RESUMO
Malaria during pregnancy is a major global health problem caused by infection with Plasmodium falciparum parasites. Severe effects arise from the accumulation of infected erythrocytes in the placenta. Here, erythrocytes infected by late blood-stage parasites adhere to placental chondroitin sulphate A (CS) via VAR2CSA-type P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion proteins. Immunity to placental malaria is acquired through exposure and mediated through antibodies to VAR2CSA. Through evolution, the VAR2CSA proteins have diversified in sequence to escape immune recognition but retained their overall macromolecular structure to maintain CS binding affinity. This structural conservation may also have allowed development of broadly reactive antibodies to VAR2CSA in immune women. Here we show the negative stain and cryo-EM structure of the only known broadly reactive human monoclonal antibody, PAM1.4, in complex with VAR2CSA. The data shows how PAM1.4's broad VAR2CSA reactivity is achieved through interactions with multiple conserved residues of different sub-domains forming conformational epitope distant from the CS binding site on the VAR2CSA core structure. Thus, while PAM1.4 may represent a class of antibodies mediating placental malaria immunity by inducing phagocytosis or NK cell-mediated cytotoxicity, it is likely that broadly CS binding-inhibitory antibodies target other epitopes at the CS binding site. Insights on both types of broadly reactive monoclonal antibodies may aid the development of a vaccine against placental malaria.
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Malária Falciparum , Malária , Humanos , Feminino , Gravidez , Antígenos de Protozoários , Malária Falciparum/parasitologia , Epitopos , Anticorpos Antiprotozoários , Anticorpos Monoclonais , Microscopia Crioeletrônica , Placenta/metabolismo , Plasmodium falciparum/metabolismo , Eritrócitos/parasitologia , Sulfatos de Condroitina/metabolismoRESUMO
OBJECTIVE: Thalamic dysfunction in lesions or neurodegeneration may alter verticality perception and lead to postural imbalance and falls. The aim of the current study was to delineate the structural and functional connectivity network architecture of the vestibular representations in the thalamus by multimodal magnetic resonance imaging. METHODS: Seventy-four patients with acute unilateral isolated thalamic infarcts were studied prospectively with emphasis on the perception of verticality (tilts of the subjective visual vertical [SVV]). We used multivariate lesion-symptom mapping based on support-vector regression to determine the thalamic nuclei associated with ipsiversive and contraversive tilts of the SVV. The lesion maps were used to evaluate the white matter disconnection and whole brain functional connectivity in healthy subjects. RESULTS: Contraversive SVV tilts were associated with lesions of the ventral posterior lateral/medial, ventral lateral, medial pulvinar, and medial central/parafascicular nuclei. Clusters associated with ipsiversive tilts were located inferiorly (ventral posterior inferior nucleus) and laterally (ventral lateral, ventral posterior lateral, and reticular nucleus) to these areas. Distinct ascending vestibular brainstem pathways terminated in the subnuclei for ipsi- or contraversive verticality processing. The functional connectivity analysis showed specific patterns of cortical connections with the somatomotor network for lesions with contraversive tilts, and with the core multisensory vestibular representations (areas Ri, OP2-3, Ig, 3av, 2v) for lesions with ipsiversive tilts. INTERPRETATION: The functional specialization may allow both a stable representation of verticality for sensorimotor integration and flexible adaption to sudden changes in the environment. A targeted modulation of this circuitry could be a novel therapeutic strategy for higher level balance disorders of thalamocortical origin. ANN NEUROL 2023;94:133-145.
