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1.
Artigo em Inglês | MEDLINE | ID: mdl-34135107

RESUMO

OBJECTIVE: Coronavirus disease (COVID-19) has been associated with a large variety of neurologic disorders. However, the mechanisms underlying these neurologic complications remain elusive. In this study, we aimed at determining whether neurologic symptoms were caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) direct infection or by either systemic or local proinflammatory mediators. METHODS: In this cross-sectional study, we checked for SARS-CoV-2 RNA by quantitative reverse transcription PCR, SARS-CoV-2-specific antibodies, and 49 cytokines/chemokines/growth factors (by Luminex) in the CSF +/- sera of a cohort of 22 COVID-19 patients with neurologic presentation and 55 neurologic control patients (inflammatory neurologic disorder [IND], noninflammatory neurologic disorder, and MS). RESULTS: We detected anti-SARS-CoV-2 immunoglobulin G in patients with severe COVID-19 with signs of intrathecal synthesis for some of them. Of the 4 categories of tested patients, the CSF of IND exhibited the highest level of cytokines, chemokines, and growth factors. By contrast, patients with COVID-19 did not present overall upregulation of inflammatory mediators in the CSF. However, patients with severe COVID-19 (intensive care unit patients) exhibited higher concentrations of CCL2, CXCL8, and vascular endothelium growth factor A (VEGF-A) in the CSF than patients with a milder form of COVID-19. In addition, we could show that intrathecal CXCL8 synthesis was linked to an elevated albumin ratio and correlated with the increase of peripheral inflammation (serum hepatocyte growth factor [HGF] and CXCL10). CONCLUSIONS: Our results do not indicate active replication of SARS-CoV-2 in the CSF or signs of massive inflammation in the CSF compartment but highlight a specific impairment of the neurovascular unit linked to intrathecal production of CXCL8.


Assuntos
Encefalopatias/etiologia , COVID-19/complicações , Citocinas/líquido cefalorraquidiano , Inflamação/etiologia , Acoplamento Neurovascular , SARS-CoV-2/patogenicidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/líquido cefalorraquidiano , Encefalopatias/líquido cefalorraquidiano , Encefalopatias/imunologia , Encefalopatias/fisiopatologia , COVID-19/líquido cefalorraquidiano , COVID-19/imunologia , Cuidados Críticos , Estudos Transversais , Citocinas/sangue , Eletroencefalografia , Feminino , Humanos , Imunoglobulina G/líquido cefalorraquidiano , Inflamação/líquido cefalorraquidiano , Inflamação/imunologia , Interleucina-8/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade , Acoplamento Neurovascular/imunologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Adulto Jovem
3.
BMC Neurol ; 21(1): 213, 2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34053436

RESUMO

BACKGROUND: DDMS is a rare disease diagnosed by clinical and radiological characteristics. But the complexity of radiological and clinical manifestations of DDMS has become a challenge diagnostically. To date, the reported cases with DDMS had highly varied clinical manifestations including seizures, contralateral hemiplegia/hemiparesis, facial asymmetry, mental retardation, etc. In addition to typical clinical findings, some new characteristics have been recently added to the spectrum of DDMS. However, few cases have been reported to be associated with neuropsychiatric symptoms according to the literature. This study aimed to investigate the neuropsychiatric manifestations associated with Dyke-Davidoff-Masson syndrome (DDMS) and related imaging findings. METHODS: This study included 7 patients diagnosed with DDMS between 2014 and 2020. The clinical characteristics, neuropsychiatric manifestations, and radiological results were retrospectively evaluated. RESULTS: Seven patients (five males and two females) with a mean age of 28.0 ± 9.73 (range 15.0-41.0) years were included. Five patients were admitted to the psychiatric unit due to psychological and behavioral disorders. Two patients were referred to the neurology unit mainly due to epilepsy. Six patients had epileptic seizures, 4 had hemiplegia, 3 had mental retardation, 2 patients had external ear deformities, and 2 had facial asymmetry. Neuropsychiatric symptoms were presented in 6 (85.7 %) cases. Cases 2-6 developed affective disorders. Deficits in verbal communication, impairment of social interaction, lack of insight, adulia and hypobulia appeared in cases 1-4. Schizophrenia with apathy, and epileptic schizoid psychosis were observed in cases 4 and 5 respectively. Case 6 had behavioral disorders, hyperactivity, tic disorder, mental retardation, anxiety, catatonic symptoms and suicidal tendency. Case 7 had seizures and mental retardation, and no psychiatric symptoms were presented. Radiological examinations showed unilateral cerebral atrophy, enlarged lateral ventricles, and various compensatory hypertrophy of the skull in all cases. The midline structure has shifted to the affected side in 5(71.4 %) cases. Atrophy of the basal ganglia or brain stem was observed in 4(57.1 %) cases. CONCLUSIONS: The hallmark imaging manifestations of DDMS facilitated the diagnosis in most cases. This study illustrated that a variety of psychoneurotic disorders and ear abnormalities were correlated with DDMS.


