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1.
Hosp Pediatr ; 11(1): 79-87, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33386296

RESUMO

OBJECTIVES: Understanding the risk factors, predictors, and clinical presentation of coronavirus disease 2019 (COVID-19) in pediatric patients with severe disease. METHODS: We conducted a retrospective chart review of pediatric patients admitted between March 1, 2020, and May 31, 2020, to a large health network in New Jersey with positive test results for severe acute respiratory syndrome coronavirus 2 on reverse transcriptase polymerase chain reaction, rapid testing, or serum immunoglobulin G testing; we included demographic characteristics, clinical features, and outcomes. RESULTS: A total of 81 patients ≤21 years old were admitted with positive test results for severe acute respiratory syndrome coronavirus 2 on reverse transcriptase polymerase chain reaction and/or serum immunoglobulin testing. Sixty-seven patients (82.7%) were admitted for management of acute COVID-19 infection, whereas 14 (17.3%) were admitted for management of multisystem inflammatory syndrome in children (MIS-C). Of the 81 hospitalized patients, 28 (34.6%) required intensive care. A majority of patients (42 [51.9%]) admitted for both acute COVID-19 infection and MIS-C were Hispanic. Underlying chronic health conditions were not present in most patients. Obesity (mean BMI of 41.1) was noted in the patients with MIS-C requiring ICU care, although not statistically significant. Absolute lymphopenia and elevated levels of inflammatory markers were statistically significant in the patients with MIS-C treated in the ICU. CONCLUSIONS: This study adds to the growing literature of potential risk factors for severe disease in pediatric patients due to COVID-19 infection and MIS-C. Patients of Hispanic ethnicity represented the majority of patients with both acute COVID-19 infection and MIS-C, despite only representing 10% to 20% of the population our hospitals serve. Infants and patients with chronic health conditions were not at increased risk for severe disease. Absolute lymphopenia and elevated levels of inflammatory markers were associated with more severe disease.


Assuntos
/diagnóstico , /terapia , Adolescente , Criança , Pré-Escolar , Feminino , Hospitalização , Humanos , Lactente , Masculino , New Jersey , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Adulto Jovem
2.
Artigo em Inglês | MEDLINE | ID: mdl-33211859

RESUMO

This is a retrospective chart review of 20 patients treated with a consensus driven treatment algorithm in MIS-C patients across a wide clinical spectrum. Their treatments and clinical status are described, as well as their favorable return to functional baseline by 30 days post presentation.

3.
Neurology ; 95(21): e2866-e2879, 2020 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-32913013

RESUMO

OBJECTIVE: To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. METHODS: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/-) to determine the sequence of events in seizure-related cardiac death. RESULTS: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death. CONCLUSIONS: We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.

4.
Neuromuscul Disord ; 30(9): 734-741, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32811700

RESUMO

McArdle disease results from a lack of muscle glycogen phosphorylase in skeletal muscle tissue. Regenerating skeletal muscle fibres can express the brain glycogen phosphorylase isoenzyme. Stimulating expression of this enzyme could be a therapeutic strategy. Animal model studies indicate that sodium valproate (VPA) can increase expression of phosphorylase in skeletal muscle affected with McArdle disease. This study was designed to assess whether VPA can modify expression of brain phosphorylase isoenzyme in people with McArdle disease. This phase II, open label, feasibility pilot study to assess efficacy of six months treatment with VPA (20 mg/kg/day) included 16 people with McArdle disease. Primary outcome assessed changes in VO2peak during an incremental cycle test. Secondary outcomes included: phosphorylase enzyme expression in post-treatment muscle biopsy, total distance walked in 12 min, plasma lactate change (forearm exercise test) and quality of life (SF36). Safety parameters. 14 participants completed the trial, VPA treatment was well tolerated; weight gain was the most frequently reported drug-related adverse event. There was no clinically meaningful change in any of the primary or secondary outcome measures including: VO2peak, 12 min walk test and muscle biopsy to look for a change in the number of phosphorylase positive fibres between baseline and 6 months of treatment. Although this was a small open label feasibility study, it suggests that a larger randomised controlled study of VPA, may not be worthwhile.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32404429

