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BACKGROUND: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a poorly understood and heterogeneous manifestation of SLE. Common major NPSLE syndromes include strokes, seizures, myelitis, and aseptic meningitis. Easily obtainable biomarkers are needed to assist in early diagnosis and improve outcomes for NPSLE. A frequent end-result of major syndromes is neuronal or glial injury. Blood-based neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) have been utilized as markers for monitoring disease activity and/or severity in other neurodegenerative and neuroinflammatory diseases; however, they have not been evaluated in active major NPSLE. METHODS: This was a case-control study. We enrolled patients aged 12-60 years with active major NPSLE, SLE without active major NPSLE, and healthy controls. Active NPSLE was defined as being <6 months from last new or worsening neuropsychiatric symptom. Demographics, clinical data, and serum or plasma biosamples were collected. RESULTS: Thirteen patients with active major NPSLE, 13 age/sex/kidney function matched SLE controls without active major NPSLE, and 13 age/sex matched healthy controls (mean ages 26.8, 27.3, 26.6 years) were included. 92% of each group were female. Major syndromes included stroke (5), autonomic disorder (3), demyelinating disease (2), aseptic meningitis (2), sensorimotor polyneuropathy (2), cranial neuropathy (1), seizures (1), and myelopathy (2). Mean (standard deviation) blood NfL and GFAP were 3.6 pg/ml (2.0) and 50.4 pg/ml (15.0), respectively, for the healthy controls. Compared to healthy controls, SLE without active major NPSLE had mean blood NfL and GFAP levels 1.3 pg/ml (p = .42) and 1.2 pg/ml higher (p = .53), respectively. Blood NfL was on average 17.9 pg/ml higher (95% CI: 9.2, 34.5; p < .001) and blood GFAP was on average 3.2 pg/ml higher (95% CI: 1.9, 5.5; p < .001) for cases of active major NPSLE compared to SLE without active major NPSLE. In a subset of 6 patients sampled at multiple time points, blood NfL and GFAP decreased after immunotherapy. CONCLUSIONS: Blood NfL and GFAP levels are elevated in persons with SLE with active major NPSLE compared to disease matched controls and may lower after immunotherapy initiation. Larger and longitudinal studies are needed to ascertain their utility in a clinical setting.
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Neuroimmunology is rapidly evolving field extending from well-known, but incompletely understood conditions like multiple sclerosis, to novel antibody-mediated disorders, of which dozens have been described in the past 10 years. The ongoing expansion in knowledge needed to effectively diagnose and treat these patients presents myriad challenges for clinicians. Here, we discuss six informative cases from our institution. By highlighting these challenging cases, we hope to instill fundamental points on the nuances of diagnosis and management for conditions including tumefactive multiple sclerosis, antibody-mediated encephalitis, antiphospholipid antibody syndrome, neuromyelitis optica, and myelin oligodendrocyte glycoprotein IgG-associated disease.
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Esclerose Múltipla , Neuromielite Óptica , Humanos , Glicoproteína Mielina-Oligodendrócito , Autoanticorpos , Imunoglobulina GRESUMO
Multiple sclerosis is being increasingly recognized and diagnosed in children. In the past several years, advances have been made in diagnosing multiple sclerosis in children, identifying new genetic and environmental risk factors, delineating underlying immunobiology, characterizing imaging findings, and implementing new treatment strategies. In this review, we discuss these advances. Future research into the determinants of multiple sclerosis in children and into new treatment options will be aided by continued international collaboration.
