid (DHA) percent was diminished in four individuals. Oral 26-week dietary DHA supplementation, 650 mg/day, raised serum DHA percent and induced a statistically significant reduction in Scale for the Assessment and Rating of Ataxia (SARA) total scores, and in stance and heel-shin slide item scores.

Conclusion: The mentioned ELOVL5 variant segregated with disease in this kindred. Downbeat nystagmus, intermittent heterotropia causing transient diplopia, vestibular impairment demonstrated by abnormal HIT, and sensory neuronopathy were part of the clinical picture in this series. DHA supplementation raised serum DHA percent in cases with diminished levels, and induced a clinical amelioration and a statistically significant reduction in SARA scores in the study group. Further studies are needed to investigate the role of these findings in SCA38, and to determine the response to prolonged DHA supplementation.
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http://dx.doi.org/10.1007/s00415-020-09840-1DOI Listing
August 2020

Clinical manifestations of episodic ataxia type 5.

Neurol Clin Pract 2019 Dec;9(6):503-504

Department of Neurology (MGS, JG), Hospital Universitario Miguel Servet; Department of Clinical Biochemistry (SI), Hospital Universitario Miguel Servet, Section of Genetics, Zaragoza; NIMGenetics (SA), Madrid; Department of Internal Medicine (REBA), Hospital Universitario Miguel Servet, Zaragoza; Department of Neurology (JB), Hospital Universitario Marqués de Valdecilla, Santander, Spain.

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http://dx.doi.org/10.1212/CPJ.0000000000000697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927442PMC
December 2019

Mating strategy is determinant of adenovirus prevalence in European bats.

PLoS One 2020 7;15(1):e0226203. Epub 2020 Jan 7.

Evolutionary Biology Unit, Estación Biológica Doñana (CSIC), Sevilla, Spain.

Adenoviruses are double-strained DNA viruses found in a great number of vertebrates, including humans. In order to understand their transmission dynamics, it is crucial, even from a human health perspective, to investigate how host traits influence their prevalence. Bats are important reservoirs for adenoviruses, and here we use the results of recent screenings in Western Europe to evaluate the association between characteristic traits of bat species and their probability of hosting adenoviruses, taking into account their phylogenetic relationships. Across species, we found an important phylogenetic component in the presence of adenoviruses and mating strategy as the most determinant factor conditioning the prevalence of adenoviruses across bat species. Contrary to other more stable mating strategies (e.g. harems), swarming could hinder transmission of adenoviruses since this strategy implies that contacts between individuals are too short. Alternatively, bat species with more promiscuous behavior may develop a stronger immune system. Outstandingly high prevalence of adenoviruses was reported for the Iberian species Pipistrellus pygmaeus, P. kuhlii and Nyctalus lasiopterus and we found that in the latter, males were more likely to be infected by adenoviruses than females, due to the immunosuppressing consequence of testosterone during the mating season. As a general trend across species, we found that the number of adenoviruses positive individuals was different across localities and that the difference in prevalence between populations was correlated with their geographic distances for two of the three studied bat species (P. pygmaeus and P.kuhlii). These results increase our knowledge about the transmission mechanisms of adenoviruses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226203PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946596PMC
April 2020

Very early Guillain-Barré syndrome: A clinical-electrophysiological and ultrasonographic study.

Clin Neurophysiol Pract 2020 30;5:1-9. Epub 2019 Nov 30.

Service of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", University of Cantabria, "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)", Santander, Spain.

Objectives: Using recent optimized electrodiagnostic criteria sets, we primarily aimed at verifying the accuracy of the initial electrophysiological test in very early Guillain-Barré syndrome (VEGBS), ≤4 days of onset, compared with the results of serial electrophysiology. Our secondary objective was to correlate early electrophysiological results with sonographic nerve changes.

Methods: This is a retrospective study based on consecutive VEGBS patients admitted to the hospital. Each patient had serial nerve conduction studies (NCS) in at least 4 nerves. Initial NCS were done within 4 days after onset, and serial ones from the second week onwards. Electrophysiological recordings of each case were re-evaluated, GBS subtype being established accordingly. Nerve ultrasonography was almost always performed within 2 weeks after onset.