RESUMO

OBJECTIVE: To investigate serum neurofilament light chain (sNfL) as a potential biomarker for disease activity and treatment response in pediatric patients with multiple sclerosis (MS). METHODS: In this retrospective cohort study, sNfL levels were measured in a pediatric MS cohort (n = 55, follow-up 12-105 months) and in a non-neurologic pediatric control cohort (n = 301) using a high-sensitivity single-molecule array assay. Association of sNfL levels and treatment and clinical and MRI parameters were calculated. RESULTS: Untreated patients had higher sNfL levels than controls (median 19.0 vs 4.6 pg/mL; CI [4.732, 6.911]), p < 0.001). sNfL levels were significantly associated with MRI activity (+9.1% per contrast-enhancing lesion, CI [1.045, 1.138], p < 0.001; +0.6% per T2-weighted lesion, CI [1.001, 1.010], p = 0.015). Higher values were associated with a relapse <90 days ago (+51.1%; CI [1.184, 1.929], p < 0.001) and a higher Expanded Disability Status Scale score (CI [1.001, 1.240], p = 0.048). In patients treated with interferon beta-1a/b (n = 27), sNfL levels declined from 14.7 to 7.9 pg/mL after 6 ± 2 months (CI [0.339, 0.603], p < 0.001). Patients with insufficient control of clinical or MRI disease activity under treatment with interferon beta-1a/b or glatiramer acetate who switched to fingolimod (n = 18) showed a reduction of sNfL levels from 16.5 to 10.0 pg/mL 6 ± 2 months after switch (CI [0.481, 0.701], p < 0.001). CONCLUSIONS: sNfL is a useful biomarker for monitoring disease activity and treatment response in pediatric MS. It is most likely helpful to predict disease severity and to guide treatment decisions in patients with pediatric MS. This study provides Class III evidence that sNfL levels are associated with disease activity in pediatric MS.

6.
Artigo em Inglês | MEDLINE | ID: mdl-32424064

RESUMO

OBJECTIVE: To study the association between serum neurofilament light chain (sNfL) and multiple optical coherence tomography (OCT) measures in patients with MS and healthy controls (HCs). METHODS: In this prospective study, 110 patients with MS were recruited, together with 52 age- and sex-matched HCs. Clinical evaluation and spectral domain OCT and sNfL were obtained at baseline and after 5.5 years of follow-up. Nested linear mixed models were used to assess differences between MS vs HC and associations between sNfL and OCT measures. Partial correlation coefficients are reported, and p values were adjusted for the false discovery rate. RESULTS: At baseline, peripapillary retinal nerve fiber layer thickness (pRNFLT) and macular ganglion cell and inner plexiform layer thickness (mGCIP) were significantly lower in MS than HC both in MS-associated optic neuritis (MSON) (p = 0.007, p = 0.001) and nonaffected MSON (n-MSON) eyes (p = 0.003, p = 0.018), along with total macular volume (TMV) in n-MSON eyes (p = 0.011). At follow-up, MS showed significantly lower pRNFLT, mGCIP, and TMV both in MSON and n-MSON eyes (p < 0.001) compared with HC. In MS n-MSON eyes, sNfL was significantly associated with baseline pRNFLT and mGCIP (q = 0.019). No significant associations were found in MSON eyes. CONCLUSIONS: This study confirms the ability of sNfL to detect neurodegeneration in MS and advocates for the inclusion of sNfL and OCT measures in clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that sNfL levels were associated with MS neurodegeneration measured by OCT.