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Encéfalo , Percepção Espacial , Humanos , Tronco Encefálico , Mapeamento Encefálico , Tálamo/diagnóstico por imagemRESUMO
BACKGROUND: In addition to other stroke-related deficits, the risk of seizures may impact driving ability after stroke. METHODS: We analysed data from a multicentre international cohort, including 4452 adults with acute ischaemic stroke and no prior seizures. We calculated the Chance of Occurrence of Seizure in the next Year (COSY) according to the SeLECT2.0 prognostic model. We considered COSY<20% safe for private and <2% for professional driving, aligning with commonly used cut-offs. RESULTS: Seizure risks in the next year were mainly influenced by the baseline risk-stratified according to the SeLECT2.0 score and, to a lesser extent, by the poststroke seizure-free interval (SFI). Those without acute symptomatic seizures (SeLECT2.0 0-6 points) had low COSY (0.7%-11%) immediately after stroke, not requiring an SFI. In stroke survivors with acute symptomatic seizures (SeLECT2.0 3-13 points), COSY after a 3-month SFI ranged from 2% to 92%, showing substantial interindividual variability. Stroke survivors with acute symptomatic status epilepticus (SeLECT2.0 7-13 points) had the highest risk (14%-92%). CONCLUSIONS: Personalised prognostic models, such as SeLECT2.0, may offer better guidance for poststroke driving decisions than generic SFIs. Our findings provide practical tools, including a smartphone-based or web-based application, to assess seizure risks and determine appropriate SFIs for safe driving.
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Condução de Veículo , AVC Isquêmico , Convulsões , Humanos , Convulsões/etiologia , Convulsões/complicações , AVC Isquêmico/complicações , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Fatores de Risco , Idoso de 80 Anos ou mais , Prognóstico , Estudos de Coortes , AdultoRESUMO
INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (SOD1-ALS), tofersen received accelerated approval in the United States and is available via expanded access programs (EAP) outside the United States. This multicenter study investigates clinical and patient-reported outcomes (PRO) and serum neurofilament light chain (sNfL) during tofersen treatment in an EAP in Germany. METHODS: Sixteen SOD1-ALS patients receiving tofersen for at least 6 months were analyzed. The ALS progression rate (ALS-PR), as measured by the monthly change of the ALS functional rating scale-revised (ALSFRS-R), slow vital capacity (SVC), and sNfL were investigated. PRO included the Measure Yourself Medical Outcome Profile (MYMOP2), Treatment Satisfaction Questionnaire for Medication (TSQM-9), and Net Promoter Score (NPS). RESULTS: Mean tofersen treatment was 11 months (6-18 months). ALS-PR showed a mean change of -0.2 (range 0 to -1.1) and relative reduction by 25%. Seven patients demonstrated increased ALSFRS-R. SVC was stable (mean 88%, range -15% to +28%). sNfL decreased in all patients except one heterozygous D91A-SOD1 mutation carrier (mean change of sNfL -58%, range -91 to +27%, p < .01). MYMOP2 indicated improved symptom severity (n = 10) or yet perception of partial response (n = 6). TSQM-9 showed high global treatment satisfaction (mean 83, SD 16) although the convenience of drug administration was modest (mean 50, SD 27). NPS revealed a very high recommendation rate for tofersen (NPS +80). DISCUSSION: Data from this EAP supported the clinical and sNfL response to tofersen in SOD1-ALS. PRO suggested a favorable patient perception of tofersen treatment in clinical practice.
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Esclerose Lateral Amiotrófica , Proteínas de Neurofilamentos , Medidas de Resultados Relatados pelo Paciente , Superóxido Dismutase-1 , Humanos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Superóxido Dismutase-1/genética , Proteínas de Neurofilamentos/sangue , Resultado do Tratamento , Progressão da Doença , Adulto , Oligonucleotídeos/uso terapêuticoRESUMO
Primary familial brain calcification (PFBC; formerly Fahr's disease) and early-onset Alzheimer's disease (EOAD) may share partially overlapping pathogenic principles. Although the heterozygous loss-of-function mutation c.1523 + 1G > T in the PFBC-linked gene SLC20A2 was detected in a patient with asymmetric tremor, early-onset dementia, and brain calcifications, CSF ß-amyloid parameters and FBB-PET suggested cortical ß-amyloid pathology. Genetic re-analysis of exome sequences revealed the probably pathogenic missense mutation c.235G > A/p.A79T in PSEN1. The SLC20A2 mutation segregated with mild calcifications in two children younger than 30 years. We thus describe the stochastically extremely unlikely co-morbidity of genetic PFBC and genetic EOAD. The clinical syndromes pointed to additive rather than synergistic effects of the two mutations. MRI data revealed the formation of PFBC calcifications decades before the probable onset of the disease. Our report furthermore exemplifies the value of neuropsychology and amyloid PET for differential diagnosis.