Results: Fifteen adult VEGBS patients were identified with a mean age of 57.8 years. At first NCS, VEGBS sub-typing was only possible in 3 (20%) cases that showed an axonal pattern, the remaining patterns being mixed (combining axonal and demyelinating features) in 6 (40%), equivocal in 5 (33.3%), and normal in 1 (6.7%). Upon serial NCS, 7 (46.7%) cases were categorized as acute demyelinating polyneuropathy, 7 (46.7%) as axonal GBS, and 1 (6.6%) as unclassified syndrome. Antiganglioside reactivity was detected in 5 out of the 7 axonal cases. Nerve US showed that lesions mainly involved the ventral rami of scanned cervical nerves.

Conclusions: Serial electrophysiological evaluation is necessary for accurate VEGBS subtype classification. Ultrasonography helps delineate the topography of nerve changes.

Significance: We provide new VEGBS pathophysiological insights into nerve conduction alterations within the first 4 days of the clinical course.
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http://dx.doi.org/10.1016/j.cnp.2019.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923288PMC
November 2019

Cognitive and Behavioral Profiles of Left and Right Semantic Dementia: Differential Diagnosis with Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease.

J Alzheimers Dis 2019 ;72(4):1129-1144

Neurology Service and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 'Marqués de Valdecilla' University Hospital, University of Cantabria, Institute for Research 'Marqués de Valdecilla' (IDIVAL), Santander, Spain.

Background: Semantic dementia (SD) is a subtype of frontotemporal dementia (FTD) characterized by semantic memory loss and preserved abilities of other cognitive functions. The clinical manifestations of SD require a differential diagnosis with Alzheimer's disease (AD), especially those with early onset, and behavioral variant FTD (bvFTD).

Objective: The present study aimed to compare cognitive performances and neuropsychiatric symptoms in a population of AD, bvFTD, and left and right SD defined with the support of molecular imaging (amyloid and 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography) and assessed the accuracy of different neuropsychological markers in distinguishing these neurodegenerative diseases.

Methods: Eighty-seven participants (32 AD, 20 bvFTD, and 35 SD (17 Left-SD and 18 Right-SD) completed a comprehensive neuropsychological battery that included memory, language, attention and executive functions, visuospatial function, visuoconstructional skills, and tasks designed specifically to evaluate prosopagnosia and facial emotions recognition. The Neuropsychiatric Inventory was administered to assess neuropsychiatric symptoms.

Results: An episodic memory test that included semantic cues, a visuospatial test (both impaired in AD), a naming test and a prosopagnosia task (both impaired in SD) were the four most valuable cognitive metrics for the differential diagnosis between groups. Several behavioral abnormalities were differentially present, of which aggression, self-care (both more frequent in bvFTD), and eating habits, specifically overeating and altered dietary preference (more frequent in SD), were the most valuable in group discrimination.

Conclusion: Our study highlights the value of a comprehensive neuropsychological and neuropsychiatric evaluation for the differential diagnosis between FTD syndromes and AD.
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http://dx.doi.org/10.3233/JAD-190877DOI Listing
December 2020

POLR3A-related spastic ataxia: new mutations and a look into the phenotype.

J Neurol 2020 Feb 21;267(2):324-330. Epub 2019 Oct 21.

Neurogenetics Laboratory, Functional and Translational Neurogenetics Unit, Department of Neuroscience, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona-Can Ruti Campus, Badalona, Barcelona, Spain.