7.
Neurology ; 94(23): e2457-e2467, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32434867

RESUMO

OBJECTIVE: To investigate the association between plasma neurofilament light chain (pNfL) levels and the risk of developing sustained disability worsening. METHODS: Concentrations of pNfL were determined in 4,385 persons with multiple sclerosis (MS) and 1,026 randomly selected population-based sex- and age-matched controls using the highly sensitive Single Molecule Array (SimoaTM) NF-Light Advantage Kit. We assessed the impact of age-stratified pNfL levels above the 80th, 95th, and 99th percentiles among controls on the risk of Expanded Disability Status Scale (EDSS) worsening within the following year and reaching sustained EDSS scores of 3.0, 4.0, and 6.0 and conversion to secondary progressive multiple sclerosis (SPMS). RESULTS: The median (interquartile range [IQR]) pNfL was 7.5 (4.1) pg/mL in controls and 11.4 (9.6) pg/mL in MS (p < 0.001). The median (IQR) duration of follow-up was 5 (5.1) years. High pNfL was associated with increased adjusted rates of EDSS worsening ranging between 1.4 (95% confidence intervals [CIs]: 1.1-1.8) and 1.7 (95% CI: 1.4-2.3). High pNfL was also associated with the risk of reaching a sustained EDSS score of 3.0, with adjusted rates ranging between 1.5 (95% CI: 1.2-1.8) and 1.55 (95% CI: 1.3-1.8) over all percentile cutoffs (all p < 0.001). Similar increases were observed for the risk of sustained EDSS score 4.0. In contrast, the risk of reaching sustained EDSS score 6.0 and conversion to SPMS was not consistently significant. CONCLUSIONS: Elevated pNfL levels at early stages of MS are associated with an increased risk of reaching sustained disability worsening. Hence, pNfL may serve as a prognostic tool to assess the risk of developing permanent disability in MS.


Assuntos
Esclerose Múltipla/sangue , Proteínas de Neurofilamentos/sangue , Adolescente , Adulto , Fatores Etários , Idoso , Biomarcadores , Estudos de Casos e Controles , Avaliação da Deficiência , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Suécia/epidemiologia , Adulto Jovem
8.
Neurology ; 94(11): e1201-e1212, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32047070

RESUMO

OBJECTIVE: To determine factors (including the role of specific disease modulatory treatments [DMTs]) associated with (1) baseline, (2) on-treatment, and (3) change (from treatment start to on-treatment assessment) in plasma neurofilament light chain (pNfL) concentrations in relapsing-remitting multiple sclerosis (RRMS). METHODS: Data including blood samples analyses and long-term clinical follow-up information for 1,261 Swedish patients with RRMS starting novel DMTs were analyzed using linear regressions to model pNfL and changes in pNfL concentrations as a function of clinical variables and DMTs (alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, rituximab, and teriflunomide). RESULTS: The baseline pNfL concentration was positively associated with relapse rate, Expanded Disability Status Scale score, Age-Related MS Severity Score, and MS Impact Score (MSIS-29), and negatively associated with Symbol Digit Modalities Test performance and the number of previously used DMTs. All analyses, which used inverse propensity score weighting to correct for differences in baseline factors at DMT start, highlighted that both the reduction in pNfL concentration from baseline to on-treatment measurement and the on-treatment pNfL level differed across DMTs. Patients starting alemtuzumab displayed the highest reduction in pNfL concentration and lowest on-treatment pNfL concentrations, while those starting teriflunomide had the smallest decrease and highest on-treatment levels, but also starting from lower values. Both on-treatment pNfL and decrease in pNfL concentrations were highly dependent on baseline concentrations. CONCLUSION: Choice of DMT in RRMS is significantly associated with degree of reduction in pNfL, which supports a role for pNfL as a drug response marker.


Assuntos
Biomarcadores/sangue , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Proteínas de Neurofilamentos/sangue , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
9.
Mult Scler ; : 1352458519901272, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31961243

RESUMO

BACKGROUND: Serum neurofilament light chain (sNfL) is a marker of neuroaxonal injury. There is a lack of studies investigating the dynamics of relationships between sNfL levels and radiological disease activity over long-term follow-up in multiple sclerosis (MS). OBJECTIVES: To investigate the relationship among repeated measures of sNfL, lesion burden accumulation, brain volume loss and clinical measures. METHODS: We investigated 172 patients in the early stages of MS (McDonald 2017 criteria). Clinical exams were performed every 3 months and brain magnetic resonance imaging (MRI) scans were collected annually over 48 months. sNfL levels were measured in serum by Simoa assay at the time of treatment initiation and then annually over 36 months. RESULTS: In repeated-measures analysis, considering all time points, we found a strong relationship between percentage changes of sNfL and lesion burden accumulation assessed by T1 lesion volume (p < 0.001) and T2 lesion number (p < 0.001). There was no relationship between percentage changes of sNfL and brain volume loss over 36 months (p > 0.1). Early sNfL levels were associated with delayed brain volume loss after 48 months (p < 0.001). Patients with No Evidence of Disease Activity (NEDA-3) status showed lower sNfL levels compared with active MS patients. CONCLUSIONS: sNfL is associated with ongoing neuroinflammation and predictive of future neurodegeneration in early MS.