Assuntos
Encefalopatias , Adolescente , Adulto , Encefalopatias/complicações , Encefalopatias/diagnóstico por imagem , Encefalopatias/fisiopatologia , Epilepsia/etiologia , Feminino , Hemiplegia/etiologia , Humanos , Deficiência Intelectual/etiologia , Masculino , Neuroimagem , Estudos Retrospectivos , Síndrome , Adulto Jovem
4.
Int J Mol Sci ; 22(9)2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33919338

RESUMO

In brain disorders, reactive astrocytes, which are characterized by hypertrophy of the cell body and proliferative properties, are commonly observed. As reactive astrocytes are involved in the pathogenesis of several brain disorders, the control of astrocytic function has been proposed as a therapeutic strategy, and target molecules to effectively control astrocytic functions have been investigated. The production of brain endothelin-1 (ET-1), which increases in brain disorders, is involved in the pathophysiological response of the nervous system. Endothelin B (ETB) receptors are highly expressed in reactive astrocytes and are upregulated by brain injury. Activation of astrocyte ETB receptors promotes the induction of reactive astrocytes. In addition, the production of various astrocyte-derived factors, including neurotrophic factors and vascular permeability regulators, is regulated by ETB receptors. In animal models of Alzheimer's disease, brain ischemia, neuropathic pain, and traumatic brain injury, ETB-receptor-mediated regulation of astrocytic activation has been reported to improve brain disorders. Therefore, the astrocytic ETB receptor is expected to be a promising drug target to improve several brain disorders. This article reviews the roles of ETB receptors in astrocytic activation and discusses its possible applications in the treatment of brain disorders.


Assuntos
Astrócitos/metabolismo , Encefalopatias/metabolismo , Receptor de Endotelina B/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Astrócitos/fisiologia , Encefalopatias/fisiopatologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/fisiopatologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Endotelina-1/metabolismo , Humanos , Neuralgia/metabolismo , Neuralgia/fisiopatologia , Receptor de Endotelina B/fisiologia
5.
J Stroke Cerebrovasc Dis ; 30(6): 105750, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33812174

RESUMO

OBJECTIVE: Vertebral artery compression of the medulla is a rare vascular finding that causes a variety of clinical presentations, from asymptomatic to neurological disability. This article presents the largest literature review to date on medullary compression of the vertebral arteries. METHODS: An English literature search was performed using the PubMed database and the keywords vertebral artery tortuosity, vertebral artery compression, and medullary compression. RESULTS: A comprehensive literature search yielded 68 patients (57% male) with medullary compression by an intracranial vertebral artery (ICVA). The left side of the medulla was compressed in 44, the right side in 19, and bilateral in 7. The most common clinical symptom was weakness - 26 patients (36%) - 6 had quadriparesis and 6 had hemiparesis. 21 patients reported imbalance; 12 various sensory symptoms; 4 patients were asymptomatic. CONCLUSIONS: Understanding the anatomy of the vasculature can help mitigate future debilitating stroke symptoms. Concrete guidelines for revascularization surgery in symptomatic patients may also be effective. Future studies are needed to further clarify the prevalence, natural history, vascular etiology, and treatment of this condition, including asymptomatic patients and the likelihood that they will develop further neurological signs and disability.