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Doença de Alzheimer , Doenças dos Gânglios da Base , Encefalopatias , Criança , Humanos , Doença de Alzheimer/genética , Mutação , Doenças dos Gânglios da Base/patologia , Encéfalo/patologia , Morbidade , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Encefalopatias/patologia , Presenilina-1/genéticaRESUMO
Humans are able to estimate head movements accurately despite the short half-life of information coming from our inner ear motion sensors. The observation that the central angular velocity estimate outlives the decaying signal of the semicircular canal afferents led to the concept of a velocity storage mechanism (VSM). The VSM can be activated via visual and vestibular modalities and becomes manifest in ocular motor responses after sustained stimulation like whole-body rotations, optokinetic or galvanic vestibular stimulation (GVS). The VSM has been the focus of many computational modelling approaches; little attention though has been paid to discover its actual structural correlates. Animal studies localized the VSM in the medial and superior vestibular nuclei. A significant modulation by cerebellar circuitries including the uvula and nodulus has been proposed. Nevertheless, the corresponding neuroanatomical structures in humans have not been identified so far. The aim of the present study was to delineate the neural substrates of the VSM using high-resolution infratentorial fMRI with a fast T2* sequence optimized for infratentorial neuroimaging and via video-oculography (VOG). The neuroimaging experiment (n=20) gave first in vivo evidence for an involvement of the vestibular nuclei in the VSM and substantiate a crucial role for cerebellar circuitries. Our results emphasize the importance of cerebellar feedback loops in VSM most likely represented by signal increases in vestibulo-cerebellar hubs like the uvula and nodulus and lobule VIIIA. The delineated activation maps give new insights regarding the function and embedment of Crus I, Crus II, and lobule VII and VIII in the human vestibular system.
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Vermis Cerebelar , Vestíbulo do Labirinto , Animais , Humanos , Movimentos Oculares , Imageamento por Ressonância Magnética , Cerebelo/fisiologia , Vestíbulo do Labirinto/fisiologia , Reflexo Vestíbulo-Ocular/fisiologiaRESUMO
All volitional movement in a three-dimensional space requires multisensory integration, in particular of visual and vestibular signals. Where and how the human brain processes and integrates self-motion signals remains enigmatic. Here, we applied visual and vestibular self-motion stimulation using fast and precise whole-brain neuroimaging to delineate and characterize the entire cortical and subcortical egomotion network in a substantial cohort (n=131). Our results identify a core egomotion network consisting of areas in the cingulate sulcus (CSv, PcM/pCi), the cerebellum (uvula), and the temporo-parietal cortex including area VPS and an unnamed region in the supramarginal gyrus. Based on its cerebral connectivity pattern and anatomical localization, we propose that this region represents the human homologue of macaque area 7a. Whole-brain connectivity and gradient analyses imply an essential role of the connections between the cingulate sulcus and the cerebellar uvula in egomotion perception. This could be via feedback loops involved updating visuo-spatial and vestibular information. The unique functional connectivity patterns of PcM/pCi hint at central role in multisensory integration essential for the perception of self-referential spatial awareness. All cortical egomotion hubs showed modular functional connectivity with other visual, vestibular, somatosensory and higher order motor areas, underlining their mutual function in general sensorimotor integration.