10.
Epilepsia ; 61(2): 310-318, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31958887

RESUMO

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is typically unwitnessed but can be preceded by seizures in the period prior to death. Peri-ictal respiratory dysfunction is a likely mechanism for some SUDEP, and central apnea has been shown following amygdala stimulation. The amygdala is enriched in neuropeptides that modulate neuronal activity and can be transiently depleted following seizures. In a postmortem SUDEP series, we sought to investigate alterations of neuropeptidergic networks in the amygdala, including cases with recent poor seizure control. METHODS: In 15 SUDEP cases, 12 epilepsy controls, and 10 nonepilepsy controls, we quantified the labeling index (LI) for galanin, neuropeptide Y (NPY), and somatostatin (SST) in the lateral, basal, and accessory basal nuclei and periamygdala cortex with whole slide scanning image analysis. Within the SUDEP group, seven had recent generalized seizures with recovery 24 hours prior to death (SUDEP-R). RESULTS: Galanin, NPY, and SST LIs were significantly lower in all amygdala regions in SUDEP cases compared to epilepsy controls (P < .05 to P < .0005), and galanin LI was lower in the lateral nucleus compared to nonepilepsy controls (P < .05). There was no difference in the LI in the SUDEP-R group compared to other SUDEP. Higher LI was noted in epilepsy controls than nonepilepsy controls; this was significant for NPY in lateral and basal nuclei (P < .005 and P < .05). SIGNIFICANCE: A reduction in galanin in the lateral nucleus in SUDEP could represent acute depletion, relevant to postictal amygdala dysfunction. In addition, increased amygdala neuropeptides in epilepsy controls support their seizure-induced modulation, which is relatively deficient in SUDEP; this could represent a vulnerability factor for amygdala dysfunction in the postictal period.


Assuntos
Tonsila do Cerebelo/metabolismo , Neuropeptídeos/metabolismo , Morte Súbita Inesperada na Epilepsia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cadáver , Causas de Morte , Epilepsia/metabolismo , Feminino , Galanina/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/metabolismo , Neuropeptídeo Y/metabolismo , Somatostatina/metabolismo , Bancos de Tecidos , Adulto Jovem
11.
Neurology ; 93(13): e1299-e1311, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31471502

RESUMO

OBJECTIVE: To test the hypothesis that serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL), which are an intermediate astrocyte and neuron filaments, respectively, are clinically useful biomarkers of disease activity and disability in neuromyelitis optica spectrum disorders (NMOSD). METHODS: Levels of GFAP and NfL in serum (sGFAP and sNfL, respectively) and in CSF samples were measured in healthy controls (HCs) (n = 49; 49 serum samples), patients with NMOSD (n = 33; 42 CSF and 102 serum samples), and patients with multiple sclerosis (MS) (n = 49; 53 CSF and 91 serum samples) by ultrasensitive single-molecule array assays. Association of sGFAP and sNfL levels with clinical parameters was determined. RESULTS: For both GFAP and NfL, CSF and serum levels were strongly correlated. Both were higher in the serum of patients with NMOSD than in HCs (both p < 0.001). Moreover, sGFAP was higher in NMOSD than in MS (median 207.7 vs 121.1 pg/mL, p < 0.001). In NMOSD, sGFAP concentration increased after recent relapse (540.9 vs 152.9 pg/mL, p < 0.001). Multivariate analyses indicated that sGFAP and sNfL were associated with Expanded Disability Status Scale score in NMOSD (p = 0.026 and p < 0.001, respectively). Higher sGFAP/sNfL quotient at relapse differentiated NMOSD from MS with a sensitivity of 73.0% and a specificity of 75.8%. CONCLUSIONS: sGFAP and sNfL are likely to be good biomarkers of disease activity and disability, and the sGFAP/sNfL quotient at relapse is a potential diagnostic marker for NMOSD.


