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1.
Pediatr Neurol ; 99: 64-68, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31248672

RESUMO

BACKGROUND: Antibodies to the myelin oligodendrocyte glycoprotein (MOG) have been identified in about 40% of children with acute disseminated encephalomyelitis (ADEM). The objective of this report is to describe three individuals with fulminant ADEM complicated by increased intracranial pressure associated with the presence of the anti-MOG antibodies. METHODS: This is a retrospective case series. Informed consent was obtained from the concerned patients or caregivers. RESULTS: High intracranial pressure associated with ADEM in the presence of MOG antibodies can result in cerebral edema, herniation, prolonged hospital stay (average intensive care unit stay: 22 days, average hospital stay: 50.6 days), and long-term disability. CONCLUSION: Increased intracranial pressure complicating MOG antibody-related ADEM is a unique finding in our cases. This can complicate the clinical picture of ADEM and confers high morbidity. Long-term immunosuppression is warranted in selected cases with persistent seropositivity.

2.
Ann Clin Transl Neurol ; 6(6): 1053-1061, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31211169

RESUMO

Objective: Onset of multiple sclerosis (MS) occurs in childhood for approximately 5% of cases (pediatric MS, or ped-MS). Epigenetic influences are strongly implicated in MS pathogenesis in adults, including the contribution from microRNAs (miRNAs), small noncoding RNAs that affect gene expression by binding target gene mRNAs. Few studies have specifically examined miRNAs in ped-MS, but individuals developing MS at an early age may carry a relatively high burden of genetic risk factors, and miRNA dysregulation may therefore play a larger role in the development of ped-MS than in adult-onset MS. This study aimed to look for evidence of miRNA involvement in ped-MS pathogenesis. Methods: GWAS results from 486 ped-MS cases and 1362 controls from the U.S. Pediatric MS Network and Kaiser Permanente Northern California membership were investigated for miRNA-specific signals. First, enrichment of miRNA-target gene network signals was evaluated using MIGWAS software. Second, SNPs in miRNA genes and in target gene binding sites (miR-SNPs) were tested for association with ped-MS, and pathway analysis was performed on associated target genes. Results: MIGWAS analysis showed that miRNA-target gene signals were enriched in GWAS (P = 0.038) and identified 39 candidate biomarker miRNA-target gene pairs, including immune and neuronal signaling genes. The miR-SNP analysis implicated dysregulation of miRNA binding to target genes in five pathways, mainly involved in immune signaling. Interpretation: Evidence from GWAS suggests that miRNAs play a role in ped-MS pathogenesis by affecting immune signaling and other pathways. Candidate biomarker miRNA-target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility.

3.
Mult Scler Relat Disord ; 30: 42-44, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30738277

RESUMO

IMPORTANCE: Patients afflicted with rare diseases often have a delay in diagnosis and treatment. Understanding the prevalence and impact of delayed diagnosis in transverse myelitis could trigger directed educational initiatives to increase clinician awareness and improve care. OBJECTIVE: To determine if symptoms at onset or care provider initially approached was associated with time to diagnosis, treatment or outcome in patients with transverse myelitis. DESIGN: This was an online patient and caregiver standardized survey to collect data about the initial medical experience. Patients were recruited through social media to complete a survey about initial symptoms, care provider approached for diagnosis, first events (hospital admission, testing, sent home, etc.), first diagnosis, time to treatment and outcomes. The data was collected by an independent, non-profit patient advocacy organization (The Transverse Myelitis Association) and provided to researchers for analysis. SETTING: This was an online survey of a prevalent cohort of individuals diagnosis with transverse myelitis. PARTICIPANTS: Patients with various autoimmune disorders responded to the survey. These included patients with multiple sclerosis, neuromyelitis optica, acute disseminated encephalomyelitis and idiopathic transverse myelitis. Only data about patients, greater than a year of age, with a diagnosis of transverse myelitis were included in the study.