Assuntos
Encefalopatias/etiologia , Bulbo/fisiopatologia , Malformações Vasculares/complicações , Artéria Vertebral/anormalidades , Adulto , Idoso , Idoso de 80 Anos ou mais , Encefalopatias/diagnóstico por imagem , Encefalopatias/fisiopatologia , Feminino , Humanos , Masculino , Bulbo/diagnóstico por imagem , Pessoa de Meia-Idade , Paresia/etiologia , Paresia/fisiopatologia , Equilíbrio Postural , Prognóstico , Quadriplegia/etiologia , Quadriplegia/fisiopatologia , Transtornos das Sensações/etiologia , Transtornos das Sensações/fisiopatologia , Malformações Vasculares/diagnóstico por imagem , Malformações Vasculares/fisiopatologia , Artéria Vertebral/diagnóstico por imagem , Artéria Vertebral/fisiopatologia , Adulto Jovem
6.
Int J Mol Sci ; 22(8)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919977

RESUMO

Numerous brain diseases are associated with abnormalities in morphology and density of dendritic spines, small membranous protrusions whose structural geometry correlates with the strength of synaptic connections. Thus, the quantitative analysis of dendritic spines remodeling in microscopic images is one of the key elements towards understanding mechanisms of structural neuronal plasticity and bases of brain pathology. In the following article, we review experimental approaches designed to assess quantitative features of dendritic spines under physiological stimuli and in pathological conditions. We compare various methodological pipelines of biological models, sample preparation, data analysis, image acquisition, sample size, and statistical analysis. The methodology and results of relevant experiments are systematically summarized in a tabular form. In particular, we focus on quantitative data regarding the number of animals, cells, dendritic spines, types of studied parameters, size of observed changes, and their statistical significance.


Assuntos
Citoesqueleto de Actina/genética , Encefalopatias/terapia , Espinhas Dendríticas/fisiologia , Citoesqueleto de Actina/fisiologia , Animais , Encefalopatias/fisiopatologia , Espinhas Dendríticas/patologia , Modelos Animais de Doenças , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Transmissão Sináptica
7.
BMC Neurol ; 21(1): 166, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879091

RESUMO

BACKGROUND: We report on a patient with an intracerebral hemorrhage (ICH), who showed delayed development of aphasia, which was demonstrated via follow up diffusion tensor tractography (DTT) to be related to neural degeneration of the arcuate fasciculus (AF). CASE PRESENTATION: A 51-year-old, right-handed male presented with right hemiparesis, which occurred at the onset of a spontaneous ICH in the left corona radiata and basal ganglia. Brain magnetic resonance images showed a hematoma in the left subcortical area at one month after onset and hemosiderin deposits in the left subcortical area at nine years after onset. At four weeks after onset, he exhibited severe aphasia, and Western Aphasia Battery (WAB) testing revealed an aphasia quotient in the 39.6 percentile (%ile). However, his aphasia improved to nearly a normal state, and at three months after onset, his aphasia quotient was in the 90.5 %ile. At approximately eight years after onset, he began to show aphasia, and his aphasia increased slowly with time resulting in a WAB aphasia quotient in the 12.5 %ile at nine years after onset. The integrity of the left AF over the hematoma was preserved on 1-month post-onset DTT. However, the middle portion of the left AF in the middle of the hemosiderin deposits showed discontinuation on 9-year post-onset DTT. The fractional anisotropy value of the left AF was higher on the 9-year post-onset DTT (0.48) than that on the 1-month post-onset DTT (0.35), whereas the mean diffusivity value was lower on the 9-year post-onset DTT (0.10) than that on the 1-month post-onset DTT (0.32). The fiber number of the left AF was decreased to 175 on the 9-year post-onset DTT from 239 on the 1-month post-onset DTT. CONCLUSIONS: We report on a patient with ICH who showed delayed development of aphasia, which appeared to be related to degeneration of the AF in the dominant hemisphere. Our results suggest that DTT would be useful in ruling out neural degeneration of the AF.


Assuntos
Afasia , Encefalopatias , Córtex Cerebral/fisiopatologia , Hemorragia Cerebral/complicações , Vias Neurais/fisiopatologia , Afasia/etiologia , Afasia/fisiopatologia , Encefalopatias/etiologia , Encefalopatias/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade
8.
Ann Clin Transl Neurol ; 8(4): 968-979, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33780166