Assuntos
Biomarcadores/sangue , Proteína Glial Fibrilar Ácida/sangue , Proteínas de Neurofilamentos/sangue , Neuromielite Óptica/sangue , Adulto , Bioensaio/métodos , Pessoas com Deficiência , Feminino , Humanos , Filamentos Intermediários/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/diagnóstico
12.
Neurology ; 93(10): e968-e974, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31383792

RESUMO

OBJECTIVE: To explore the correlation between serum and CSF neurofilament light chain (NfL) and the association of NfL levels and future disease activity in pediatric patients with a first attack of acquired demyelinating syndromes (ADS). METHODS: In total, 102 children <18 years with a first attack of CNS demyelination and 23 age-matched controls were included. Clinically definite multiple sclerosis (CDMS) was set as an endpoint for analysis. CSF NfL was tested by the commercially available ELISA (UmanDiagnostics); serum NfL (sNfL) was tested with a Simoa assay. Hazard ratios (HR) were calculated with Cox regression analysis. RESULTS: Of the 102 patients, 47 (46%) were tested for CSF NfL. CSF and serum NfL correlated significantly in the total group (ρ 0.532, p < 0.001) and even more significantly in the subgroup of patients with future CDMS diagnosis (ρ 0.773, p < 0.001). sNfL was higher in patients than in controls (geometric mean 6.1 pg/mL, p < 0.001), and was highest in ADS presenting with encephalopathy (acute disseminated encephalomyelitis, n = 28, 100.4 pg/mL), followed by patients without encephalopathy (ADS-) with future CDMS diagnosis (n = 40, 32.5 pg/mL), and ADS- who remained monophasic (n = 34, 17.6 pg/mL). sNfL levels higher than a median of 26.7 pg/mL at baseline are associated with a shorter time to CDMS diagnosis in ADS- (p = 0.045). HR for CDMS diagnosis was 1.09 for each 10 pg/mL increase of sNfL, after correction for age, oligoclonal bands, and MRI measures (p = 0.012). CONCLUSION: The significant correlation between CSF and serum NfL strengthens its reliability as a peripheral marker of neuroaxonal damage. Higher sNfL levels at baseline were associated with higher probability of future CDMS diagnosis in ADS-.


Assuntos
Esclerose Múltipla/sangue , Esclerose Múltipla/diagnóstico por imagem , Proteínas de Neurofilamentos/sangue , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/diagnóstico por imagem , Feminino , Humanos , Masculino , Estudos Prospectivos , Síndrome
13.
Epilepsy Behav ; 101(Pt B): 106432, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31375414

RESUMO

Functional outcome in patients with postanoxic encephalopathy after cardiac arrest (CA) often remains unclear, and there is a strong need of new prognostication measures. We aimed at investigating serum neurofilament light (NfL) chain concentration in patients with a postanoxic encephalopathy after CA and its prognostic potential. Serum samples were prospectively collected at different time points after CA in consecutive patients admitted to the intensive care unit (ICU) of Ticino Cardiocentre (Lugano, Switzerland) between June 2017 and March 2018. Serum NfL concentration was measured using a single molecule array (SIMOA) assay. The association of NfL levels with time to return of spontaneous circulation (ROSC), serum neuronal specific enolase (NSE) concentration, time between CA and sample collection, electroencephalogram (EEG) pattern and clinical outcome (death status at one month) were explored. Fourteen patients experiencing 15 CAs were included in the study (median age = 58 (57-68) years, 8 males). Median serum NfL concentration was 1027.0 (25.5-6033.7) pg/ml. There were positive associations between serum NfL and time to ROSC (rho = 0.60, p < 0.0001), NSE concentration (rho = 0.76, p < 0.0001), and severity of brain damage as estimated by EEG, with the highest concentrations measured in patients with suppressed electrical activity (14,954.0 [9006.0-25,364.0] pg/ml). Neurofilament light concentration remained high in samples collected up to 17 days after CA. Median NfL levels were higher among dead than alive patients at one month (6401.7 [3768.5-15,573.3] vs 25.5 [25.2-75.4] pg/ml). High NfL levels performed better than NSE in predicting death status at one month (NfL area under the curve (AUC) = 0.98, 95% confidence interval (CI) = 0.94-1.00; NSE AUC = 0.80, 95% CI = 0.67-0.94). These results support the potential inclusion of serum NfL in the battery of prognostication measures to be used in patients with postanoxic encephalopathy in ICU settings. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".