Adolescent-onset spastic ataxia is a proposed novel phenotype in compound heterozygous carriers of an intronic mutation (c.1909 + 22G > A) in the POLR3A gene. Here, we present ten new cases of POLR3A-related spastic ataxia and discuss the genetic, clinical and imaging findings. Patients belonged to six pedigrees with hereditary spastic paraplegia or cerebellar ataxia of unknown origin. All affected subjects presented with compound heterozygous variants, comprising c.1909 + 22G > A in combination in each pedigree with one of the following novel mutations (Thr596Met, Tyr665LeufsTer11, Glu198Ter, c.646-687_1185 + 844del). The new mutations segregated with the phenotype in all families. The phenotype combined variable cerebellar ataxia, gait and lower limb spasticity, involvement of central sensory tracts and in some cases also intention tremor. The reportedly characteristic hyperintensity along the superior cerebellar peduncle on MRI was observed in ~ 80% of the cases. Our study extends the clinical and molecular phenotype further supporting the pathogenic role of the c.1909 + 22G4A intronic mutation and identifying four novel causative mutations in POLR3A-related spastic ataxia. Certain characteristic MRI features may be useful to guide genetic diagnosis.
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http://dx.doi.org/10.1007/s00415-019-09574-9DOI Listing
February 2020

A Brief Drawing Task for the Differential Diagnosis of Semantic Dementia.

J Alzheimers Dis 2019 ;72(1):151-160

Neurology Service and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 'Marqués de Valdecilla' University Hospital, University of Cantabria, Institute for Research 'Marqués de Valdecilla' (IDIVAL), Santander, Spain.

Background: Semantic dementia (SD) is a subtype of frontotemporal lobe degeneration characterized by semantic loss, with other cognitive functions initially preserved. SD requires differential diagnosis with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Semantic knowledge can be evaluated through different tests; however, most of them depend on language.

Objective: We describe the development of a brief drawing task that may be helpful for the differential diagnosis of SD.

Methods: Seventy-two patients, including 32 AD, 19 bvFTD, and 21 SD were asked to draw 12 items with different age of acquisition and familiarity, belonging to four different semantic categories. We employed the drawings of healthy volunteers to build a scoring scheme.

Results: Turtle, strawberry, train, and envelope were the items of each category that best discriminated between groups and were selected for the Brief drawing task. The discriminatory power of the Brief drawing task between SD versus AD and bvFTD patients, estimated through the area under the curve was 0.84 (95% CI = 0.72-0.96, p = 0.000007). In a logistic model, the Brief drawing task (p = 0.003) and VOSP "number location" subtest (p = 0.016) were significant predictors of the diagnosis of SD versus AD and bvFTD after adjustment by the main covariates. The Brief drawing task provided clinically useful qualitative information. SD drawings were characterized by loss of the distinctive features, intrusions, tendency to prototype, and answers like "I don't know what this is".

Conclusion: The Brief drawing task appears to reveal deficits in semantic knowledge among patients with SD that may assist in the differential diagnosis with other neurodegenerative diseases.
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http://dx.doi.org/10.3233/JAD-190660DOI Listing
November 2020

Prediction of Survival With Long-Term Disease Progression in Most Common Spinocerebellar Ataxia.

Mov Disord 2019 08 18;34(8):1220-1227. Epub 2019 Jun 18.

INSERM U 1136, Sorbonne Universités, Institut Pierre Louis d'Epidémiologie et de Santé Publique, IPLESP, Paris, France.

Background: Spinocerebellar ataxias are rare dominantly inherited neurodegenerative diseases that lead to severe disability and premature death.

Objective: To quantify the impact of disease progression measured by the Scale for the Assessment and Rating of Ataxia on survival, and to identify different profiles of disease progression and survival.

Methods: Four hundred sixty-two spinocerebellar ataxia patients from the EUROSCA prospective cohort study, suffering from spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, and spinocerebellar ataxia type 6, and who had at least two measurements of Scale for the Assessment and Rating of Ataxia score, were analyzed. Outcomes were change over time in Scale for the Assessment and Rating of Ataxia score and time to death. Joint model was used to analyze disease progression and survival.