RESUMO

OBJECTIVE: Many neurological manifestations are associated with COVID-19, including a distinct form of encephalopathy related to cytokine storm, the acute systemic inflammatory syndrome present in a subgroup of COVID-19 patients. Cytokine storm is also associated with immune effector cell-associated neurotoxicity syndrome (ICANS), a complication of chimeric antigen receptor T-cell (CAR-T) therapy, a highly effective treatment for refractory hematological malignancies. We investigated whether COVID-19-related encephalopathy, ICANS, and other encephalopathies associated with cytokine storm, share clinical and investigative findings. METHODS: Narrative literature review. RESULTS: Comparisons between COVID-19-related encephalopathy and ICANS revealed several overlapping features. Clinically, these included dysexecutive syndrome, language disturbances, akinetic mutism and delirium. EEG showed a prevalence of frontal abnormalities. Brain MRI was often unrevealing. CSF elevated cytokine levels have been reported. A direct correlation between cytokine storm intensity and severity of neurological manifestations has been shown for both conditions. Clinical recovery occurred spontaneously or following immunotherapies in most of the patients. Similar clinical and investigative features were also reported in other encephalopathies associated with cytokine storm, such as hemophagocytic lymphohistiocytosis, sepsis, and febrile infection-associated encephalopathies. INTERPRETATION: COVID-19-related encephalopathy and ICANS are characterized by a predominant electro-clinical frontal lobe dysfunction and share several features with other encephalopathies associated with cytokine storm, which may represent the common denominator of a clinical spectrum of neurological disorders. Therefore, we propose a unifying definition of cytokine storm-associated encephalopathy (CySE), and its diagnostic criteria.


Assuntos
Encefalopatias/fisiopatologia , Encéfalo/fisiopatologia , COVID-19/fisiopatologia , Síndrome da Liberação de Citocina/fisiopatologia , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos , Encefalopatias/epidemiologia , Encefalopatias/terapia , COVID-19/epidemiologia , COVID-19/terapia , Síndrome da Liberação de Citocina/epidemiologia , Síndrome da Liberação de Citocina/terapia , Humanos , Imunoterapia Adotiva/tendências
9.
BMJ Case Rep ; 14(3)2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33653852

RESUMO

The COVID-19 pandemic has dealt a devastating blow to healthcare systems globally. Approximately 3.2% of patients infected with COVID-19 require invasive ventilation during the course of the illness. Within this population, 25% of patients are affected with neurological manifestations. Among those who are affected by severe neurological manifestations, some may have acute cerebrovascular complications (5%), impaired consciousness (15%) or exhibit skeletal muscle hypokinesis (20%). The cause of the severe cognitive impairment and hypokinesis is unknown at this time. Potential causes include COVID-19 viral encephalopathy, toxic metabolic encephalopathy, post-intensive care unit syndrome and cerebrovascular pathology. We present a case of a 60 year old patient who sustained a prolonged hospitalization with COVID-19, had a cerebrovascular event and developed a persistent unexplained encephalopathy along with a hypokinetic state. He was treated successfully with modafinil and carbidopa/levodopa showing clinical improvement within 3-7 days and ultimately was able to successfully discharge home.


Assuntos
Encefalopatias , COVID-19 , Carbidopa/administração & dosagem , Hipocinesia , AVC Isquêmico , Levodopa/administração & dosagem , Modafinila/administração & dosagem , Reabilitação/métodos , SARS-CoV-2/isolamento & purificação , Coagulação Sanguínea , Encefalopatias/fisiopatologia , Encefalopatias/virologia , COVID-19/sangue , COVID-19/complicações , COVID-19/fisiopatologia , COVID-19/terapia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Cuidados Críticos/métodos , Combinação de Medicamentos , Humanos , Hipocinesia/diagnóstico , Hipocinesia/etiologia , Hipocinesia/terapia , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/etiologia , AVC Isquêmico/fisiopatologia , AVC Isquêmico/terapia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Respiração Artificial/métodos , Índice de Gravidade de Doença , Resultado do Tratamento , Desmame do Respirador/métodos
10.
ACS Chem Neurosci ; 12(4): 573-580, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33538586

RESUMO

Long-COVID is a postviral illness that can affect survivors of COVID-19, regardless of initial disease severity or age. Symptoms of long-COVID include fatigue, dyspnea, gastrointestinal and cardiac problems, cognitive impairments, myalgia, and others. While the possible causes of long-COVID include long-term tissue damage, viral persistence, and chronic inflammation, the review proposes, perhaps for the first time, that persistent brainstem dysfunction may also be involved. This hypothesis can be split into two parts. The first is the brainstem tropism and damage in COVID-19. As the brainstem has a relatively high expression of ACE2 receptor compared with other brain regions, SARS-CoV-2 may exhibit tropism therein. Evidence also exists that neuropilin-1, a co-receptor of SARS-CoV-2, may be expressed in the brainstem. Indeed, autopsy studies have found SARS-CoV-2 RNA and proteins in the brainstem. The brainstem is also highly prone to damage from pathological immune or vascular activation, which has also been observed in autopsy of COVID-19 cases. The second part concerns functions of the brainstem that overlap with symptoms of long-COVID. The brainstem contains numerous distinct nuclei and subparts that regulate the respiratory, cardiovascular, gastrointestinal, and neurological processes, which can be linked to long-COVID. As neurons do not readily regenerate, brainstem dysfunction may be long-lasting and, thus, is long-COVID. Indeed, brainstem dysfunction has been implicated in other similar disorders, such as chronic pain and migraine and myalgic encephalomyelitis or chronic fatigue syndrome.