Assuntos
Encefalopatias/diagnóstico , Hipóxia/complicações , Proteínas de Neurofilamentos/sangue , Idoso , Biomarcadores/sangue , Encefalopatias/sangue , Encefalopatias/etiologia , Feminino , Humanos , Hipóxia/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico
14.
Ann Clin Transl Neurol ; 6(9): 1757-1770, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31437387

RESUMO

BACKGROUND: Gray matter (GM) pathology is closely associated with physical and cognitive impairment in persons with multiple sclerosis (PwMS). Similarly, serum neurofilament light chain (sNfL) levels are related to MS disease activity and progression. OBJECTIVES: To assess the cross-sectional and longitudinal associations between sNfL and MRI-derived lesion and brain volume outcomes in PwMS and age-matched healthy controls (HCs). MATERIALS AND METHODS: Forty-seven HCs and 120 PwMS were followed over 5 years. All subjects underwent baseline and follow-up 3T MRI and sNfL examinations. Lesion volumes (LV) and global, tissue-specific and regional brain volumes were assessed. sNfL levels were analyzed using single molecule array (Simoa) assay and quantified in pg/mL. The associations between sNfL levels and MRI outcomes were investigated using regression analyses adjusted for age, sex, baseline disease modifying treatment (DMT) use and change in DMT over the follow-up. False discovery rate (FDR)-adjusted q-values <0.05 were considered significant. RESULTS: In PwMS, baseline sNfL was associated with baseline T1 -, T2 - and gadolinium-LV (q = 0.002, q = 0.001 and q < 0.001, respectively), but not with their longitudinal changes. Higher baseline sNfL levels were associated with lower baseline deep GM (ß = -0.257, q = 0.017), thalamus (ß = -0.216, q = 0.0017), caudate (ß = -0.263, q = 0.014) and hippocampus (ß = -0.267, q = 0.015) volumes. Baseline sNfL was associated with longitudinal decline of deep GM (ß = -0.386, q < 0.001), putamen (ß = -0.395, q < 0.001), whole brain (ß = -0.356, q = 0.002), thalamus (ß = -0.272, q = 0.049), globus pallidus (ß = -0.284, q = 0.017), and GM (ß = -0.264, q = 0.042) volumes. No associations between sNfL and MRI-derived measures were seen in the HCs. CONCLUSION: Higher sNfL levels were associated with baseline LVs and greater development of GM atrophy in PwMS.


Assuntos
Encéfalo/patologia , Substância Cinzenta/patologia , Esclerose Múltipla/patologia , Proteínas de Neurofilamentos/sangue , Adulto , Encéfalo/diagnóstico por imagem , Progressão da Doença , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Filamentos Intermediários , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/diagnóstico por imagem
15.
JAMA Neurol ; 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31403661