Assuntos
Diagnóstico Tardio , Erros de Diagnóstico , Mielite Transversa/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Inquéritos Epidemiológicos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mielite Transversa/epidemiologia , Mielite Transversa/fisiopatologia , Mielite Transversa/terapia , Mídias Sociais , Adulto Jovem
4.
Mult Scler Relat Disord ; 28: 86-90, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30576847

RESUMO

BACKGROUND: Optic nerve involvement in anti-myelin oligodendrocyte glycoprotein antibody associated syndrome (MOG ab syndrome) tends to have unique features. Few studies have reported optical coherence tomography (OCT) measures like retinal nerve fiber layer thickness findings in the setting of pediatric MOG ab syndrome. OBJECTIVES: The aim of this study is to compare visual acuity between MOG ab positive and MOG ab negative pediatric cohorts and examine correlations with OCT findings. METHODS: We included outpatients less than 18 years of age who had optic neuritis (ON) of at least one eye and who completed visual testing and OCT in the study. ON was defined based on clinical or OCT findings. Antibody testing was obtained using cell-based assay. The primary analyses of interest investigated differences in low-contrast visual acuity stratified by the defined RNFL ranges and by antibody positivity. RESULTS: We analyzed 28 eyes from 14 anti-MOG ab patients (MOG-ON cohort), 18 eyes from 9 anti-AQP4 ab (AQP4-ON cohort) patients and 26 eyes from 13 patients who tested negative for both the antibodies (seronegative ON cohort). MOG-ON eyes with zero reported clinical events had lower RNFL thickness, than the minimum RNFL thickness of either the seronegative-ON or AQP4-ON eyes with zero clinical attacks in most retinal segments. Within the lowest range of the RNFL (RNFL <50 um) in most retinal segments, the MOG-ON cohort had a statistically significant greater visual acuity relative to the AQP4 cohort. CONCLUSIONS: Patients with anti-MOG antibody mediated CNS disorders can suffer from subclinical ON events with significant reductions in RNFL. Despite equally significant damage to the optic nerve, MOG-Ab positive patients have relatively preserved visual acuity.


Assuntos
Autoanticorpos/imunologia , Olho/diagnóstico por imagem , Glicoproteína Mielina-Oligodendrócito/imunologia , Neurite Óptica/diagnóstico , Neurite Óptica/imunologia , Tomografia de Coerência Óptica , Acuidade Visual , Adolescente , Feminino , Humanos , Masculino , Estudos Retrospectivos
5.
Neurology ; 91(17): e1642-e1651, 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30258024

RESUMO

OBJECTIVE: To define the frequency, duration, and severity of intractable nausea, vomiting, or hiccups in aquaporin-4-immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and propose diagnostic criteria and a severity scale for area postrema syndrome (APS). METHODS: An International NMOSD database was interrogated for frequency of APS. Patients with AQP4-IgG-positive NMOSD completed an APS symptom questionnaire. Nausea and vomiting severity was derived from the Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) score. The diagnostic criteria, severity scale, and immunotherapy response was applied to a prospective validation cohort of patients from multiple centers. RESULTS: Analysis of an international database for AQP4-IgG-seropositive NMOSD (n = 430) revealed a high prevalence of isolated APS attacks (onset 7.1%-10.3%; subsequent 9.4%-14.5%) across continents. For 100 patients with 157 episodes of APS, nausea (n = 127, 81%) lasted for a median of 14 days (range 2-365), vomiting (113, 72%) with a median of 5 episodes/d (2-40) lasted 1-20 minutes, and hiccups (102, 65%) lasted a median of 14 days (2-365). Symptoms consistently and completely resolved following immunotherapy. Data were used to propose APS diagnostic criteria and repurpose PUQE score (hiccups severity grade based on symptom duration). The clinical utility was demonstrated in a prospective validation cohort. CONCLUSION: Isolated APS attacks are frequently encountered both at onset and during the NMOSD course. The diagnostic criteria proposed here will assist clinicians in recognizing APS. Diagnosis of an APS attack earlier than 48 hours is possible if a dorsal medulla lesion is detected. Accurate diagnosis and evaluation of APS attack severity will assist in outcome measurement in NMOSD clinical trials.