Results: Disease progression was the strongest predictor for death in all genotypes: An increase of 1 standard deviation in total Scale for the Assessment and Rating of Ataxia score increased the risk of death by 1.28 times (95% confidence interval: 1.18-1.38) for patients with spinocerebellar ataxia type 1; 1.19 times (1.12-1.26) for spinocerebellar ataxia type 2; 1.30 times (1.19-1.42) for spinocerebellar ataxia type 3; and 1.26 times (1.11-1.43) for spinocerebellar ataxia type 6. Three subgroups of disease progression and survival were identified for patients with spinocerebellar ataxia type 1: "severe" (n = 13; 12%), "intermediate" (n = 31; 29%), and "moderate" (n = 62; 58%). Patients in the severe group were more severely affected at baseline with higher Scale for the Assessment and Rating of Ataxia scores and frequency of nonataxia signs compared to those in the other groups.

Conclusion: Rapid ataxia progression is associated with poor survival of the most common spinocerebellar ataxia. Theses current results have implications for the design of future interventional studies of spinocerebellar ataxia. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27739DOI Listing
August 2019

Description of Restrictively Defined Acute Flaccid Myelitis.

JAMA Pediatr 2019 07;173(7):701-702

Neuromuscular Pathology Unit, Service of Neurology, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain.

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http://dx.doi.org/10.1001/jamapediatrics.2019.1266DOI Listing
July 2019

Livedo racemosa generalisata: an anthological vision through Vladímir Lébedev painting.

Authors:
José Berciano

J Neurol 2019 07 4;266(7):1801-1802. Epub 2019 Apr 4.

Service of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", University of Cantabria, Santander, Spain.

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http://dx.doi.org/10.1007/s00415-019-09303-2DOI Listing
July 2019

A unicenter, prospective study of Guillain-Barré syndrome in Spain.

Acta Neurol Scand 2019 Jun 10;139(6):546-554. Epub 2019 Apr 10.

Service of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", University of Cantabria, and "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)", Santander, Spain.

Objective: We report a prospective study analysing clinical characteristics, subtyping and prognosis in Guillain-Barré syndrome (GBS).

Method: The study was based on consecutive GBS patients admitted between 2009 and 2017. Disability was serially assessed using the GBS disability scale.

Results: Fifty-six GBS patients were identified with an average age of 55 years (range, 5-86 years) and a male/female ratio of 2.1. The interval to nadir was <7 days in 59% of cases, and 7 to 28 days in the remainder; at nadir, 35.5% of patients were able to walk unaided, and 64.5% did not. Mechanical ventilation was needed in 20% of cases. There were two fatal cases. Clinical variants included paraparetic GBS seven cases, Miller Fisher syndrome one case, and acute sensory ataxic neuropathy (ASAN) one case. Serial electrophysiology showed a demyelinating pattern in 62.5% of cases, axonal in 28.5%, inexcitable in 1.8%, equivocal in 1.8%, and normal in 5.4%. Very early (1 to 4 days after onset) electrophysiology was done in 18 patients; equivocal or normal features in six of them evolved into an axonal pattern in four. Reversible conduction failure of sensitive nerves occurred in ASAN. Antiganglioside antibodies were only detected in axonal GBS. At 24-month follow-up, functional outcome did not differ between demyelinating and axonal GBS. Clinico-pathological correlation in an early fatal case is reported.

Conclusions: This GBS study demonstrates comparable clinical features to previous investigations from well-defined populations. There was a relatively high prevalence of axonal GBS. We provide new pathophysiological insights on nerve conduction alterations.
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http://dx.doi.org/10.1111/ane.13092DOI Listing
June 2019

Novel GARS mutation presenting as autosomal dominant intermediate Charcot-Marie-Tooth disease: Intermediate or axonal?

J Peripher Nerv Syst 2019 03;24(1):161

Service of Clinical Neurophysiology, University Hospital "Marqués de Valdecilla (IDIVAL)", "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)", Santander, Spain.

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http://dx.doi.org/10.1111/jns.12300DOI Listing
March 2019

Hereditary primary lateral sclerosis and progressive nonfluent aphasia.

J Neurol 2019 May 5;266(5):1079-1090. Epub 2019 Mar 5.