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Mapeamento Encefálico , Imageamento por Ressonância Magnética , Humanos , Estimulação Luminosa , Imageamento por Ressonância Magnética/métodos , Córtex Cerebral/fisiologia , Encéfalo/fisiologiaRESUMO
OBJECTIVE: The purpose of this study was to identify risk factors for acute symptomatic seizures and post-stroke epilepsy after acute ischemic stroke and evaluate the effects of reperfusion treatment. METHODS: We assessed the risk factors for post-stroke seizures using logistic or Cox regression in a multicenter study, including adults from 8 European referral centers with neuroimaging-confirmed ischemic stroke. We compared the risk of post-stroke seizures between participants with or without reperfusion treatment following propensity score matching to reduce confounding due to treatment selection. RESULTS: In the overall cohort of 4,229 participants (mean age 71 years, 57% men), a higher risk of acute symptomatic seizures was observed in those with more severe strokes, infarcts located in the posterior cerebral artery territory, and strokes caused by large-artery atherosclerosis. Strokes caused by small-vessel occlusion carried a small risk of acute symptomatic seizures. 6% developed post-stroke epilepsy. Risk factors for post-stroke epilepsy were acute symptomatic seizures, more severe strokes, infarcts involving the cerebral cortex, and strokes caused by large-artery atherosclerosis. Electroencephalography findings within 7 days of stroke onset were not independently associated with the risk of post-stroke epilepsy. There was no association between reperfusion treatments in general or only intravenous thrombolysis or mechanical thrombectomy with the time to post-stroke epilepsy or the risk of acute symptomatic seizures. INTERPRETATION: Post-stroke seizures are related to stroke severity, etiology, and location, whereas an early electroencephalogram was not predictive of epilepsy. We did not find an association of reperfusion treatment with risks of acute symptomatic seizures or post-stroke epilepsy. ANN NEUROL 2021;90:808-820.
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Isquemia Encefálica/complicações , Epilepsia/complicações , Convulsões/complicações , Convulsões/diagnóstico , Acidente Vascular Cerebral/complicações , Adulto , Idoso , Epilepsia/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Convulsões/fisiopatologia , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: We aimed to delineate common principles of reorganization after infarcts of the subcortical vestibular circuitry related to the clinical symptomatology. Our hypothesis was that the recovery of specific symptoms is associated with changes in distinct regions within the core vestibular, somatosensory, and visual cortical and subcortical networks. METHODS: We used voxel- and surface-based morphometry to investigate structural reorganization of subcortical and cortical brain areas in 42 patients with a unilateral, subcortical infarct with vestibular and ocular motor deficits in the acute phase. The patients received structural neuroimaging and clinical monitoring twice (acute phase and after 6 months) to detect within-subject changes over time. RESULTS: In patients with vestibular signs such as tilts of the subjective visual vertical (SVV) and ocular torsion in the acute phase, significant volumetric increases in the superficial white matter around the parieto-opercular (retro-)insular vestibular cortex (PIVC) were found at follow-up. In patients with SVV tilts, spontaneous nystagmus, and rotatory vertigo in the acute phase, gray matter volume decreases were located in the cerebellum and the visual cortex bilaterally at follow-up. Patients with saccade pathology demonstrated volumetric decreases in cerebellar, thalamic, and cortical centers for ocular motor control. CONCLUSIONS: The findings support the role of the PIVC as the key hub for vestibular processing and reorganization. The volumetric decreases represent the reciprocal interaction of the vestibular, visual, and ocular motor systems during self-location and egomotion detection. A modulation in vestibular and ocular motor as well as visual networks was induced independently of the vestibular lesion site.
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Vestíbulo do Labirinto , Substância Branca , Encéfalo/patologia , Córtex Cerebral , Infarto Cerebral/patologia , Humanos , VertigemRESUMO
In coming decades, drought is expected to expand globally owing to increased evaporation and reduced rainfall. Understanding, predicting, and controlling crop plants' rhizosphere has the potential to manipulate its responses to environmental stress. Our plant growth-promoting rhizobacteria (PGPR) are isolated from a natural laboratory, 'The Evolution Canyon', Israel, (EC), from the wild progenitors of cereals, where they have been co-habituating with their hosts for long periods of time. The study revealed that commercial TM50 silica particles (SN) triggered the PGPR production of exopolysaccharides (EPS) containing D-glucuronate (D-GA). The increased EPS content increased the PGPR water-holding capacity (WHC) and osmotic pressure of the biofilm matrix, which led to enhanced plant biomass in drought-stressed growth environments. Light- and cryo-electron- microscopic studies showed that, in the presence of silica (SN) particles, bacterial morphology is changed, indicating that SNs are associated with significant reprogramming in bacteria. The findings encourage the development of large-scale methods for isolate formulation with natural silicas that ensure higher WHC and hyperosmolarity under field conditions. Osmotic pressure involvement of holobiont cohabitation is also discussed.