6.
Urology ; 2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30267726

RESUMO

OBJECTIVE: To evaluate predictors of renal deterioration (RD) in patients with multiple sclerosis (MS) at a tertiary referral center. METHODS: We reviewed adult patients with MS presenting for evaluation of lower urinary tract symptoms, with baseline urodynamic study (UDS) and either serum creatinine (SCr) or renal ultrasound, from a prospectively maintained database, and excluded patients with abnormal renal function. RD was defined as doubled SCr, new hydronephrosis, or renal atrophy on follow-up ultrasound. Demographic and UDS parameters were evaluated in multivariable models of RD. RESULTS: From 1999 to 2016, 660 patients were evaluated, and 355 met criteria with median follow-up of 79 months. SCr doubled in 8 patients, 4 had decline by renal ultrasound, and 1 by both (3%). Overall, 46 patients met less strict criteria of decrease in estimated glomerular filtration rate by ≥30%. Using the less rigid criterion, detrusor overactivity (DO) remained associated with RD on multivariable analysis. Eleven of 355 patients had RD by either imaging or doubled Cr, with which only history of diabetes mellitus and nephrolithiasis were associated. CONCLUSION: By strict criteria, the rate of RD in patients with neurogenic bladder due to MS was low (3%) at intermediate-term follow-up and was not associated with UDS parameters. Using more liberal criteria, DO was associated with deterioration, suggesting that study of the impact of more aggressive control of DO in this population may be warranted.

7.
Neurol Clin Pract ; 8(4): 327-330, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30140584

RESUMO

Background: We sought to review safety and efficacy of therapeutic plasma exchange (TPE) in a cohort of pediatric patients with transverse myelitis. Methods: Billing data of all plasma exchanges performed at our tertiary care pediatric hospital between August 2010 and August 2016 were compared to electronic medical records to find all patients whose indication for apheresis was transverse myelitis. Patient outcomes were quantified on the modified Rankin Scale. Results: Fifteen of 19 patients (79%) had major improvement in symptoms after a course of 4-7 therapeutic plasma exchanges. The majority required further inpatient (6, 32%) or outpatient (8, 42%) physical therapy. Four (21%) patients returned to baseline and over 75% regained their ability to ambulate as of last follow-up. Four adverse events were noted over 114 treatments. Conclusions: TPE can be a useful treatment for pediatric transverse myelitis. The retrospective nature of this study without a comparator group limits conclusions about efficacy. However, controlled trials would help to validate our results. Classification of evidence: This study provides Class IV evidence that plasma exchange is safe and effective in pediatric transverse myelitis.

8.
Ann Neurol ; 84(1): 147-152, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30014527

RESUMO

Rosai-Dorfman disease (RDD) is an uncommon histiocytic proliferative disorder that can present in nodal, extranodal, or, extremely rarely, in central nervous system (CNS)-restricted form. RDD is characterized histologically as a non-Langerhans cell histiocytosis composed of atypical CD68+ /S-100+ /CD1a- macrophages demonstrating prominent emperipolesis and effacement of the surrounding tissue. Previously thought to represent a reactive process, recent studies have raised the possibility that RDD and other histiocytic lesions, including Erdheim-Chester and Langerhans cell histiocytosis, are clonal processes linked to somatic mutations in the mitogen-activated protein (MAP) kinase pathway. Herein, we present a fatal case of RDD isolated to the CNS and used a next-generation targeted gene panel and Sanger sequencing to uncover a pathogenic deletion in the ß3-αC loop of the kinase domain in exon 12 of BRAF. This mutation, previously described in melanoma and Langerhans cell histiocytosis, represents the first BRAF mutation of this kind identified in RDD. These findings support the idea that RDD is a neoplastic condition and raise the possibility that inhibitors of the MAP kinase pathway may be effective in RDD. Ann Neurol 2018;83:147-152.

9.
Nat Commun ; 9(1): 1929, 2018 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-29769526

RESUMO

Neuromyelitis optica (NMO) is a rare autoimmune disease that affects the optic nerve and spinal cord. Most NMO patients ( > 70%) are seropositive for circulating autoantibodies against aquaporin 4 (NMO-IgG+). Here, we meta-analyze whole-genome sequences from 86 NMO cases and 460 controls with genome-wide SNP array from 129 NMO cases and 784 controls to test for association with SNPs and copy number variation (total N = 215 NMO cases, 1244 controls). We identify two independent signals in the major histocompatibility complex (MHC) region associated with NMO-IgG+, one of which may be explained by structural variation in the complement component 4 genes. Mendelian Randomization analysis reveals a significant causal effect of known systemic lupus erythematosus (SLE), but not multiple sclerosis (MS), risk variants in NMO-IgG+. Our results suggest that genetic variants in the MHC region contribute to the etiology of NMO-IgG+ and that NMO-IgG+ is genetically more similar to SLE than MS.

