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OBJECTIVES: To report an autoimmune paraneoplastic encephalitis characterized by immunoglobulin G (IgG) antibody targeting synaptic protein calmodulin kinase-like vesicle-associated (CAMKV). METHODS: Serum and cerebrospinal fluid (CSF) samples harboring unclassified antibodies on murine brain-based indirect immunofluorescence assay (IFA) were screened by human protein microarray. In 5 patients with identical cerebral IFA staining, CAMKV was identified as top-ranking candidate antigen. Western blots, confocal microscopy, immune-absorption, and mass spectrometry were performed to substantiate CAMKV specificity. Recombinant CAMKV-specific assays (cell-based [fixed and live] and Western blot) provided additional confirmation. RESULTS: Of 5 CAMKV-IgG positive patients, 3 were women (median symptom-onset age was 59 years; range, 53-74). Encephalitis-onset was subacute (4) or acute (1) and manifested with: altered mental status (all), seizures (4), hyperkinetic movements (4), psychiatric features (3), memory loss (2), and insomnia (2). Paraclinical testing revealed CSF lymphocytic pleocytosis (all 4 tested), electrographic seizures (3 of 4 tested), and striking MRI abnormalities in all (mesial temporal lobe T2 hyperintensities [all patients], caudate head T2 hyperintensities [3], and cortical diffusion weighted hyperintensities [2]). None had post-gadolinium enhancement. Cancers were uterine adenocarcinoma (3 patients: poorly differentiated or neuroendocrine-differentiated in 2, both demonstrated CAMKV immunoreactivity), bladder urothelial carcinoma (1), and non-Hodgkin lymphoma (1). Two patients developed encephalitis following immune checkpoint inhibitor cancer therapy (atezolizumab [1], pembrolizumab [1]). All treated patients (4) demonstrated an initial response to immunotherapy (corticosteroids [4], IVIG [2]), though 3 died from cancer. INTERPRETATION: CAMKV-IgG is a biomarker of immunotherapy-responsive paraneoplastic encephalitis with temporal and extratemporal features and uterine cancer as a prominent oncologic association. ANN NEUROL 2024;96:21-33.
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Autoanticorpos , Encefalite , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Encefalite/líquido cefalorraquidiano , Autoanticorpos/líquido cefalorraquidiano , Autoanticorpos/sangue , Masculino , Doença de Hashimoto/líquido cefalorraquidiano , Imunoglobulina G/líquido cefalorraquidiano , Imunoglobulina G/sangue , Síndromes Paraneoplásicas do Sistema Nervoso/líquido cefalorraquidiano , Síndromes Paraneoplásicas do Sistema Nervoso/imunologia , CamundongosRESUMO
Acute disseminated encephalomyelitis (ADEM) is one characteristic manifestation of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). A previously healthy man presented with retro-orbital headache and urinary retention 14 days after Tdap vaccination. Brain and spine MRI suggested a CNS demyelinating process. Despite treatment with IV steroids, he deteriorated, manifesting hemiparesis and later impaired consciousness, requiring intubation. A repeat brain MRI demonstrated new bilateral supratentorial lesions associated with venous sinus thrombosis, hemorrhage, and midline shift. Anti-MOG antibody was present at a high titer. CSF IL-6 protein was >2,000 times above the upper limits of normal. He improved after plasma exchange, then began monthly treatment alone with anti-IL-6 receptor antibody, tocilizumab, and has remained stable. This case highlights how adult-onset MOGAD, like childhood ADEM, can rapidly become life-threatening. The markedly elevated CSF IL-6 observed here supports consideration for evaluating CSF cytokines more broadly in patients with acute MOGAD.