Assuntos
Encefalopatias/fisiopatologia , Tronco Encefálico/fisiopatologia , COVID-19/complicações , Inflamação/fisiopatologia , Trombose/fisiopatologia , Enzima de Conversão de Angiotensina 2/metabolismo , Encefalopatias/metabolismo , Encefalopatias/virologia , Tronco Encefálico/irrigação sanguínea , Tronco Encefálico/metabolismo , Tronco Encefálico/virologia , COVID-19/metabolismo , COVID-19/fisiopatologia , Humanos , Inflamação/metabolismo , Inflamação/virologia , Neuropilina-1/metabolismo , RNA Viral/isolamento & purificação , RNA Viral/metabolismo , Receptores de Coronavírus/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/patogenicidade , Trombose/metabolismo , Trombose/virologia , Tropismo Viral
11.
IEEE Pulse ; 12(1): 2-6, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33606616

RESUMO

In March 2020 -still the early days of the U.K.'s COVID-19 crisis-Rhys Thomas, a neurologist at Newcastle University, got a call at home from a concerned colleague. The colleague's cousin was hospitalized, critically ill with COVID-19, and had developed brainstem encephalitis, a severe inflammatory condition of the brain causing a suite of symptoms, from eye problems to balance problems and drowsiness. He wanted to know if Thomas knew anything about these conditions. At the time, the research coming out of Wuhan, China, only suggested a mild whiff of neurological symptoms-headache, dizziness, and the loss of taste and smell. Clearly the virus could affect the brain in some ways, but it wasn't, Thomas thought then, anything serious. But this report sounded much more concerning. Symptoms like this patient's would mean the virus was accessing more of the nervous system than scientists originally thought.


Assuntos
Encefalopatias/etiologia , COVID-19/complicações , Pandemias , SARS-CoV-2 , Encefalopatias/fisiopatologia , Encefalopatias/psicologia , COVID-19/tratamento farmacológico , COVID-19/fisiopatologia , COVID-19/psicologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/fisiopatologia , Encefalite/etiologia , Encefalite/fisiopatologia , Humanos , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/fisiopatologia , Doenças do Sistema Nervoso/psicologia , SARS-CoV-2/patogenicidade , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/fisiopatologia
12.
BMJ Case Rep ; 14(2)2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33526531

RESUMO

This report describes two patients with acute-onset ptosis, oculomotor dysfunction, ataxia and drowsiness, referable to the midbrain tegmentum. Both patients had previously suffered severe closed head injuries requiring craniotomy for cerebral decompression. Serial brain scans in both cases revealed a newly developing cleft in the midbrain, with features suggestive of abnormal cerebrospinal fluid (CSF) flow across the aqueduct. A trial of acetazolamide was initiated to reduce CSF production, followed by a third ventriculostomy for CSF diversion in one patient, which resulted in arrested disease progression and partial recovery. There are only two previous reports in the literature of midbrain clefts that developed as remote sequelae of head trauma. We postulate that altered CSF flow dynamics in the aqueduct, possibly related to changes in brain compliance, may be contributory. Early recognition and treatment may prevent irreversible structural injury and possible death.


Assuntos
Encefalopatias/diagnóstico por imagem , Lesões Encefálicas Difusas/diagnóstico por imagem , Aqueduto do Mesencéfalo/diagnóstico por imagem , Craniectomia Descompressiva , Traumatismos Cranianos Fechados/cirurgia , Mesencéfalo/diagnóstico por imagem , Acetazolamida/uso terapêutico , Ataxia/fisiopatologia , Blefaroptose , Encefalopatias/fisiopatologia , Encefalopatias/terapia , Lesões Encefálicas Difusas/fisiopatologia , Inibidores da Anidrase Carbônica/uso terapêutico , Líquido Cefalorraquidiano , Progressão da Doença , Disartria/fisiopatologia , Humanos , Hidrodinâmica , Imageamento por Ressonância Magnética , Masculino , Transtornos da Motilidade Ocular/fisiopatologia , Ventriculostomia , Adulto Jovem
13.
BMC Neurol ; 21(1): 85, 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33618681