10.
Neurol Clin ; 36(1): 135-149, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29157395

RESUMO

Pediatric-onset multiple sclerosis (MS) is a rare but increasingly recognized condition that both parallels and diverges from adult-onset MS. Exposure to key risk determinants for MS disease pathogenesis may occur during childhood. The diagnosis of pediatric MS can be challenging due to potential for atypical presentations and a broad differential diagnosis. MS disease-modifying therapies have not been rigorously studied in children and raise difficult questions on how to manage a chronic inflammatory neurologic disease in a population of patients with developing central nervous and immune systems.


Assuntos
Esclerose Múltipla , Criança , Diagnóstico Diferencial , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Fatores de Risco
11.
J Autoimmun ; 86: 104-115, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28964723

RESUMO

Myelin oligodendrocyte glycoprotein (MOG) is exposed on the outer surface of the myelin sheath, and as such, represents a possible target antigen for antibodies in multiple sclerosis (MS) and other demyelinating diseases. However, despite extensive analyses, whether MOG-specific antibodies contribute to pathogenesis in human MS remains an area of uncertainty. In the current study we demonstrate that antibodies derived from adult MS patients exacerbate experimental autoimmune encephalomyelitis (EAE) in 'humanized' mice that transgenically express human FcγRs (hFcγRs). Importantly, this exacerbation is dependent on MOG recognition by the human-derived antibodies. The use of mice that express hFcγRs has allowed us to also investigate the contribution of these receptors to disease in the absence of confounding effects of cross-species differences. Specifically, by engineering the Fc region of MOG-specific antibodies to modulate FcγR and complement (C1q) binding, we reveal that FcγRs but not complement activation contribute to EAE pathogenesis. Importantly, selective enhancement of the affinities of these antibodies for specific FcγRs reveals that FcγRIIA is more important than FcγRIIIA in mediating disease exacerbation. These studies not only provide definitive evidence for the contribution of MOG-specific antibodies to MS, but also reveal mechanistic insight that could lead to new therapeutic targets.

12.
Child Neuropsychol ; 24(5): 575-597, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28637379

RESUMO

Immune-mediated central nervous system (CNS) demyelinating diseases impact various areas of the brain, optic nerves, and/or spinal cord and can result in a wide range of neurologic symptoms including adverse cognitive outcomes. Neuropsychological outcomes in adult multiple sclerosis (MS) are well documented, while literature on such outcomes in pediatric cohorts is more limited. Furthermore, literature on neuropsychological outcomes in pediatric acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO), and transverse myelitis (TM) is even more limited. This paper is the first to review what is known about neuropsychological outcomes associated with immune-mediated CNS demyelinating diseases, with a focus on pediatric MS, ADEM, NMO, and TM. Additionally, this review illuminates the need to clarify differences in neuropsychological sequelae between conditions, characterize longitudinal cognitive outcomes, and investigate neuropsychological outcomes in relation to clinical variables (e.g., age of onset, disease duration, number of relapses) and psychosocial variables (e.g., fatigue, emotional problems, behavioral functioning) to better understand neuropsychological outcomes associated with these conditions.

13.
Neurocrit Care ; 29(3): 504-507, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29047014

RESUMO

BACKGROUND: The use of weight loss drugs and dietary supplements is common, but safety profiles for these drugs are largely unknown. Reports of toxicity have been published, and the use of these agents should be considered in clinical differential diagnoses. METHODS: We report the case of a patient with toxic leukoencephalopathy and hyponatremia associated with oral consumption of a thermogenic dietary supplement and essential oils. RESULTS: A 30-year-old woman presented after 2 days of headache, blurred vision, photophobia, vomiting, and hand spasms. She was taking a thermogenic dietary supplement daily for 6 months as well as a number of essential oils. Examination revealed mild right sided ataxia and diffuse hyperreflexia. Neuroimaging demonstrated bilaterally symmetric T2 hyperintensities of the corpus callosum and periventricular white matter. Approximately 18 h after admission she became unresponsive with brief extensor posturing and urinary incontinence. She partially recovered, but 1 h later became unresponsive with dilated nonreactive pupils and extensor posturing (central herniation syndrome). She was intubated, hyperventilated, and given hyperosmotic therapy. Emergent imaging showed diffuse cerebral edema. Intracranial pressure was elevated but normalized with treatment; she regained consciousness the following day. She was extubated one day later and discharged on hospital day 5. She was seen 2 months later with no further symptoms and a normal neurologic examination. CONCLUSIONS: The pathophysiology of this patient's hyponatremia and toxic leukoencephalopathy is unknown. However, physicians must be aware of the association between thermogenic dietary supplements and toxic leukoencephalopathy. Vigilance for life-threatening complications including hyponatremia and cerebral edema is critical.