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Esclerose Múltipla/diagnóstico , Esclerose Múltipla/etiologia , Esclerose Múltipla/terapia , Criança , HumanosRESUMO
Insulin resistance creates an environment that promotes ß-cell failure and development of diabetes. Understanding the events that lead from insulin resistance to diabetes is necessary for development of effective preventional and interventional strategies, and model systems that reflect the pathophysiology of disease progression are an important component toward this end. We have confirmed that insulin enhances glucose uptake in zebrafish skeletal muscle and have developed a zebrafish model of skeletal muscle insulin resistance using a dominant-negative IGF-IR. These zebrafish exhibit blunted insulin signaling and glucose uptake in the skeletal muscle, confirming insulin resistance. In young animals, we observed an increase in the number of ß-cells and normal glucose tolerance that was indicative of compensation for insulin resistance. In older animals, the ß-cell mass was reduced to that of control with the appearance of impaired glucose clearance but no elevation in fasting blood glucose. Combined with overnutrition, the insulin-resistant animals have an increased fasting blood glucose compared with the control animals, demonstrating that the ß-cells in the insulin-resistant fish are in a vulnerable state. The relatively slow progression from insulin resistance to glucose intolerance in this model system has the potential in the future to test cooperating genes or metabolic conditions that may accelerate the development of diabetes and provide new therapeutic targets.
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Envelhecimento , Intolerância à Glucose/etiologia , Resistência à Insulina , Células Secretoras de Insulina/patologia , Músculo Esquelético/metabolismo , Hipernutrição/fisiopatologia , Receptor IGF Tipo 1/metabolismo , Animais , Animais Geneticamente Modificados , Transporte Biológico , Contagem de Células , Progressão da Doença , Glucose/metabolismo , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Intolerância à Glucose/fisiopatologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hiperglicemia/etiologia , Insulina/genética , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Células Secretoras de Insulina/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Receptor IGF Tipo 1/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Proteína Vermelha FluorescenteRESUMO
OBJECTIVE: Bystander cardiopulmonary resuscitation (CPR) provides treatment for out-of-hospital cardiac arrest since perfusion of vital organs is critical to resuscitation. Alternatives to standard CPR are evaluated for effectiveness based upon outcome predictive metrics and survival studies. This study focuses on evaluating the performance of rhythmic-only abdominal compression CPR (OAC-CPR) relative to chest compression (CC-CPR) using a complementary suite of mechanistically based CPR outcome predictors. Combined, these predictors provide insight on the transduction of compression-induced pressures into flow perfusing vital organs. METHODS: Intrasubject comparisons between the CPR techniques were made during multiple 2-min intervals of induced fibrillation in 17 porcine subjects. Arterial pO2, cardiac output, carotid blood flow, coronary perfusion pressure (CPP), minute alveolar ventilation (MAV), end-tidal CO2, and time from defibrillation to the return of spontaneous circulation (ROSC) were recorded. Organ damage was assessed by necropsy. RESULTS: Compared with CC-CPR, OAC-CPR had higher pressure and ventilation metrics with increased relative CPP (+16â mmâ Hg), MAV (+75/ml/min/kg) and a lower reduction in arterial pO2(-22% baseline), but suffered from lower carotid flows (-9.3â ml/min). No significant difference was found comparing cardiac outputs. Furthermore, resuscitation was qualitatively more difficult after OAC-CPR, with a longer time to ROSC (+70â s). No abdominal damage was observed over short periods of OAC-CPR. CONCLUSIONS: Although OAC-CPR appeared superior to CC-CPR by pressure and ventilation metrics, lower carotid flow and longer delay until ROSC raise concerns about overall performance. These paradoxical observations suggest that the evaluation of efficacious alternative CPR techniques may require more direct measurements of vital organ perfusion.