RESUMO

BACKGROUND: The mu-opioid agonist methadone is administered orally and used in opioid detoxification and in the treatment of moderate-to-severe pain. Acute oral methadone-use and -abuse have been associated with inflammatory and toxic central nervous system (CNS) damage in some cases and cognitive deficits can develop in long-term methadone users. In contrast, reports of intravenous methadone adverse effects are rare. CASE PRESENTATION: Here, we report a patient who developed acute bilateral hearing loss, ataxia and paraparesis subsequently to intravenous methadone-abuse. While the patient gradually recovered from these deficits, widespread magnetic resonance imaging changes progressed and delayed-onset encephalopathy with signs of cortical dysfunction persisted. This was associated with changes in the composition of monocyte and natural killer cell subsets in the cerebrospinal fluid. CONCLUSION: This case suggests a potential bi-phasic primary toxic and secondary inflammatory CNS damage induced by intravenous methadone.


Assuntos
Analgésicos Opioides/envenenamento , Ataxia/induzido quimicamente , Encefalopatias/induzido quimicamente , Disfunção Cognitiva/induzido quimicamente , Perda Auditiva Bilateral/induzido quimicamente , Metadona/envenenamento , Paraparesia/induzido quimicamente , Abuso de Substâncias por Via Intravenosa , Administração Intravenosa , Ataxia/fisiopatologia , Encéfalo/diagnóstico por imagem , Encefalopatias/diagnóstico por imagem , Encefalopatias/imunologia , Encefalopatias/fisiopatologia , Edema Encefálico/induzido quimicamente , Edema Encefálico/diagnóstico por imagem , Edema Encefálico/imunologia , Edema Encefálico/fisiopatologia , Disfunção Cognitiva/imunologia , Disfunção Cognitiva/fisiopatologia , Imagem de Difusão por Ressonância Magnética , Perda Auditiva Bilateral/fisiopatologia , Humanos , Inflamação/imunologia , Células Matadoras Naturais/imunologia , Imageamento por Ressonância Magnética , Masculino , Monócitos/imunologia , Síndromes Neurotóxicas/diagnóstico por imagem , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/imunologia , Síndromes Neurotóxicas/fisiopatologia , Paraparesia/fisiopatologia , Adulto Jovem
15.
J Neurochem ; 157(3): 370-392, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33301616

RESUMO

A comprehensive overview of the interplay between glucocorticoids (GCs) and adult hippocampal neurogenesis (AHN) is presented, particularly, in the context of a diseased brain. The effectors of GCs in the dentate gyrus neurogenic niche of the hippocampal are reviewed, and the consequences of the GC signaling on the generation and integration of new neurons are discussed. Recent findings demonstrating how GC signaling mediates impairments of the AHN in various brain pathologies are overviewed. GC-mediated effects on the generation and integration of adult-born neurons in the hippocampal dentate gyrus depend on the nature, severity, and duration of the acting stress factor. GCs realize their effects on the AHN primarily via specific glucocorticoid and mineralocorticoid receptors. Disruption of the reciprocal regulation between the hypothalamic-pituitary-adrenal (HPA) axis and the generation of the adult-born granular neurons is currently considered to be a key mechanism implicating the AHN into the pathogenesis of numerous brain diseases, including those without a direct hippocampal damage. These alterations vary from reduced proliferation of stem and progenitor cells to increased cell death and abnormalities in morphology, connectivity, and localization of young neurons. Although the involvement of the mutual regulation between the HPA axis and the AHN in the pathogenesis of cognitive deficits and mood impairments is evident, several unresolved critical issues are stated. Understanding the details of GC-mediated mechanisms involved in the alterations in AHN could enable the identification of molecular targets for ameliorating pathology-induced imbalance in the HPA axis/AHN mutual regulation to conquer cognitive and psychiatric disturbances.