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Bactérias/isolamento & purificação , Secas , Polissacarídeos Bacterianos/metabolismo , Dióxido de Silício/farmacologia , Microbiologia do Solo , Solo/química , Triticum/crescimento & desenvolvimento , Bactérias/classificação , Bactérias/metabolismo , Rizosfera , Triticum/efeitos dos fármacos , Triticum/metabolismoRESUMO
The tetanus neurotoxin (TeNT) is a highly potent toxin produced by Clostridium tetani that inhibits neurotransmission of inhibitory interneurons, causing spastic paralysis in the tetanus disease. TeNT differs from the other clostridial neurotoxins by its unique ability to target the central nervous system by retrograde axonal transport. The crystal structure of the tetanus toxin reveals a "closed" domain arrangement stabilised by two disulphide bridges, and the molecular details of the toxin's interaction with its polysaccharide receptor. An integrative analysis combining X-ray crystallography, solution scattering and single particle electron cryo-microscopy reveals pH-mediated domain rearrangements that may give TeNT the ability to adapt to the multiple environments encountered during intoxication, and facilitate binding to distinct receptors.
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Toxina Tetânica/química , Toxina Tetânica/metabolismo , Animais , Cristalografia por Raios X , Humanos , Concentração de Íons de Hidrogênio , Metaloendopeptidases/química , Metaloendopeptidases/metabolismo , Microscopia Eletrônica , Neurotoxinas/química , Neurotoxinas/metabolismo , Ligação Proteica , Domínios Proteicos , Transmissão Sináptica/efeitos dos fármacos , Toxina Tetânica/farmacologiaRESUMO
BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) and posterior reversible encephalopathy syndrome (PRES) are both rare disorders. The pathophysiology of both diseases is not yet fully understood. METHODS: We report the unique case of a 19-year-old comatose woman who was brought to the ER after a series of generalized tonic-clonic seizures 6 days post peridural anesthesia for cesarean section. Vital signs and initial laboratory testing including urine analysis and drug screening were unremarkable. Initial cranial CT scan showed an acute small subdural hematoma (17 mm length × 6 mm width × 30 mm height), cerebral edema with slit ventricles, and slight cerebellar tonsillar herniation as signs of intracranial hypotension. CT angiography depicted narrowing of the proximal intracranial vessels consistent with RCVS. MR imaging was also suggestive of both intracranial hypotension and RCVS and showed, in addition, vasogenic edema consistent with PRES. An extensive CSF leakage involving T1 to L2/L3 was confirmed by spinal MRI. RESULTS: The patient underwent conservative therapy for intracranial hypotension (e.g., head-down position) as well as epidural blood patch, which led to regression of the clinical symptoms within a few days. Follow-up MRI showed complete resolution of all radiological changes. CONCLUSIONS: In summary, our patient developed clinical and neuroradiological signs of intracranial hypotension and a combination of PRES and RCVS associated with a CSF leakage caused by peridural anesthesia; by treating the intracranial hypotension, the other syndromes resolved. From a clinical point of view, it is important to look for CSF leakage as a treatable possible cause of PRES and/or RCVS triggered by intracranial hypotension as in our patient postpartum. Moreover, it is vital to obtain a good history as, in cases of suspected CSF leakage with classic postural headache, a recent spinal/cranial procedure is typically present.