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Encefalomielite Aguda Disseminada , Masculino , Adulto , Humanos , Criança , Interleucina-6/metabolismo , Glicoproteína Mielina-Oligodendrócito , Encéfalo/patologia , Citocinas/metabolismoRESUMO
OBJECTIVE: Co-occurring anti-tripartite motif-containing protein 9 and 67 autoantibodies (TRIM9/67-IgG) have been reported in only a very few cases of paraneoplastic cerebellar syndrome. The value of these biomarkers and the most sensitive methods of TRIM9/67-IgG detection are not known. METHODS: We performed a retrospective, multicenter study to evaluate the cerebrospinal fluid and serum of candidate TRIM9/67-IgG cases by tissue-based immunofluorescence, peptide phage display immunoprecipitation sequencing, overexpression cell-based assay (CBA), and immunoblot. Cases in which TRIM9/67-IgG was detected by at least 2 assays were considered TRIM9/67-IgG positive. RESULTS: Among these cases (n = 13), CBA was the most sensitive (100%) and revealed that all cases had TRIM9 and TRIM67 autoantibodies. Of TRIM9/67-IgG cases with available clinical history, a subacute cerebellar syndrome was the most common presentation (n = 7/10), followed by encephalitis (n = 3/10). Of these 10 patients, 70% had comorbid cancer (7/10), 85% of whom (n = 6/7) had confirmed metastatic disease. All evaluable cancer biopsies expressed TRIM9 protein (n = 5/5), whose expression was elevated in the cancerous regions of the tissue in 4 of 5 cases. INTERPRETATION: TRIM9/67-IgG is a rare but likely high-risk paraneoplastic biomarker for which CBA appears to be the most sensitive diagnostic assay. ANN NEUROL 2023;94:1086-1101.
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Proteínas do Tecido Nervoso , Degeneração Paraneoplásica Cerebelar , Humanos , Estudos Retrospectivos , Proteínas do Tecido Nervoso/metabolismo , Biomarcadores/líquido cefalorraquidiano , Autoanticorpos/líquido cefalorraquidiano , Imunoglobulina GRESUMO
The evaluation of new seizures is a common clinical query for neurologists. It can be challenging to delineate between the numerous etiologies of new focal or generalized seizures and, if focal, to localize their onset. In this case report, we present a 26-year-old patient with a new onset of stereotyped events concerning for seizures featuring facial grimacing, dystonic left-hand posturing, and convulsions with immediate return to baseline. Throughout the case, we highlight a stepwise diagnostic approach to the evaluation of new-onset seizures, discuss clues that seizure semiology can provide for localization of ictal onset, and review a novel and atypical presentation of a disease entity frequently encountered by neurologists.
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Eletroencefalografia , Convulsões , Humanos , Adulto Jovem , Adulto , Convulsões/diagnóstico , Convulsões/etiologia , Raciocínio ClínicoRESUMO
A patient in California, USA, with rare and usually fatal Balamuthia mandrillaris granulomatous amebic encephalitis survived after receiving treatment with a regimen that included the repurposed drug nitroxoline. Nitroxoline, which is a quinolone typically used to treat urinary tract infections, was identified in a screen for drugs with amebicidal activity against Balamuthia.
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Amebíase , Balamuthia mandrillaris , Encefalite Infecciosa , Humanos , Amebíase/tratamento farmacológico , Granuloma , EncéfaloRESUMO
BACKGROUND: Eosinophilic meningitis is uncommon and often attributed to infectious causes. CASE PRESENTATION: We describe a case of a 72-year-old man who presented with subacute onset eosinophilic meningitis, vasculitis, and intracranial hypertension with progressive and severe neurologic symptoms. Brain MRI demonstrated multifocal strokes and co-localized right temporo-parieto-occipital vasogenic edema, cortical superficial siderosis, and diffuse leptomeningeal enhancement. He ultimately underwent brain biopsy with immunohistochemical stains for amyloid-ß and Congo red that were extensively positive in the blood vessel walls and in numerous diffuse and neuritic parenchymal confirming a diagnosis of amyloid-ß related angiitis. He was treated with immunosuppression with clinical stabilization. CONCLUSIONS: Amyloid-ß related angiitis is an underrecognized cause of eosinophilic meningitis that can present fulminantly and is typically responsive to immunosuppression. The presence of eosinophils may provide additional clues to the underlying pathophysiology of amyloid-ß related angiitis.