Department of Neurology, Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, CIBERNED, Santander, Spain.

Objective: To report a kindred with an association between hereditary primary lateral sclerosis (PLS) and progressive nonfluent aphasia.

Patients And Methods: Six members from a kindred with 15 affected individuals spanning three generations, suffered from spasticity without muscle atrophy or fasciculation, starting in the lower limbs and spreading to the upper limbs and bulbar musculature, followed by effortful speech, nonfluent language and dementia, in 5 deceased members. Disease onset was during the sixth decade of life, or later. Cerebellar ataxia was the inaugural manifestation in two patients, and parkinsonism, in another.

Results: Neuropathological examination in two patients demonstrated degeneration of lateral corticospinal tracts in the spinal cord, without loss of spinal, brainstem, or cerebral motor neurons. Greater loss of corticospinal fibers at sacral and lumbar, rather than at cervical or medullary levels was demonstrated, supporting a central axonal dying-back pathogenic mechanism. Marked reduction of myelin and nerve fibers in the frontal lobes was also present. Argyrophilic grain disease and primary age-related tauopathy were found in one case each, and considered incidental findings. Genetic testing, including exome sequencing aimed at PLS, ataxia, hereditary spastic paraplegia, and frontotemporal lobe dementia, triplet-repeated primed polymerase chain reaction aimed at dominant spinocerebellar ataxias, and massive sequencing of the human genome, yielded negative results.

Conclusion: A central distal axonopathy affecting the corticospinal tract, exerted a pathogenic role in the dominantly inherited PLS-progressive nonfluent aphasia association, described herein. Further molecular studies are needed to identify the causative mutation in this disease.
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http://dx.doi.org/10.1007/s00415-019-09235-xDOI Listing
May 2019

Reversible conduction failure on the deep tendon reflex response recording in early Guillain-Barré syndrome.

Clin Neurophysiol Pract 2018 3;3:159-163. Epub 2018 Nov 3.

Service of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", University of Cantabria and "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)", Santander, Spain.

Objective: To describe the case of a patient with Guillain-Barré syndrome (GBS) showing early reversible conduction failure (RCF) detected by means of serial deep tendon reflex response (T-reflex) study.

Methods: A 36-year-old woman had a 5-day history of foot and hand paresthesias ascending to thighs and arms, throbbing interscapular and neck pain, mild to moderate tetraparesis, and areflexia. Nerve conduction studies (NCS) were performed on days 7 and 33 after onset.

Results: NCS showed an equivocal electrophysiologic pattern, just an isolated distal RCF being detected on the right radial nerve at initial examination. Motor latency on deltoid muscle after Erb's point stimulation was preserved. Sensory conduction velocities were normal or slightly slowed. Somatosensory evoked potentials from median and tibial nerves were normal. Initially, F-wave study demonstrated reversible abnormalities, consisting of multiple A waves and low F-wave persistence, minimal F-wave latencies being preserved. Biceps brachii T-reflex was normal, whereas Achilles T-reflex was absent bilaterally, appearing on the second study with normal T-wave morphology and latency, thus conforming to the requirements for RCF diagnosis. Soleus H-reflex was also initially absent.

Conclusions: Serial T-reflex study is a useful technique for detecting early RCF of proximal nerve trunks in early GBS.

Significance: T-reflex is useful tool for GBS in association with NCS.
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http://dx.doi.org/10.1016/j.cnp.2018.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247394PMC
November 2018

Acute Flaccid Myelitis With Early, Severe Compound Muscle Action Potential Amplitude Reduction: A 3-Year Follow-up of a Child Patient.

J Clin Neuromuscul Dis 2018 12;20(2):100-101

Neuromuscular Pathology Unit, Service of Neurology, Hospital "Sant Joan de Déu," Esplugues de Llobregat, Barcelona, Spain.

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http://dx.doi.org/10.1097/CND.0000000000000217DOI Listing
December 2018

New Adenovirus Groups in Western Palaearctic Bats.