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Reanimação Cardiopulmonar/métodos , Fibrilação Ventricular/terapia , Animais , Pressão Sanguínea/fisiologia , Débito Cardíaco/fisiologia , Reanimação Cardiopulmonar/efeitos adversos , Artérias Carótidas/fisiologia , Circulação Coronária/fisiologia , Modelos Animais de Doenças , Feminino , Masculino , Avaliação de Resultados em Cuidados de Saúde , Ventilação Pulmonar/fisiologia , Fluxo Sanguíneo Regional/fisiologia , Suínos , Fibrilação Ventricular/fisiopatologiaRESUMO
OBJECTIVE: To determine the prevalence of neuroimaging abnormalities in individuals with Down syndrome regression disorder (DSRD) and evaluate if neuroimaging abnormalities were predictive of therapeutic responses. METHODS: A multicenter, retrospective, case-control study which reviewed neuroimaging studies of individuals with DSRD and compared them to a control cohort of individuals with Down syndrome (DS) alone was performed. Individuals aged 10-30 years and meeting international consensus criteria for DSRD were included. The presence of T1, T2/FLAIR, and SWI signal abnormalities was reviewed. Response rates to various therapies, including immunotherapy, were evaluated in the presence of neuroimaging abnormalities. RESULTS: In total, 74 individuals (35%) had either T2/FLAIR and/or SWI signal abnormality compared to 14 individuals (12%) without DSRD (p < 0.001, 95%CI: 2.18-7.63). T2/FLAIR signal abnormalities were not appreciated more frequently in individuals with DSRD (14%, 30/210) than in the control cohort (9%, 11/119) (p = 0.18, OR: 1.63, 95%CI: 0.79-3.40). SWI signal abnormalities were appreciated at a higher frequency in individuals with DSRD (24%, 51/210) compared to the control cohort (4%, 5/119) (p < 0.001, OR: 7.31, 95%CI: 2.83-18.90). T2/FLAIR signal abnormalities were localized to the frontal (40%, 12/30) and parietal lobes (37%, 11/30). SWI signal abnormalities were predominantly in the bilateral basal ganglia (94%, 49/52). Individuals with DSRD and the presence of T2/FLAIR and/or SWI signal abnormalities were much more likely to respond to immunotherapy (p < 0.001, OR: 8.42. 95%CI: 3.78-18.76) and less likely to respond to benzodiazepines (p = 0.01, OR: 0.45, 95%CI: 0.25-0.83), antipsychotics (p < 0.001, OR: 0.28, 95%CI: 0.11-0.55), or electroconvulsive therapy (p < 0.001, OR: 0.12; 95%CI: 0.02-0.78) compared to individuals without these neuroimaging abnormalities. INTERPRETATION: This study indicates that in individuals diagnosed with DSRD, T2/FLAIR, and SWI signal abnormalities are more common than previously thought and predict response to immunotherapy.
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Síndrome de Down , Humanos , Síndrome de Down/terapia , Estudos Retrospectivos , Estudos de Casos e Controles , Neuroimagem/métodos , ImunoterapiaRESUMO
BACKGROUND: Isolated psychiatric symptoms can be the initial symptom of pediatric anti-N-methyl-d-aspartate (NMDA) receptor autoimmune encephalitis (pNMDARE). Here we report on the prevalence of isolated psychiatric symptoms in pNMDARE. We also assess whether initial neurodiagnostic tests (brain magnetic resonance imaging [MRI], electroencephalography [EEG], and/or cerebrospinal fluid [CSF] white blood cell count) are abnormal in children with isolated psychiatric symptoms and pNMDARE. METHODS: This multicenter retrospective cohort study from CONNECT (Conquering Neuroinflammation and Epilepsies Consortium) from 14 institutions included children under age 18 years who were diagnosed with pNMDARE. Descriptive statistics using means, medians, and comparisons for continuous versus discrete data was performed. RESULTS: Of 249 children included, 12 (5%) had only psychiatric symptoms without other typical clinical features of autoimmune encephalitis at presentation. All but one (11 of 12 = 92%) had at least one abnormal finding on initial ancillary testing: eight of 12 (67%) had an abnormal EEG, six of 12 (50%) had an abnormal MRI, and five of 12 (42%) demonstrated CSF pleocytosis. The single patient with a normal MRI, EEG, and CSF profile had low positive CSF NMDA antibody (titer of 1:1), and symptoms improved without immunotherapy. CONCLUSIONS: Isolated first-episode psychiatric symptoms in pNMDARE are uncommon, and the majority of children will exhibit additional neurodiagnostic abnormalities. Delaying immunotherapy in a child with isolated psychiatric symptoms and normal neurodiagnostic testing may be warranted while awaiting confirmatory antibody testing.