14.
Mult Scler ; 24(13): 1737-1742, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28857723

RESUMO

BACKGROUND:: Debate exists about whether neuromyelitis optica spectrum disorder seronegative disease represents the same immune-mediated attack on astrocytic aquaporin-4 as in seropositive disease. OBJECTIVE:: We investigated whether response to common treatments for neuromyelitis optica spectrum disorder differed by serostatus, as assessed by change in annualized relapse rate. METHODS:: We performed a multicenter retrospective analysis of 245 patients with neuromyelitis optica spectrum disorder who were treated with either rituximab or mycophenolate mofetil as their first-line immunosuppressive treatment for disease prevention. Patients were followed for a minimum of 6 months following treatment initiation. RESULTS:: In those started on rituximab, the pre-treatment annualized relapse rates for seropositive and seronegative patients were 1.81 and 1.93, respectively. On-treatment annualized relapse rates significantly declined to 0.32 (seropositive; p < 0.0001) and 0.12 (seronegative; p = 0.0001). In those started on mycophenolate mofetil, the pre-treatment annualized relapse rates for seropositive and seronegative patients were 1.79 and 1.45, respectively. On-treatment annualized relapse rates declined to 0.29 (seropositive; p < 0.0001) and 0.30 (seronegative; p < 0.005). CONCLUSION:: In this international collaboration involving a large number of neuromyelitis optica spectrum disorder patients, treatment was effective regardless of serostatus. This suggests that treatment should not differ when considering these treatments.

15.
J Pharm Pract ; 31(5): 481-488, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28847230

RESUMO

The multiple sclerosis (MS) treatment landscape in the United States has changed dramatically over the past decade. While many disease-modifying therapies (DMTs) have been approved by the US Food and Drug Administration (FDA) for the treatment of relapsing forms of MS, DMT costs continue to rise. The availability of generics and biosimilars in the MS-treatment landscape is unlikely to have a major impact on clinical benefit. However, their availability will provide alternative treatment options and potentially lower costs through competition, thus increasing the affordability of and access to these drugs. In April 2015, the first generic version of the complex drug glatiramer acetate (Glatopa® 20 mg/mL) injection was approved in the United States as a fully substitutable generic for all approved indications of the 20 mg/mL branded glatiramer acetate (Copaxone®) dosage form. Despite glatiramer acetate's complex nature-being a chemically synthesized (ie, nonbiologic) mixture of peptides-the approval occurred without conducting any clinical trials. Rather, extensive structural and functional characterization was performed to demonstrate therapeutic equivalence to the innovator drug. The approval of Glatopa signifies an important milestone in the US MS-treatment landscape, with the hope that the introduction of generic DMTs and eventually biosimilar DMTs will lead to future improvements in the affordability and access of these much-needed treatments for MS.

16.
Mult Scler ; 24(8): 1067-1076, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28608728

RESUMO

BACKGROUND: The role of diet in multiple sclerosis (MS) is largely uncharacterized, particularly as it pertains to pediatric-onset disease. OBJECTIVE: To determine the association between dietary factors and MS in children. METHODS: Pediatric MS patients and controls were recruited from 16 US centers (MS or clinically isolated syndrome onset before age 18, <4 years from symptom onset and at least 2 silent lesions on magnetic resonance imaging). The validated Block Kids Food Screener questionnaire was administered 2011-2016. Chi-squared test compared categorical variables, Kruskal-Wallis test compared continuous variables, and multivariable logistic regression analysis was performed. RESULTS: In total, 312 cases and 456 controls were included (mean ages 15.1 and 14.4 years). In unadjusted analyses, there was no difference in intake of fats, proteins, carbohydrates, sugars, fruits, or vegetables. Dietary iron was lower in cases ( p = 0.04), and cases were more likely to consume below recommended guidelines of iron (77.2% of cases vs 62.9% of controls, p < 0.001). In multivariable analysis, iron consumption below recommended guidelines was associated with MS (odds ratio = 1.80, p < 0.01). CONCLUSION: Pediatric MS cases may be less likely to consume sufficient iron compared to controls, and this warrants broader study to characterize a temporal relationship. No other significant difference in intake of most dietary factors was found.