Viruses 2018 08 20;10(8). Epub 2018 Aug 20.

Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera de Majadahonda-Pozuelo km 2. Majadahonda 28220, Madrid, Spain.

In the context of long-term screening for viruses on Western Palaearctic bats, we tested for the presence of adenovirus 1392 oropharyngeal swabs and 325 stool samples taken from 27 bat species. Adenoviruses were detected in 12 species of the Vespertilionidae and the Rhinolophidae families. Fifty positive respiratory and 26 positive stool samples were studied. Phylogenetic analyses of partial hexon protein and partial DNA-dependent DNA polymerase genes indicate that all these bat adenoviruses belong to the genus but without constituting a monophyletic cluster. According to genetic identities, the new groups are distinct to the previously described and species and contribute with potentially new members. Our data support that diversity of bat mastadenovirus is host-dependent and increase the knowledge of potentially pathogenic virus from bats. Due to the active role of bats as viral reservoirs, the characterization of these viruses is relevant for Public Health.
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http://dx.doi.org/10.3390/v10080443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116233PMC
August 2018

Sneddon syndrome and non-bacterial thrombotic endocarditis: a clinicopathological study.

J Neurol 2018 Sep 6;265(9):2143-2145. Epub 2018 Jul 6.

Service of Pathology, University Hospital "Marqués de Valdecilla (IDIVAL)", University of Cantabria, Santander, Spain.

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http://dx.doi.org/10.1007/s00415-018-8962-0DOI Listing
September 2018

Long-term evolution of patient-reported outcome measures in spinocerebellar ataxias.

J Neurol 2018 Sep 29;265(9):2040-2051. Epub 2018 Jun 29.

German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

Introduction: To study the long-term evolution of patient-reported outcome measures (PROMs) in the most common spinocerebellar ataxias (SCAs), we analyzed 8 years follow-up data of the EUROSCA Natural History Study, a cohort study of 526 patients with SCA1, SCA2, SCA3 and SCA6.

Methods: To assess the functional capacity in daily living, we used the functional assessment (part IV) of the Unified Huntington's Disease Rating Scale (UHDRS-IV), for health-related quality of life the visual analogue scale of the EuroQol Five Dimensions Questionnaire (EQ-5D VAS), and for depressive symptoms the Patient Health Questionnaire (PHQ-9). Severity of ataxia was assessed using the Scale for the Assessment and Rating of Ataxia (SARA) and neurological symptoms other than ataxia with the Inventory of Non-Ataxia Signs (INAS).

Results: UHDRS-IV [SCA1: - 1.35 (0.12); SCA2: - 1.15 (0.11); SCA3: - 1.16 (0.11); SCA6: - 0.99 (0.12)] and EQ-5D [SCA1: - 2.88 (0.72); SCA2: - 1.97 (0.49); SCA3: - 2.06 (0.55); SCA6: - 1.03 (0.57)] decreased linearly, whereas PHQ-9 increased [SCA1: 0.15 (0.04); SCA2: 0.09 (0.03); SCA3: 0.06 (0.04); SCA6: 0.07 (0.04)] during the observational period. Standard response means (SRMs) of UHDRS-IV (0.473-0.707) and EQ-5D VAS (0.053-0.184) were lower than that of SARA (0.404-0.979). In SCA1, higher SARA scores [- 0.0288 (0.01), p = 0.0251], longer repeat expansions [- 0.0622 (0.02), p = 0.0002] and the presence of cognitive impairment at baseline [- 0.5381 (0.25), p = 0.0365] were associated with faster UHDRS-IV decline. In SCA3, higher INAS counts were associated with a faster UHDRS-IV decline [- 0.05 (0.02), p = 0.0212]. In SCA1, PHQ-9 progression was faster in patients with cognitive impairment [0.14 (0.07); p = 0.0396].

Conclusions: In the common SCAs, PROMs give complementary information to the information provided by neurological scales. This underlines the importance of PROMs as additional outcome measures in future interventional trials.
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http://dx.doi.org/10.1007/s00415-018-8954-0DOI Listing
September 2018

Neuropathic Pain in Early Guillain-Barré Syndrome.