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OBJECTIVE: There has been increasing utilization of genetic testing for pediatric epilepsy in recent years. Little systematic data is available examining how practice changes have impacted testing yields, diagnostic pace, incidence of variants of uncertain significance (VUSs), or therapeutic management. METHODS: A retrospective chart review was performed at Children's Hospital Colorado from February 2016 through February 2020. All patients under 18 years for whom an epilepsy gene panel was sent were included. RESULTS: A total of 761 epilepsy gene panels were sent over the study period. During the study period, there was a 292% increase in the average number of panels sent per month. The time from seizure onset to panel result decreased over the study period from a median of 2.9 years to 0.7 years. Despite the increase in testing, the percentage of panels yielding a disease-causing result remained stable at 11-13%. A total of 90 disease-causing results were identified, > 75% of which provided guidance in management. Children were more likely to have a disease-causing result if they were < 3 years old at seizure onset (OR 4.4, p < 0.001), had neurodevelopmental concerns (OR 2.2, p = 0.002), or had a developmentally abnormal MRI (OR 3.8, p < 0.001). A total of 1417 VUSs were identified, equating to 15.7 VUSs per disease-causing result. Non-Hispanic white patients had a lower average number of VUSs than patients of all other races/ethnicities (1.7 vs 2.1, p < 0.001). SIGNIFICANCE: Expansion in the volume of genetic testing corresponded to a decrease in the time from seizure onset to testing result. Diagnostic yield remained stable, resulting in an increase in the absolute number of disease-causing results annually-most of which have implications for management. However, there has also been an increase in total VUSs, which likely resulted in additional clinical time spent on VUS resolution.
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Epilepsia , Predisposição Genética para Doença , Humanos , Criança , Adolescente , Pré-Escolar , Estudos Retrospectivos , Testes Genéticos/métodos , Epilepsia/diagnóstico , Epilepsia/genética , Epilepsia/terapia , Convulsões/genéticaRESUMO
Jaw dystonia and laryngospasm in the context of subacute brainstem dysfunction have been described in a small number of diseases, including antineuronal nuclear antibody type 2 (ANNA-2, also known as anti-Ri) paraneoplastic neurologic syndrome. Severe episodes of laryngospasms causing cyanosis are potentially fatal. Jaw dystonia can also cause eating difficulty, resulting in severe weight loss and malnutrition. In this report, we highlight the multidisciplinary management of this syndrome associated with ANNA-2/anti-Ri paraneoplastic neurologic syndrome and discuss its pathogenesis.
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Distonia , Laringismo , Síndromes Paraneoplásicas do Sistema Nervoso , Humanos , Laringismo/complicações , Laringismo/diagnóstico , Diplopia , Distonia/diagnóstico , Distonia/etiologia , Anticorpos AntinuclearesRESUMO
Cognitive dysfunction (CD) is a neurologic complication of pediatric systemic lupus erythematosus (SLE) that remains poorly understood and understudied, despite the potential negative effects of CD on long-term socioeconomic status and quality of life. Data regarding the prevalence and risk factors for CD in pediatric SLE as well as the optimal screening, treatment, and long-term outcomes for CD are lacking. In this review, we present current knowledge on CD in pediatric SLE with a focus on the application to clinical practice. We discuss the challenges in diagnosis, clinical screening methods, potential impacts, and interventions for this complication. Finally, we discuss the remaining gaps in our knowledge of CD in pediatric SLE, and avenues for future research efforts.