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Anestesia Epidural/efeitos adversos , Cesárea/efeitos adversos , Hipotensão Intracraniana/diagnóstico , Síndrome da Leucoencefalopatia Posterior/diagnóstico , Convulsões/induzido quimicamente , Vasoconstrição , Adulto , Feminino , Humanos , Hipotensão Intracraniana/terapia , Síndrome da Leucoencefalopatia Posterior/terapia , Adulto JovemRESUMO
OBJECTIVE: Thinning of the peripapillary retinal nerve fiber layer (p-RNFL), as measured by optical coherence tomography (OCT), was recently introduced as a promising marker for cerebral neuronal loss in people with epilepsy (PwE). However, its clinical implication remains to be elucidated. We thus aimed to (1) systematically characterize the extent of the retinal neuroaxonal loss in a broad spectrum of unselected PwE and (2) to evaluate the main clinical determinants. METHODS: In this prospective study, a spectral-domain OCT evaluation was performed on 98 well-characterized PwE and 85 healthy controls (HCs) (18-55 years of age). All inner retinal layers and the total macula volume were assessed. Group comparisons and linear regression analyses with stepwise backward selection were performed to identify relevant clinical and demographic modulators of the retinal neuroaxonal integrity. RESULTS: PwE (age: 33.7 ± 10.6 years; 58.2% female) revealed a significant neuroaxonal loss across all assessed retinal layers (global pRNFL, P = 0.001, Δ = 4.24 µm; macular RNFL, P < 0.001, Δ = 0.05 mm3 ; ganglion cell inner plexiform layer, P < 0.001, Δ = 0.11 mm3 ; inner nuclear layer, INL, P = 0.03, Δ = 0.02 mm3 ) as well as significantly reduced total macula volumes (TMV, P < 0.001, Δ = 0.18 mm3 ) compared to HCs (age: 31.2 ± 9.0 years; 57.6% female). The extent of retinal neuroaxonal loss was associated with the occurrence and frequency of tonic-clonic seizures and the number of antiseizure medications, and was most pronounced in male patients. SIGNIFICANCE: PwE presented an extensive retinal neuroaxonal loss, affecting not only the peripapillary but also macular structures. The noninvasive and economic measurement via OCT bears the potential to establish as a practical tool to inform patient management, as the extent of the retinal neuroaxonal loss reflects aspects of disease severity and sex-specific vulnerability. PLAIN LANGUAGE SUMMARY: The retina is an extension of the brain and closely connected to it. Thus, cerebral alterations like atrophy reflect also on the retinal level. This is advantageous, as the retina is easily accessible and measureable with help of the optical coherence tomography. Here we report that adults with epilepsy have a significantly thinner retina than healthy persons. Especially people with many big seizures and a lot of medications have a thinner retina. We propose that measurement of the retina can be useful as a marker of disease severity and to inform patient management.
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Epilepsia , Células Ganglionares da Retina , Adulto , Humanos , Masculino , Feminino , Adulto Jovem , Tomografia de Coerência Óptica/métodos , Estudos Transversais , Estudos Prospectivos , Retina/diagnóstico por imagem , Epilepsia/diagnóstico por imagemRESUMO
BACKGROUND: Since the antisense oligonucleotide tofersen has recently become available for the treatment of amyotrophic lateral sclerosis (ALS) caused by mutations in SOD1, determining the causality of the over 230 SOD1 variants has become even more important. The most common SOD1 variant worldwide is p.D91A (c.272A > C), whose causality for ALS is contested when in a heterozygous state. The reason is the high allele frequency of SOD1D91A in Europe, exceeding 1% in Finno-Scandinavia. METHODS: We present the clinical disease course and serum neurofilament light chain (NfL) results of treating 11 patients either homo- or heterozygous for the SOD1D91A allele for up to 16 months with tofersen. RESULTS: Tofersen decreases serum neurofilament levels (sNFL), which are associated with the ALS progression rate, in the 6 ALS patients homozygous for SOD1D91A. We observe significantly lower sNfL levels in the 5 patients heterozygous for SOD1D91A. The results indicate that both mono- and bi-allelic SOD1D91A are causally relevant targets, with a possibly reduced effect size of SOD1D91Ahet. CONCLUSIONS: The finding is relevant for decision making regarding tofersen treatment, patient counseling and inclusion of SOD1D91A patients in drug trials. As far as we are aware, the approach is conceptually new since it provides evidence for the causality of an ALS variant based on a biomarker response to gene-specific treatment.
Amyotrophic lateral sclerosis (ALS) is a disease that can be inherited which affects nerve cells in the brain and spinal cord. Changes within a gene called SOD1 that result in a mutation named p.D91A can lead to the development of ALS. People have two copies of the SOD1 gene. It has been unclear whether the presence of only one copy of p.D91A can cause ALS. We treated ALS patients with the p.D91A variant of SOD1 with a drug called tofersen. We found that a marker of disease progression was reduced in patients with one or two copies of the p.D91A mutation. This suggests that the presence of just one p.D91A variant of SOD1 contributes to disease development. This information could be used to improve treatment decisions for people with ALS.