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Meningite , Vasculite , Idoso , Peptídeos beta-Amiloides , Biópsia , Humanos , Imageamento por Ressonância Magnética , Masculino , Meningite/complicações , Meningite/diagnóstico , Vasculite/complicações , Vasculite/diagnóstico , Vasculite/patologiaRESUMO
A 67-year-old woman was admitted to our hospital for progressive weakness, dysphagia, muscle pain, and weight loss. Here we detail the clinical problem solving involved in diagnosing and treating her immune-mediated necrotizing myopathy caused by anti-HMGCoA reductase autoantibodies. Interestingly, this diagnosis coincided with discovery of a gastrointestinal stromal tumor (GIST) and positivity for anti-nuclear matrix protein (anti-NXP2), another myositis specific autoantibody.
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We present a case of a healthy 62-year-old woman who developed recurrent seizures preceded by subacute cognitive slowing, ataxia, night sweats, and weight loss. She was found to have cytopenias, multifocal T2/FLAIR hyperintensities on magnetic resonance imaging (MRI), and magnetic susceptibility artifact lesions on susceptibility weighted imaging (SWI). Her symptoms, imaging and laboratory abnormalities all improved with high-doses of steroids and intravenous immunoglobulin (IVIG). But recurred several weeks after completing treatment. Despite extensive work-up, she required multiple hospitalizations and repeat diagnostic studies to arrive at a diagnosis. With an expert discussant in hematology and oncology, we review the differential diagnosis and stepwise approach of unexplained neuro-inflammatory syndromes with cytopenias and systemic symptoms. Our case highlights how time, empiric treatment response, and repeated diagnostic studies refine differential diagnoses and subsequent evaluation. After revealing the diagnosis, we discuss the heterogenous clinical manifestations of this disease process.
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Myelopathy can present acutely or more insidiously and has a broad differential diagnosis. In addition to the clinical history and neurologic examination, diagnostic testing, including MRI and cerebrospinal fluid analysis, as well as thorough review of patient comorbidities, risk factors, and potential toxic exposures, can help neurohospitalists distinguish between various causes and potentially start appropriate empiric therapy while awaiting definitive testing. This article focuses on how imaging can help in determining the most likely cause of myelopathy and highlights a range of causes, including compressive, vascular, metabolic and toxic, infectious, autoimmune, neoplastic, and paraneoplastic causes of spinal cord dysfunction.
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Mielite Transversa , Doenças da Medula Espinal , Diagnóstico Diferencial , Humanos , Imageamento por Ressonância Magnética , Mielite Transversa/diagnóstico , Mielite Transversa/etiologia , Mielite Transversa/terapia , Medula Espinal/irrigação sanguínea , Doenças da Medula Espinal/diagnóstico por imagem , Doenças da Medula Espinal/etiologiaRESUMO
Importance: Cerebrospinal fluid (CSF) cytologic testing and flow cytometry are insensitive for diagnosing neoplasms of the central nervous system (CNS). Such clinical phenotypes can mimic infectious and autoimmune causes of meningoencephalitis. Objective: To ascertain whether CSF metagenomic next-generation sequencing (mNGS) can identify aneuploidy, a hallmark of malignant neoplasms, in difficult-to-diagnose cases of CNS malignant neoplasm. Design, Setting, and Participants: Two case-control studies were performed at the University of California, San Francisco (UCSF). The first study used CSF specimens collected at the UCSF Clinical Laboratories between July 1, 2017, and December 31, 2019, and evaluated test performance in specimens from patients with a CNS malignant neoplasm (positive controls) or without (negative controls). The results were compared with those from CSF cytologic testing and/or flow cytometry. The second study evaluated patients who were enrolled in an ongoing prospective study between April 1, 2014, and July 31, 2019, with presentations that were suggestive of neuroinflammatory disease but who were ultimately diagnosed with a CNS malignant neoplasm. Cases of individuals whose tumors could have been detected earlier without additional invasive testing are discussed. Main Outcomes and Measures: The primary outcome measures