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Emerging evidence is encouraging and suggests that a substantial proportion of patients without antibody responses (due to anti-CD20 therapy or other etiologies) to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines develop T cell responses. However, antigen-specific T cellular responses are notoriously difficult to assess clinically, given the lack of such assays under satisfactory CAP/CLIA regulation, and the laborious nature of the flow cytometric assessment. To evaluate the ability to apply a clinically feasible assay to measure T cellular responses to SARS-CoV-2 mRNA vaccination, we compared flow cytometric and enzyme-linked immunosorbent assay (ELISA) based assays in 24 participants treated with anti-CD20 therapy. T cellular activation (CD69 + CD137+ surface expression, i.e., activation induced markers [AIM]) and intracellular interferon gamma (INFγ) production via flow cytometry was compared to plasma Interferon Gamma Release Assay (IGRA) via ELISA. Plasma INFγ production measured by IGRA correlated with the percent of INFγ-producing AIM positive T cells, supporting the use of IGRA assay as a robust assessment of T cellular response to the SARS-CoV-2 vaccine for B-cell depleted patients that is clinically feasible, time efficient, and cost effective.
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Vacinas contra COVID-19 , COVID-19 , Interferon gama , Linfócitos T , Humanos , Anticorpos Antivirais , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Interferon gama/imunologia , SARS-CoV-2 , Linfócitos T/imunologia , Linfócitos BRESUMO
OBJECTIVES: How brain MRI lesions associate with outcomes in pediatric anti-NMDA receptor encephalitis (pNMDARE) is unknown. In this study, we correlate T2-hyperintense MRI brain lesions with clinical outcomes in pNMDARE. METHODS: This was a multicenter retrospective cohort study from 11 institutions. Children younger than 18 years with pNMDARE were included. One-year outcomes were assessed by the modified Rankin Score (mRS) with good (mRS ≤2) and poor (mRS ≥3) outcomes. RESULTS: A total of 175 pNMDARE subjects were included, with 1-year mRS available in 142/175 (81%) and 60/175 (34%) had abnormal brain MRIs. The most common T2-hyperintense lesion locations were frontal, temporal, and parietal. MRI features that predicted poor 1-year outcomes included abnormal MRI, particularly T2 lesions in the frontal and occipital lobes. After adjusting for treatment within 4 weeks of onset, improvement within 4 weeks, and intensive care unit admission, MRI features were no longer associated with poor outcomes, but after multiple imputation for missing data, T2 frontal and occipital lesions associated with poor outcomes. DISCUSSION: Abnormal frontal and occipital lesions on MRI may associate with 1-year mRS in pNMDARE. MRI of the brain may be a helpful prognostication tool that should be examined in future studies.
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Encefalite Antirreceptor de N-Metil-D-Aspartato , Humanos , Criança , Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico por imagem , Encefalite Antirreceptor de N-Metil-D-Aspartato/patologia , Estudos Retrospectivos , Imageamento por Ressonância Magnética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Lobo OccipitalRESUMO
Down syndrome regression disorder (DSRD) is a clinical symptom cluster consisting of neuropsychiatric regression without an identifiable cause. This study evaluated the clinical effectiveness of IVIg and evaluated clinical characteristics associated with relapse after therapy discontinuation. A prospective, multi-center, non-randomized, observational study was performed. Patients met criteria for DSRD and were treated with IVIg. All patients underwent a standardized wean off therapy after 9-12 months of treatment. Baseline, on therapy, and relapse scores of the Neuropsychiatric Inventory Total Score (NPITS), Clinical Global Impression-Severity (CGI-S), and the Bush-Francis Catatonia Rating Scale (BFCRS) were used to track clinical symptoms. Eighty-two individuals were enrolled in this study. Patients had lower BFCRS (MD: -6.68; 95% CI: -8.23, -5.14), CGI-S (MD: -1.27; 95% CI: -1.73, -0.81), and NPITS scores (MD: -6.50; 95% CI: -7.53, -5.47) while they were on therapy compared to baseline. Approximately 46% of the patients (n = 38) experienced neurologic relapse with wean of IVIg. Patients with neurologic relapse were more likely to have any abnormal neurodiagnostic study (χ2 = 11.82, p = 0.001), abnormal MRI (χ2 = 7.78, p = 0.005), and abnormal LP (χ2 = 5.45, p = 0.02), and a personal history of autoimmunity (OR: 6.11, p < 0.001) compared to patients without relapse. IVIg was highly effective in the treatment of DSRD. Individuals with a history of personal autoimmunity or neurodiagnostic abnormalities were more likely to relapse following weaning of immunotherapy, indicating the potential for, a chronic autoimmune etiology in some cases of DSRD.