17.
BMC Bioinformatics ; 18(1): 401, 2017 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-28882107

RESUMO

BACKGROUND: Deep sequencing of lymphocyte receptor repertoires has made it possible to comprehensively profile the clonal composition of lymphocyte populations. This opens the door for novel approaches to diagnose and prognosticate diseases with a driving immune component by identifying repertoire sequence patterns associated with clinical phenotypes. Indeed, recent studies support the feasibility of this, demonstrating an association between repertoire-level summary statistics (e.g., diversity) and patient outcomes for several diseases. In our own prior work, we have shown that six codons in VH4-containing genes in B cells from the cerebrospinal fluid of patients with relapsing remitting multiple sclerosis (RRMS) have higher replacement mutation frequencies than observed in healthy controls or patients with other neurological diseases. However, prior methods to date have been limited to focusing on repertoire-level summary statistics, ignoring the vast amounts of information in the millions of individual immune receptors comprising a repertoire. We have developed a novel method that addresses this limitation by using innovative approaches for accommodating the extraordinary sequence diversity of immune receptors and widely used machine learning approaches. We applied our method to RRMS, an autoimmune disease that is notoriously difficult to diagnose. RESULTS: We use the biochemical features encoded by the complementarity determining region 3 of each B cell receptor heavy chain in every patient repertoire as input to a detector function, which is fit to give the correct diagnosis for each patient using maximum likelihood optimization methods. The resulting statistical classifier assigns patients to one of two diagnosis categories, RRMS or other neurological disease, with 87% accuracy by leave-one-out cross-validation on training data (N = 23) and 72% accuracy on unused data from a separate study (N = 102). CONCLUSIONS: Our method is the first to apply statistical learning to immune repertoires to aid disease diagnosis, learning repertoire-level labels from the set of individual immune repertoire sequences. This method produced a repertoire-based statistical classifier for diagnosing RRMS that provides a high degree of diagnostic capability, rivaling the accuracy of diagnosis by a clinical expert. Additionally, this method points to a diagnostic biochemical motif in the antibodies of RRMS patients, which may offer insight into the disease process.


Assuntos
Modelos Estatísticos , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Sequência de Aminoácidos , Área Sob a Curva , Linfócitos B/metabolismo , Regiões Determinantes de Complementaridade/química , Regiões Determinantes de Complementaridade/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Esclerose Múltipla Recidivante-Remitente/classificação , Esclerose Múltipla Recidivante-Remitente/imunologia , Doenças do Sistema Nervoso/classificação , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/imunologia , Curva ROC
18.
Neurourol Urodyn ; 36(2): 360-363, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-26587780

RESUMO

AIMS: To characterize urodynamic findings in patients referred with transverse myelitis (TM) and lower urinary tract symptoms (LUTS), as well as to identify any characteristics predictive of urodynamics findings. METHODS: This is a retrospective review of an IRB-approved neurogenic bladder database of patients followed by a single surgeon between 2001 and 2013. Patient characteristics, questionnaire data, radiologic studies, and urodynamic parameters were analyzed. RESULTS: Of the 836 patients in the neurogenic bladder database, 28 patients (17 females, 11 males) were referred with a principle diagnosis of TM (3%). Twenty-one of twenty-eight patients (75%) underwent urodynamics testing. Bladder management at initial urologic evaluation was CIC or urethral catheter for 16/28 patients (57.1%). Median MCC was 303 ml (85-840 ml), detrusor overactivity (DO) was present in 16/21 (76%), detrusor sphincter dyssynergia (DSD) in 10/21 (48%), and decreased compliance in 7/21 (33%). For those voiding, mean Qmax was 12 ± 10 ml/sec and pdet at Qmax was 41 ± 17 cmH2 O. Longitudinally extensive TM (LETM) was the only patient characteristic associated with DO (P = 0.0276). No other patient characteristics were associated with urodynamics parameters. CONCLUSIONS: Significant urodynamic testing abnormalities are noted in the majority of TM patients undergoing urodynamics, with 95% having DO, DSD, altered compliance, or detrusor underactivity. Other than the association between LETM and DO, there were no patient characteristics predictive of urodynamics findings. Based on the severity of urodynamics findings in our series, patients with TM and LUTS should have thorough baseline urological evaluations including urodynamics and be offered ongoing surveillance. Neurourol. Urodynam. 36:360-363, 2017. © 2015 Wiley Periodicals, Inc.