were the sensitivity and specificity of aneuploidy detection by CSF mNGS. Secondary subset analyses included a comparison of CSF and tumor tissue chromosomal abnormalities and the identification of neuroimaging characteristics that were associated with test performance. Results: Across both studies, 130 participants were included (median [interquartile range] age, 57.5 [43.3-68.0] years; 72 men [55.4%]). The test performance study used 125 residual laboratory CSF specimens from 47 patients with a CNS malignant neoplasm and 56 patients with other neurological diseases. The neuroinflammatory disease study enrolled 12 patients and 17 matched control participants. The sensitivity of the CSF mNGS assay was 75% (95% CI, 63%-85%), and the specificity was 100% (95% CI, 96%-100%). Aneuploidy was detected in 64% (95% CI, 41%-83%) of the patients in the test performance study with nondiagnostic cytologic testing and/or flow cytometry, and in 55% (95% CI, 23%-83%) of patients in the neuroinflammatory disease study who were ultimately diagnosed with a CNS malignant neoplasm. Of the patients in whom aneuploidy was detected, 38 (90.5%) had multiple copy number variations with tumor fractions ranging from 31% to 49%. Conclusions and Relevance: This case-control study showed that CSF mNGS, which has low specimen volume requirements, does not require the preservation of cell integrity, and was orginally developed to diagnose neurologic infections, can also detect genetic evidence of a CNS malignant neoplasm in patients in whom CSF cytologic testing and/or flow cytometry yielded negative results with a low risk of false-positive results.
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Biomarcadores Tumorais/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Metagenômica , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Análise de Sequência de DNA/métodosRESUMO
Herein, the micropatterning of supramolecular gels with oriented growth direction and controllable spatial dimensions by directing the self-assembly of small molecular gelators is reported. This process is associated with an acid-catalyzed formation of gelators from two soluble precursor molecules. To control the localized formation and self-assembly of gelators, micropatterned poly(acrylic acid) (PAA) brushes are employed to create a local and controllable acidic environment. The results show that the gel formation can be well confined in the catalytic surface plane with dimensions ranging from micro- to centimeter. Furthermore, the gels show a preferential growth along the normal direction of the catalytic surface, and the thickness of the resultant gel patterns can be easily controlled by tuning the grafting density of PAA brushes. This work shows an effective "bottom-up" strategy toward control over the spatial organization of materials and is expected to find promising applications in, e.g., microelectronics, tissue engineering, and biomedicine.
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Géis/química , Engenharia Tecidual/métodos , Resinas Acrílicas/química , CatáliseRESUMO
Importance: Identifying infectious causes of subacute or chronic meningitis can be challenging. Enhanced, unbiased diagnostic approaches are needed. Objective: To present a case series of patients with diagnostically challenging subacute or chronic meningitis using metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) supported by a statistical framework generated from mNGS of control samples from the environment and from patients who were noninfectious. Design, Setting, and Participants: In this case series, mNGS data obtained from the CSF of 94 patients with noninfectious neuroinflammatory disorders and from 24 water and reagent control samples were used to develop and implement a weighted scoring metric based on z scores at the species and genus levels for both nucleotide and protein alignments to prioritize and rank the mNGS results. Total RNA was extracted for mNGS from the CSF of 7 participants with subacute or chronic meningitis who were recruited between September 2013 and March 2017 as part of a multicenter study of mNGS pathogen discovery among patients with suspected neuroinflammatory conditions. The neurologic infections identified by mNGS in these 7 participants represented a diverse array of pathogens. The patients were referred from the University of California, San Francisco Medical Center (n = 2), Zuckerberg San Francisco General Hospital and Trauma Center (n = 2), Cleveland Clinic (n = 1), University of Washington (n = 1), and Kaiser Permanente (n = 1). A weighted z score was used to filter out environmental contaminants and facilitate efficient data triage and analysis. Main Outcomes and Measures: Pathogens identified by mNGS and the ability of a statistical model to prioritize, rank, and simplify mNGS results. Results: The 7 participants ranged in age from 10 to 55 years, and 3 (43%) were female. A parasitic worm (Taenia solium, in 2 participants), a virus (HIV-1), and 4 fungi (Cryptococcus neoformans, Aspergillus oryzae, Histoplasma capsulatum, and Candida dubliniensis) were identified among the 7 participants by using mNGS. Evaluating mNGS data with a weighted z score-based scoring algorithm reduced the reported microbial taxa by a mean of 87% (range, 41%-99%) when taxa with a combined score of 0 or less were removed, effectively separating bona fide pathogen sequences from spurious environmental sequences so that, in each case, the causative pathogen was found within the top 2 scoring microbes identified using the algorithm. Conclusions and Relevance: Diverse microbial pathogens were identified by mNGS in the CSF of patients with diagnostically challenging subacute or chronic meningitis, including a case of subarachnoid neurocysticercosis that defied diagnosis for 1 year, the first reported case of CNS vasculitis caused by Aspergillus oryzae, and the fourth reported case of C dubliniensis meningitis. Prioritizing metagenomic data with a scoring algorithm greatly clarified data interpretation and highlighted the problem of attributing biological significance to organisms present in control samples used for metagenomic sequencing studies.
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Meningite/diagnóstico , Metagenoma/genética , Adolescente , Adulto , Animais , Aspergillus oryzae/genética , Candida/genética , Candidíase/líquido cefalorraquidiano , Candidíase/diagnóstico , Criança , Doença Crônica , Cryptococcus neoformans/genética , Feminino , Infecções por HIV/líquido cefalorraquidiano , Infecções por HIV/diagnóstico , HIV-1/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Histoplasma/genética , Histoplasmose/líquido cefalorraquidiano , Histoplasmose/diagnóstico , Humanos , Masculino , Meningite/líquido cefalorraquidiano , Meningite/microbiologia , Meningite Criptocócica/líquido cefalorraquidiano , Meningite Criptocócica/diagnóstico , Metagenômica , Pessoa de Meia-Idade , Neuroaspergilose/líquido cefalorraquidiano , Neuroaspergilose/diagnóstico , Neurocisticercose/líquido cefalorraquidiano , Neurocisticercose/diagnóstico , Análise de Sequência de RNA/métodos , Taenia solium/genética , Adulto JovemRESUMO
The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient's case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant. This icon represents the patient's case. Each paragraph that follows represents the discussant's thoughts.
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Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Diagnóstico Diferencial , Glutationa Sintase/deficiência , Síndrome de Guillain-Barré/diagnóstico , Debilidade Muscular/etiologia , Complicações Pós-Operatórias , Feminino , Derivação Gástrica , Síndrome de Guillain-Barré/patologia , Humanos , Pessoa de Meia-Idade , Obesidade/cirurgiaRESUMO
Drug eluting stents are considered the "gold standard" for the percutaneous treatment of coronary artery disease. Recent publications have suggested that a reasonable alternative, in well selected cases, may be the ABSORBTM bioresorbable vascular scaffold (BVS) stent. © 2016 Wiley Periodicals, Inc.
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Implantes Absorvíveis , Doença da Artéria Coronariana/cirurgia , Vasos Coronários/cirurgia , Aprovação de Drogas , Stents Farmacológicos , Alicerces Teciduais , Idoso , Idoso de 80 Anos ou mais , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico , Vasos Coronários/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Desenho de Prótese , Estados Unidos , United States Food and Drug AdministrationRESUMO
After severe neurocognitive decline developed in an otherwise healthy 63-year-old man, brain magnetic resonance imaging showed eosinophilic meningoencephalitis and enhancing lesions. The patient tested positive for antibodies to Baylisascaris spp. roundworms, was treated with albendazole and dexamethasone, and showed improvement after 3 months. Baylisascariasis should be considered for all patients with eosinophilic meningitis.