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Down syndrome regression disorder (DSRD) is a clinical symptom cluster consisting of neuropsychiatric regression without an identifiable cause. This study evaluated the clinical effectiveness of IVIg and evaluated clinical characteristics associated with relapse after therapy discontinuation. A prospective, multi-center, non-randomized, observational study was performed. Patients met criteria for DSRD and were treated with IVIg. All patients underwent a standardized wean-off therapy after 9-12 months of treatment. Baseline, on-therapy, and relapse scores of the Neuropsychiatric Inventory Total Score (NPITS), Clinical Global Impression-Severity (CGI-S), and the Bush-Francis Catatonia Rating Scale (BFCRS) were used to track clinical symptoms. Eighty-two individuals were enrolled in this study. Patients had lower BFCRS (MD: -6.68; 95% CI: -8.23, -5.14), CGI-S (MD: -1.27; 95% CI: -1.73, -0.81), and NPITS scores (MD: -6.50; 95% CI: -7.53, -5.47) while they were on therapy compared to baseline. Approximately 46% of the patients (n = 38) experienced neurologic relapse with wean of IVIg. Patients with neurologic relapse were more likely to have any abnormal neurodiagnostic study (χ2 = 11.82, P = 0.001), abnormal MRI (χ2 = 7.78, P = 0.005), and abnormal LP (χ2 = 5.45, P = 0.02), and a personal history of autoimmunity (OR: 6.11, P < 0.001) compared to patients without relapse. IVIg was highly effective in the treatment of DSRD. Individuals with a history of personal autoimmunity or neurodiagnostic abnormalities were more likely to relapse following weaning of immunotherapy, indicating the potential for, a chronic autoimmune etiology in some cases of DSRD.
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Síndrome de Down , Humanos , Síndrome de Down/terapia , Imunoglobulinas Intravenosas , Estudos Prospectivos , Imunoterapia , RecidivaRESUMO
Myelopathy is an increasingly recognized presentation of many antibody-mediated neuroinflammatory disorders. While specific features of certain autoimmune myelopathies such as aquaporin-4 antibody associated neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein associated disorder (MOGAD) are well-characterized, other less commonly seen antibody-associated myelopathies are not as well-defined. These include but are not limited to, Hu/ANNA1, anti-glial fibrillary acidic protein (GFAP), anti-CV2/collapsin response mediator protein (CRMP5), and amphiphysin. Here, we review the mentioned more common antibody mediated myelopathies as well those that as less common, followed by a review of differentials that may mimic these disorders.