Assuntos
Encefalopatias/fisiopatologia , Glucocorticoides/farmacologia , Hipocampo/fisiopatologia , Neurogênese/efeitos dos fármacos , Animais , Grânulos Citoplasmáticos/efeitos dos fármacos , Giro Denteado/fisiopatologia , Hipocampo/crescimento & desenvolvimento , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia
16.
Clin Neurophysiol ; 132(1): 218-225, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33060058

RESUMO

OBJECTIVE: Encephalopathy is a major neurological complication of severe Coronavirus Disease 2019 (COVID-19), but has not been fully defined yet. Further, it remains unclear whether neurological manifestations are primarily due to neurotropism of the virus, or indirect effects, like cerebral hypoxia. METHODS: We analysed the electroencephalograms (EEGs) of 19 consecutive patients with laboratory-confirmed COVID-19, performed at peak disease severity as part of their clinical management. Disease severity, respiratory failure, immune and metabolic dysfunction, sedation status, and neurological examination on the day of the EEG were noted. RESULTS: Severe encephalopathy was confirmed in 13 patients, all with severe COVID-19; 10 remained comatose off sedation, and five of them had alpha coma (AC). Disease severity, sedation, immune and metabolic dysfunction were not different between those with AC and those without. CONCLUSIONS: Severe COVID-19 encephalopathy is a principal cause of persisting coma after sedation withdrawal. The relatively high incidence of the rare AC pattern may reflect direct SARS-CoV-2 neurotropism with a predilection for the brainstem ascending reticular system. SIGNIFICANCE: Systematic early EEG detection of encephalopathy related to severe COVID-19 is important for the acute care and the management of long-term neurological and cognitive sequelae, and may help our better understanding of its pathophysiology.


Assuntos
Encefalopatias/fisiopatologia , Encéfalo/fisiopatologia , COVID-19/fisiopatologia , Coma/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Encefalopatias/etiologia , COVID-19/complicações , Coma/etiologia , Eletroencefalografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
17.
Eur J Neurol ; 28(1): 248-258, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32853434

RESUMO

BACKGROUND AND PURPOSE: Neurological manifestations in coronavirus disease (COVID)-2019 may adversely affect clinical outcomes. Severe COVID-19 and uremia are risk factors for neurological complications. However, the lack of insight into their pathogenesis, particularly with respect to the role of the cytokine release syndrome (CRS), is currently hampering effective therapeutic interventions. The aims of this study were to describe the neurological manifestations of patients with COVID-19 and to gain pathophysiological insights with respect to CRS. METHODS: In this longitudinal study, we performed extensive clinical, laboratory and imaging phenotyping in five patients admitted to our renal unit. RESULTS: Neurological presentation included confusion, tremor, cerebellar ataxia, behavioral alterations, aphasia, pyramidal syndrome, coma, cranial nerve palsy, dysautonomia, and central hypothyroidism. Notably, neurological disturbances were accompanied by laboratory evidence of CRS. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was undetectable in the cerebrospinal fluid (CSF). Hyperalbuminorrachia and increased levels of the astroglial protein S100B were suggestive of blood-brain barrier (BBB) dysfunction. Brain magnetic resonance imaging findings comprised evidence of acute leukoencephalitis (n = 3, one of whom had a hemorrhagic form), cytotoxic edema mimicking ischaemic stroke (n = 1), or normal results (n = 2). Treatment with corticosteroids and/or intravenous immunoglobulins was attempted, resulting in rapid recovery from neurological disturbances in two cases. SARS-CoV2 was undetectable in 88 of the 90 patients with COVID-19 who underwent Reverse Transcription-PCR testing of CSF. CONCLUSIONS: Patients with COVID-19 can develop neurological manifestations that share clinical, laboratory and imaging similarities with those of chimeric antigen receptor T-cell-related encephalopathy. The pathophysiological underpinnings appear to involve CRS, endothelial activation, BBB dysfunction, and immune-mediated mechanisms.


Assuntos
Encefalopatias/etiologia , COVID-19/complicações , Síndrome da Liberação de Citocina/etiologia , Corticosteroides/uso terapêutico , Idoso , Barreira Hematoencefálica/fisiopatologia , Encéfalo/diagnóstico por imagem , Encefalopatias/fisiopatologia , Edema Encefálico/etiologia , COVID-19/metabolismo , COVID-19/fisiopatologia , Síndrome da Liberação de Citocina/metabolismo , Síndrome da Liberação de Citocina/fisiopatologia , Feminino , Humanos , Imunoglobulinas/uso terapêutico , AVC Isquêmico/diagnóstico , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/fisiopatologia , Resultado do Tratamento
18.
Neuron ; 109(1): 59-72.e5, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33147442

RESUMO

SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) complex, composed of synaptobrevin, syntaxin, and SNAP25, forms the essential fusion machinery for neurotransmitter release. Recent studies have reported several mutations in the gene encoding SNAP25 as a causative factor for developmental and epileptic encephalopathies of infancy and childhood with diverse clinical manifestations. However, it remains unclear how SNAP25 mutations give rise to these disorders. Here, we show that although structurally clustered mutations in SNAP25 give rise to related synaptic transmission phenotypes, specific alterations in spontaneous neurotransmitter release are a key factor to account for disease heterogeneity. Importantly, we identified a single mutation that augments spontaneous release without altering evoked release, suggesting that aberrant spontaneous release is sufficient to cause disease in humans.