RESUMO
Background: In April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of SOD1-amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated. Methods: Between 03/2022 and 04/2023, 24 patients with SOD1-ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events. Findings: During the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0-42.0) to 35.0 (IQR 29.0-42.0), corresponding to a median progression rate of 0.11 (IQR -0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0 pg/ml (IQR 37.0-147.0 pg/ml; n = 23) to 36.0 pg/ml (IQR 22.0-65.0 pg/ml; n = 23; p = 0.02), median pNfH in CSF from 2226 pg/ml (IQR 1061-6138 pg/ml; n = 18) to 1151 pg/ml (IQR 521-2360 pg/ml; n = 18; p = 0.02). In the CSF, we detected a pleocytosis in 73% of patients (11 of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported. Interpretation: Consistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction. Funding: No funding was received towards this study.
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BACKGROUND AND PURPOSE: In previous imaging studies, the posterior insular cortex (IC) was identified as an essential part for vestibular otolith perception and considered as a core region of a human vestibular cortical network. However, it is still unknown whether lesions exclusively restricted to the posterior IC suffice to provoke signs of vestibular otolith dysfunction. Thus, present data aimed to test whether patients with lesions restricted to the IC showed vestibular otolith dysfunction. METHODS: We studied 10 acute unilateral stroke patients with lesions restricted to the IC which were tested for signs of vestibular otolith dysfunction, such as tilts of subjective visual vertical, out of 475 stroke patients. RESULTS: None of the patients was with stroke exclusively affecting the IC-specified vertigo as a symptom. In addition, neither showed a deficit in the perception of verticality (subjective visual vertical tilts) nor showed any further vestibular otolith deficits, such as ocular torsion or skew deviation. CONCLUSIONS: It seems that lesions of the posterior IC might have to be combined with lesions of adjacent regions of the cortical and subcortical vestibular network to cause vestibular otolith deficits.
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Córtex Cerebral/fisiopatologia , Acidente Vascular Cerebral/classificação , Acidente Vascular Cerebral/complicações , Doenças Vestibulares/etiologia , Idoso , Idoso de 80 Anos ou mais , Córtex Cerebral/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Membrana dos Otólitos/fisiopatologia , Acidente Vascular Cerebral/patologia , Vertigem/diagnóstico , Vertigem/etiologia , Doenças Vestibulares/diagnósticoRESUMO
OBJECTIVE: We aimed to relate clinical measures of disability in chronic cerebellar degeneration to structural whole-brain changes using voxel-based and surface-based morphometry (vbm and sbm). We were particularly interested in remote effects of cerebellar degeneration in the cerebral cortex. METHODS: We recruited 30 patients with cerebellar degeneration of different aetiologies (downbeat nystagmus syndrome, DBN n = 14, spinocerebellar ataxia, SCA n = 9, sporadic adult late-onset ataxia, SAOA n = 7). All patients were thoroughly characterised in the motor, cognitive, vestibular and ocular-motor domains. Vbm and sbm were used to evaluate structural differences between cerebellar degeneration patients and a group of healthy age- and gender-matched volunteers. Linear regression models were used to correlate functional measures of disease progression and postural stability with whole brain volumetry. RESULTS: Patients with SCA and SAOA showed widespread volume loss in the cerebellar hemispheres and less prominently in the vermis. Patients with DBN showed a distinct pattern of grey matter volume (GMV) loss that was restricted to the vestibular and ocular-motor representations in lobules IX, X and V-VII. Falls were associated with brainstem white matter volume. VBM and SBM linear regression models revealed associations between severity of ataxic symptoms, cognitive performance and preferred gait velocity. This included extra-cerebellar (sub-)cortical hubs of the motor and locomotion network (putamen, caudate, thalamus, primary motor cortex, prefrontal cortex) and multisensory areas involved in spatial navigation and cognition. CONCLUSION: Functional disability in multiple domains was associated with structural changes in the cerebral cortex.