Authors:
Jose Berciano

Pain Physician 2018 05;21(3):E279-E280

Service of Neurology, University Hospital, "Marqués de Valdecilla (IDIVAL)", University of Cantabria Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)", University of Cantabria, Santander, Spain.

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May 2018

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) with chronic cough and preserved muscle stretch reflexes: evidence for selective sparing of afferent Ia fibres.

J Neurol 2018 Jun 25;265(6):1454-1462. Epub 2018 Apr 25.

Service of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", University of Cantabria, and "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)", Santander, Spain.

The aim of this study was to describe five patients with cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) with chronic cough and preserved limb muscle stretch reflexes. All five patients were in the seventh decade of age, their gait imbalance having been initiated in the fifth decade. In four patients cough antedated gait imbalance between 15 and 29 years; cough was spasmodic and triggered by variable factors. Established clinical picture included severe hypopallesthesia predominating in the lower limbs with postural imbalance, and variable degree of cerebellar axial and appendicular ataxia, dysarthria and horizontal gaze-evoked nystagmus. Upper- and lower-limb tendon jerks were preserved, whereas jaw jerk was absent. Vestibular function testing showed bilateral impairment of the vestibulo-ocular reflex. Nerve conduction studies demonstrated normal motor conduction parameters and absence or severe attenuation of sensory nerve action potentials. Somatosensory evoked potentials were absent or severely attenuated. Biceps and femoral T-reflex recordings were normal, while masseter reflex was absent or attenuated. Sympathetic skin responses were normal. Cranial MRI showed vermian and hemispheric cerebellar atrophy predominating in lobules VI, VII and VIIa. We conclude that spasmodic cough may be an integral part of the clinical picture in CANVAS, antedating the appearance of imbalance in several decades and that sparing of muscle spindle afferents (Ia fibres) is probably the pathophysiological basis of normoreflexia.
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http://dx.doi.org/10.1007/s00415-018-8872-1DOI Listing
June 2018

First cases of European bat lyssavirus type 1 in Iberian serotine bats: Implications for the molecular epidemiology of bat rabies in Europe.

PLoS Negl Trop Dis 2018 04 23;12(4):e0006290. Epub 2018 Apr 23.

National Center for Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.

Previous studies have shown that EBLV-1 strains exclusively hosted by Eptesicus isabellinus bats in the Iberian Peninsula cluster in a specific monophyletic group that is related to the EBLV-1b lineage found in the rest of Europe. More recently, enhanced passive surveillance has allowed the detection of the first EBLV-1 strains associated to Eptesicus serotinus south of the Pyrenees. The aim of this study is the reconstruction of the EBLV-1 phylogeny and phylodynamics in the Iberian Peninsula in the context of the European continent. We have sequenced 23 EBLV-1 strains detected on nine E. serotinus and 14 E. isabellinus. Phylogenetic analyses were performed on the first 400-bp-5' fragment of the Nucleoprotein (N) gene together with other 162 sequences from Europe. Besides, fragments of the variable region of the phosphoprotein (P) gene and the glycoprotein-polymerase (G-L) intergenic region were studied on Spanish samples. Phylogenies show that two of the new EBLV-1a strains from Iberian E. serotinus clustered together with French strains from the North of the Pyrenees, suggesting a recent expansion southwards of this subtype. The remaining seven Iberian strains from E. serotinus grouped, instead, within the cluster linked, so far, to E. isabellinus, indicating that spatial distribution prevails over species specificity in explaining rabies distribution and supporting interspecific transmission. The structure found within the Iberian Peninsula for EBLV-1b is in concordance with that described previously for E. isabellinus. Finally, we have found that the current EBLV-1 European strains could have emerged only 175 years ago according to our evolutionary dynamics analyses.
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http://dx.doi.org/10.1371/journal.pntd.0006290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933805PMC
April 2018