Assuntos
Sintomas do Trato Urinário Inferior/fisiopatologia , Mielite Transversa/fisiopatologia , Bexiga Urinaria Neurogênica/fisiopatologia , Bexiga Urinária Hiperativa/fisiopatologia , Urodinâmica/fisiologia , Adulto , Idoso , Feminino , Humanos , Sintomas do Trato Urinário Inferior/complicações , Sintomas do Trato Urinário Inferior/diagnóstico , Masculino , Pessoa de Meia-Idade , Mielite Transversa/complicações , Encaminhamento e Consulta , Estudos Retrospectivos , Bexiga Urinaria Neurogênica/complicações , Bexiga Urinaria Neurogênica/diagnóstico , Bexiga Urinária Hiperativa/complicações , Bexiga Urinária Hiperativa/diagnóstico
19.
Acta Neuropathol ; 133(1): 43-60, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27730299

RESUMO

Plasmablasts are a highly differentiated, antibody secreting B cell subset whose prevalence correlates with disease activity in Multiple Sclerosis (MS). For most patients experiencing partial transverse myelitis (PTM), plasmablasts are elevated in the blood at the first clinical presentation of disease (known as a clinically isolated syndrome or CIS). In this study we found that many of these peripheral plasmablasts are autoreactive and recognize primarily gray matter targets in brain tissue. These plasmablasts express antibodies that over-utilize immunoglobulin heavy chain V-region subgroup 4 (VH4) genes, and the highly mutated VH4+ plasmablast antibodies recognize intracellular antigens of neurons and astrocytes. Most of the autoreactive, highly mutated VH4+ plasmablast antibodies recognize only a portion of cortical neurons, indicating that the response may be specific to neuronal subgroups or layers. Furthermore, CIS-PTM patients with this plasmablast response also exhibit modest reactivity toward neuroantigens in the plasma IgG antibody pool. Taken together, these data indicate that expanded VH4+ peripheral plasmablasts in early MS patients recognize brain gray matter antigens. Peripheral plasmablasts may be participating in the autoimmune response associated with MS, and provide an interesting avenue for investigating the expansion of autoreactive B cells at the time of the first documented clinical event.


Assuntos
Autoanticorpos/metabolismo , Linfócitos B/imunologia , Encéfalo/imunologia , Esclerose Múltipla/imunologia , Plasmócitos/imunologia , Adulto , Idoso , Astrócitos/imunologia , Astrócitos/patologia , Linfócitos B/patologia , Encéfalo/patologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Substância Cinzenta/imunologia , Substância Cinzenta/patologia , Humanos , Imunoglobulina G/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Neuromielite Óptica/imunologia , Neuromielite Óptica/patologia , Neurônios/imunologia , Neurônios/patologia , Plasmócitos/fisiologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologia , Adulto Jovem
20.
Mult Scler J Exp Transl Clin ; 3(4): 2055217317743097, 2017 Oct-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29348926

RESUMO

Objective: The objective of this paper is to assess, in individuals with clinically stable multiple sclerosis (MS), the safety, tolerability, pharmacokinetics (PK) and exploratory pharmacodynamics of the monoclonal recombinant human antibody IgM22 (rHIgM22). Methods: Seventy-two adults with stable MS were enrolled in a double-blind, randomized, placebo-controlled, single ascending-dose, Phase 1 trial examining rHIgM22 from 0.025 to 2.0 mg/kg. Assessments included MRI, MR spectroscopy, plasma PK, and changes in clinical status, laboratory values and adverse events for three months. The final cohort had additional clinical, ophthalmologic, CSF collection and exploratory biomarker evaluations. Participants were monitored for six months. Results: rHIgM22 was well tolerated with no clinically significant safety signals. Noncompartmental PK modeling demonstrated linear dose-proportionality both of Cmax and AUC0-Last. The steady-state apparent volume of distribution of approximately 58 ml/kg suggested primarily vascular compartmentalization. CSF:plasma rHIgM22 concentration increased from 0.003% on Day 2 for both 1.0 and 2.0 mg/kg to 0.056% and 0.586% for 1.0 and 2.0 mg/kg, respectively, on Day 29. No statistically significant treatment-related changes were observed in exploratory pharmacodynamic outcome measures included for the 21 participants of the extension cohort. Conclusions: Single doses of rHIgM22 were well tolerated and exhibited linear PK, and antibody was detected in the CSF.

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