Assuntos
Ataxia Cerebelar , Doenças Cerebelares , Adulto , Humanos , Ataxia Cerebelar/diagnóstico por imagem , Imageamento por Ressonância Magnética , Ataxia , Cerebelo , SíndromeRESUMO
Importance: Acute symptomatic seizures occurring within 7 days after ischemic stroke may be associated with an increased mortality and risk of epilepsy. It is unknown whether the type of acute symptomatic seizure influences this risk. Objective: To compare mortality and risk of epilepsy following different types of acute symptomatic seizures. Design, Setting, and Participants: This cohort study analyzed data acquired from 2002 to 2019 from 9 tertiary referral centers. The derivation cohort included adults from 7 cohorts and 2 case-control studies with neuroimaging-confirmed ischemic stroke and without a history of seizures. Replication in 3 separate cohorts included adults with acute symptomatic status epilepticus after neuroimaging-confirmed ischemic stroke. The final data analysis was performed in July 2022. Exposures: Type of acute symptomatic seizure. Main Outcomes and Measures: All-cause mortality and epilepsy (at least 1 unprovoked seizure presenting >7 days after stroke). Results: A total of 4552 adults were included in the derivation cohort (2547 male participants [56%]; 2005 female [44%]; median age, 73 years [IQR, 62-81]). Acute symptomatic seizures occurred in 226 individuals (5%), of whom 8 (0.2%) presented with status epilepticus. In patients with acute symptomatic status epilepticus, 10-year mortality was 79% compared with 30% in those with short acute symptomatic seizures and 11% in those without seizures. The 10-year risk of epilepsy in stroke survivors with acute symptomatic status epilepticus was 81%, compared with 40% in survivors with short acute symptomatic seizures and 13% in survivors without seizures. In a replication cohort of 39 individuals with acute symptomatic status epilepticus after ischemic stroke (24 female; median age, 78 years), the 10-year risk of mortality and epilepsy was 76% and 88%, respectively. We updated a previously described prognostic model (SeLECT 2.0) with the type of acute symptomatic seizures as a covariate. SeLECT 2.0 successfully captured cases at high risk of poststroke epilepsy. Conclusions and Relevance: In this study, individuals with stroke and acute symptomatic seizures presenting as status epilepticus had a higher mortality and risk of epilepsy compared with those with short acute symptomatic seizures or no seizures. The SeLECT 2.0 prognostic model adequately reflected the risk of epilepsy in high-risk cases and may inform decisions on the continuation of antiseizure medication treatment and the methods and frequency of follow-up.
Assuntos
Epilepsia , AVC Isquêmico , Estado Epiléptico , Acidente Vascular Cerebral , Adulto , Humanos , Masculino , Feminino , Idoso , Estudos de Coortes , Prognóstico , AVC Isquêmico/complicações , Epilepsia/tratamento farmacológico , Acidente Vascular Cerebral/complicações , Estado Epiléptico/tratamento farmacológicoRESUMO
In rare cases, cortical infarcts lead to vertigo. We evaluated structural and functional disconnection in patients with acute vertigo due to unilateral ischemic cortical infarcts compared to infarcts without vertigo in a similar location with a focus on the connectivity of the vestibular cortex, i.e., the parieto-opercular (retro-)insular cortex (PIVC). Using lesion maps from the ten published case reports, we computed lesion-functional connectivity networks in a set of healthy individuals from the human connectome project. The probability of lesion disconnection was evaluated by white matter disconnectome mapping. In all ten cases with rotational vertigo, disconnections of interhemispheric connections via the corpus callosum were present but were spared in lesions of the PIVC without vertigo. Further, the arcuate fascicle was affected in 90% of the lesions that led to vertigo and spared in lesions that did not lead to vertigo. The lesion-functional connectivity network included vestibulo-cerebellar hubs, the vestibular nuclei, the PIVC, the retro-insular and posterior insular cortex, the multisensory vestibular ventral intraparietal area, motion-sensitive areas (temporal area MT+ and cingulate visual sulcus) as well as hubs for ocular motor control (lateral intraparietal area, cingulate and frontal eye fields). However, this was not sufficient to differentiate between lesions with and without vertigo. Disruption of interhemispheric connections of both PIVC via the corpus callosum and intra-hemispheric disconnection via the arcuate fascicle might be the distinguishing factor between vestibular cortical network lesions that manifest with vertigo compared to those without vertigo.