Assuntos
Encefalopatias/genética , Encefalopatias/fisiopatologia , Transmissão Sináptica/genética , Proteína 25 Associada a Sinaptossoma/genética , Adolescente , Sequência de Aminoácidos , Animais , Células Cultivadas , Criança , Pré-Escolar , Feminino , Células HEK293 , Haploinsuficiência/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Estrutura Secundária de Proteína , Ratos , Ratos Sprague-Dawley , Proteína 25 Associada a Sinaptossoma/química
19.
Clin EEG Neurosci ; 52(1): 69-73, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32412802

RESUMO

Frontal intermittent rhythmic delta activity (FIRDA), rhythmic slow wave pattern lasting several seconds over the anterior leads of electroencephalography (EEG), has been reported in a wide variety of clinical conditions. We investigated the clinical significance of FIRDA without structural brain lesions. We reviewed 7689 EEGs between October 2017 and September 2019 at a university hospital. Patients (age >18 years) who were confirmed to have "nonsignificant neuroimaging" were examined. Clinical data were retrospectively collected, and the estimated cause was carefully decided. We found 83 FIRDA among 7689 EEGs (1.08%). After patients with any structural lesion identified on neuroimaging were excluded, 37 FIRDAs were reviewed. There were 20 (51.35%) patients of metabolic encephalopathy. Six patients showed FIRDA due to neurodegenerative disease (16.21%). In addition, we found 6 (16.21%) of neurodegenerative disease and 5 (13.51%) of hypoxic encephalopathy (cardiac arrest). Four (16.21%) patients were related to systemic infection (10.81%), whereas 2 were related to encephalitis (5.40%). We demonstrated several potential etiologies, including metabolic encephalopathy, neurodegenerative disease, hypoxic encephalopathy, and infections, which should be considered in the case of FIRDA without structural brain lesions.


Assuntos
Encefalopatias/fisiopatologia , Ritmo Delta/fisiologia , Lobo Frontal/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Adulto , Eletroencefalografia/métodos , Feminino , Humanos , Hipóxia Encefálica/fisiopatologia , Masculino
20.
Mol Psychiatry ; 26(1): 151-167, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32346158

RESUMO

Cognitive dysfunctions, including impaired attention, learning, memory, planning and problem solving, occur in depressive episodes, often persist during remission, predict relapse, worsen with recurrent episodes, and are not treated by current antidepressants or other medications. Cognitive symptoms are also present in other psychiatric disorders, are a hallmark of aging, and define several late-life disorders, including Alzheimer's disease. This pervasive occurrence suggests either a non-specific outcome of a diseased brain, or a shared underlying pathology contributing to this symptom dimension. Recent findings suggest a role for altered GABAergic inhibition in cognitive symptoms. Cellular, molecular and biochemical studies in human subjects report changes affecting the gamma-amino butyric acid (GABA) system, specifically somatostatin-expressing (SST+) GABAergic interneurons, across brain disorders and during aging. SST+ neurons gate excitatory input onto pyramidal neurons within cortical microcircuits. Experimentally reducing the function of these neurons affects excitatory signal-to-noise ratio, reduces synchronized cellular and neural activity, and leads to cognitive dysfunctions. Conversely, augmenting SST+ cell post-synaptic α5-GABA-A receptor activity has pro-cognitive efficacy in stress and aging models. Together, this suggests that reduced signaling of the SST+ neuron/α5-GABA-A receptor pathway contributes to cognitive dysfunctions, and that it represents a novel therapeutic target for remediating mood and cognitive symptoms in depression, other psychiatric disorders and during aging.


Assuntos
Encefalopatias/metabolismo , Encefalopatias/fisiopatologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Depressão/metabolismo , Depressão/fisiopatologia , Ácido gama-Aminobutírico/metabolismo , Cognição , Humanos , Interneurônios/metabolismo
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