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Objective: To evaluate the sensitivity and specificity of current criteria for the diagnosis of autoimmune encephalitis (AE) and the temporal onset of neuropsychiatric symptoms (NP) in a pediatric encephalitis cohort. Background: Multiple criteria for AE have been developed, including the Graus and pediatric-focused Cellucci consensus criteria, and the Determining Etiology in Encephalitis (DEE) score for patients with encephalitis. Early identification and treatment of AE is crucial to improve outcomes, but this can be difficult given the frequent overlap of clinical presentation between AE and infectious encephalitis (IE). Design/methods: A retrospective review was conducted of patients seen at our institution from 2000 to 2021 with a final diagnosis of AE or IE. These were narrowed through multiple exclusions to etiology-confirmed IE or antibody-positive/negative AE. Time of onset or results of all symptoms and diagnostics were recorded. Sensitivity and specificity of each criterion under various clinical scenarios were calculated over the first month after initial NP symptom onset. Results: A total of 23 antibody-positive AE, 9 antibody-negative AE and 23 IE patients were included in final analysis. Under an idealized scenario with rapid initial diagnostic evaluations, the sensitivity for pediatric AE by day 28 after onset of NP symptoms approached 90% for both Cellucci and Graus criteria. Specificity within these 28 days was low without infectious testing results, increasing the greatest with rapid PCR testing and second with infectious antibody testing-reaching ~90% with both. A DEE score of 3 provided a specificity of 100% in identifying IE, but low sensitivity (29%). Symptoms were noted to cluster within several days of onset in IE, but in AE were spread out. Personality/behavioral change, speech change, affective disorder, and sleep disturbance were noted more often in AE, while fever, elevated C-reactive protein or CSF protein, and abnormal MRI-Brain occurred more often in IE. Conclusion: In this study, we provide the first evaluation of the Cellucci criteria and the first validation of the DEE score in the differentiation of pediatric AE and IE. Further refinement of AE criteria is needed to improve early detection and treatment of pediatric AE.
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We herein report a case of Childhood Primary Central Nervous System (CNS) Angiitis. This case consisted of a 14-year-old girl who presented with right-sided weakness, aphasia, and a fever. A Magnetic Resonance Imaging of the brain showed multifocal areas of ischemia. Magnetic Resonance Angiography of the head and neck showed narrowing and irregularities of the left middle cerebral artery and right posterior cerebral artery. Cerebrospinal Fluid studies showed a lymphocytic pleocytosis and brain biopsy revealed leptomeningeal and perivascular inflammation. The epidemiology, presenting symptoms, work-up, pathophysiology, diagnostic criteria, and treatment of Childhood Primary CNS angiitis are discussed. This case serves as a reminder that when pediatric patients present with stroke-like symptoms inflammatory etiologies including Primary CNS Angiitis must be considered and treated appropriately in a time sensitive manner.
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Objective: To evaluate plasma neurofilament light (NfL) levels in autoimmune neurologic disorders (AINDs) and autoimmune encephalitis (AE). Background: Each particular neural autoantibody syndrome has a different clinical phenotype, making one unifying clinical outcome measure difficult to assess. While this is a heterogeneous group of disorders, the final common pathway is likely CNS damage and inflammation. Defining a biomarker of CNS injury that is easily obtainable through a blood sample and reflects a positive treatment response would be highly advantageous in future therapeutic trials. Measurement of blood concentration of neurofilament light (NfL) chain, however, may provide a biomarker of central nervous system (CNS) injury in AE and other AINDs. Here we provide an initial evaluation of plasma NfL levels in AE as well as other AINDs during active and chronic phases of disease and demonstrate its potential utility as a minimally-invasive biomarker for AE and AINDs. Design/Methods: Patients were retrospectively identified who were enrolled in the biorepository at the Rocky Mountain MS Center at the University of Colorado, or were prospectively enrolled after initial presentation. Patients had a well-defined AIND and were followed between 2014 and 2021. NfL was tested using the Single Molecule Array (SIMOA) technology. Patients with headaches but without other significant neurologic disease were included as controls. Results: Twenty-six plasma and 14 CSF samples of patients with AINDs, and 20 plasma control samples stored in the biorepository were evaluated. A positive correlation was found between plasma and CSF NfL levels for patients with an AIND (R 2 = 0.83, p < 0.001). Elevated plasma levels of NfL were seen in patients with active AE compared to controls [geometric mean (GM) 51.4 vs. 6.4 pg/ml, p = 0.002]. Patients with chronic symptoms (>6 months since new or worsening symptoms) of AE or cerebellar ataxia (CA) showed a trend toward lower plasma NfL levels (GM 15.1 pg/ml) compared to active AE or CA. Six patients with longitudinal, prospective sampling available demonstrated a trend in decreased plasma NfL levels over time. Conclusions: Our findings support the use of plasma NfL as a potential minimally-invasive biomarker of CNS injury.
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BACKGROUND: Down syndrome regression disorder is a symptom cluster consisting of neuropsychiatric regression without cause. This study evaluated the incidence of neurodiagnostic abnormalities in individuals with Down syndrome regression disorder and determined if abnormalities are indicative of responses to therapeutic intervention. METHODS: A retrospective, multi-center, case-control study was performed. Patients were required to have subacute onset and the presence of four of five symptom groups present (cognitive decline, expressive language, sleep derangement, loss of ability to perform activities of daily living, and/or a new movement disorder) and no other explanation for symptoms. RESULTS: Individuals with Down syndrome regression disorder were comparable to a cohort of individuals with only Down syndrome although had higher rates of autoimmune disease (p = 0.02, 95%CI 1.04-1.75). Neurodiagnostic abnormalities were found on EEG (n = 19, 26%), neuroimaging (n = 16, 22%), and CSF (n = 9, 17%). Pleocytosis was appreciated in five cases, elevated total protein in nine, elevated IgG index in seven, and oligoclonal bands in two. Testing within 2 years of symptom onset was more likely to have neurodiagnostic abnormalities (p = 0.01, 95%CI 1.64-37.06). In individuals with neurodiagnostic abnormalities, immunotherapy was nearly four times more likely to have a therapeutic effect than in those without neurodiagnostic abnormalities (OR 4.11, 95%CI 1.88-9.02). In those with normal neurodiagnostic studies (n = 43), IVIg was effective in 14 of 17 (82%) patients as well although other immunotherapies were uniformly ineffective. CONCLUSIONS: This study reports the novel presence of neurodiagnostic testing abnormalities in individuals with Down syndrome regression disorder, providing credence to this symptom cluster potentially being of neurologic and/or neuroimmunologic etiology.
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Síndrome de Down , Atividades Cotidianas , Estudos de Casos e Controles , Síndrome de Down/complicações , Síndrome de Down/terapia , Humanos , Imunoterapia/métodos , Doenças Neuroinflamatórias , Estudos RetrospectivosRESUMO
Objective: To develop standardization for nomenclature, diagnostic work up and diagnostic criteria for cases of neurocognitive regression in Down syndrome. Background: There are no consensus criteria for the evaluation or diagnosis of neurocognitive regression in persons with Down syndrome. As such, previously published data on this condition is relegated to smaller case series with heterogenous data sets. Lack of standardized assessment tools has slowed research in this clinical area. Methods: The authors performed a two-round traditional Delphi method survey of an international group of clinicians with experience in treating Down syndrome to develop a standardized approach to clinical care and research in this area. Thirty-eight potential panelists who had either previously published on neurocognitive regression in Down syndrome or were involved in national or international working groups on this condition were invited to participate. In total, 27 panelists (71%) represented nine medical specialties and six different countries reached agreement on preliminary standards in this disease area. Moderators developed a proposed nomenclature, diagnostic work up and diagnostic criteria based on previously published reports of regression in persons with Down syndrome. Results: During the first round of survey, agreement on nomenclature for the condition was reached with 78% of panelists agreeing to use the term Down Syndrome Regression Disorder (DSRD). Agreement on diagnostic work up and diagnostic criteria was not reach on the first round due to low agreement amongst panelists with regards to the need for neurodiagnostic testing. Following incorporation of panelist feedback, diagnostic criteria were agreed upon (96% agreement on neuroimaging, 100% agreement on bloodwork, 88% agreement on lumbar puncture, 100% agreement on urine studies, and 96% agreement on "other" studies) as were diagnostic criteria (96% agreement). Conclusions: The authors present international consensus agreement on the nomenclature, diagnostic work up, and diagnostic criteria for DSRD, providing an initial practical framework that can advance both research and clinical practices for this condition.