RESUMO

Importance: Blood sample-based biomarkers that are associated with clinically meaningful outcomes for patients with multiple sclerosis (MS) have not been developed. Objective: To evaluate the potential of serum neurofilament light chain (sNFL) measurements as a biomarker of disease activity and progression in a longitudinal MS data set. Design, Setting, and Participants: Single-center, ongoing, prospective observational cohort study of 607 patients with MS from the longitudinal EPIC (Expression, Proteomics, Imaging, Clinical) study at the University of California, San Francisco from July 1, 2004, through August 31, 2017. Clinical evaluations and sample collection were performed annually for 5 years, then at different time points for up to 12 years, with a median follow-up duration of 10 (interquartile range, 7-11) years. Serum NFL levels were measured using a sensitive single molecule array platform and compared with clinical and magnetic resonance imaging variables with the use of univariable and multivariable analyses. Main Outcomes and Measures: The main outcomes were disability progression defined as clinically significant worsening on the Expanded Disability Status Scale (EDSS) score and brain fraction atrophy. Results: Mean (SD) age of the 607 study participants at study entry was 42.5 (9.8) years; 423 (69.7%) were women; and all participants were of non-Hispanic European descent. Of 3911 samples sequentially collected, 3904 passed quality control for quantification of sNFL. Baseline sNFL levels showed significant associations with EDSS score (ß, 1.080; 95% CI, 1.047-1.114; P < .001), MS subtype (ß, 1.478; 95% CI, 1.279-1.707; P < .001), and treatment status (ß, 1.120; 95% CI, 1.007-1.245; P = .04). A significant interaction between EDSS worsening and change in levels of sNFL over time was found (ß, 1.015; 95% CI, 1.007-1.023; P < .001). Baseline sNFL levels alone were associated with approximately 11.6% of the variance in brain fraction atrophy at year 10. In a multivariable analysis that considered sex, age, and disease duration, baseline sNFL levels were associated with 18.0% of the variance in brain fraction atrophy at year 10. After 5 years' follow-up, active treatment was associated with lower levels of sNFL, with high-potency treatments associated with the greater decreases in sNFL levels compared with platform therapies (high-potency vs untreated: ß, 0.946; 95% CI, 0.915-0.976; P < .001; high-potency vs platform: ß, 0.972; 95% CI, 0.948-0.998; P = .04). Conclusions and Relevance: This study found that statistically significant associations of sNFL with relevant clinical and neuroimaging outcomes in MS were confirmed and extended, supporting the potential of sNFL as an objective surrogate of ongoing MS disease activity. In this data set of patients with MS who received early treatment, the prognostic power of sNFL for relapse activity and long-term disability progression was limited. Further prospective studies are necessary to assess the assay's utility for decision-making in individual patients.

16.
Neurology ; 93(8): e804-e814, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31345959

RESUMO

OBJECTIVE: To determine hippocampal morphometric measures, including granule cell dispersion and features of malrotation, as potential biomarkers for sudden unexpected death in epilepsy (SUDEP) from an archival postmortem series. METHODS: In a retrospective study of 187 archival postmortems from 3 groups, SUDEP (68; 14 with hippocampal sclerosis [HS]), non-SUDEP epilepsy controls (EP-C = 66; 25 with HS), and nonepilepsy controls (NEC = 53), Nissl/hematoxylin & eosin-stained sections from left and right hippocampus from 5 coronal levels were digitized. Image analysis was carried out for granule cell layer (GCL) thickness and measurements of hippocampal dimensions (HD) for shape (width [HD1], height [HD2]) and medial hippocampal positioning in relation to the parahippocampal gyrus (PHG) length (HD3). A qualitative evaluation of hippocampal malrotational (HMAL) features, dentate gyrus invaginations (DGI), and subicular/CA1 folds (SCF) was also made. RESULTS: GCL thickness was increased in HS more than those without (p < 0.001). In non-HS cases, increased GCL thickness was noted in EP-C compared to NEC (p < 0.05) but not between SUDEP and NEC. There was no difference in the frequency of DGI, SCF, measurements of hippocampal shape (HD1, HD2, or ratio), or medial positioning among SUDEP, EP-C, and NEC groups, when factoring in HS, coronal level, and age at death. Comparison between left and right sides within cases showed greater PHG lengths (HD3) on the right side in the SUDEP group only (p = 0.018). CONCLUSIONS: No hippocampal morphometric features were identified in support of either excessive granule cell dispersion or features of HMAL as definitive biomarkers for SUDEP. Asymmetries in PHG measurements in SUDEP warrant further investigation as they may indicate abnormal central autonomic networks.


Assuntos
Morte Súbita/patologia , Epilepsia/patologia , Hipocampo/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Esclerose/patologia , Adulto Jovem
17.
Clin Chem Lab Med ; 57(10): 1556-1564, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31251725

RESUMO

Background Phosphorylated neurofilament heavy (pNfH), a neuronal cytoskeleton protein, might provide a promising blood biomarker of neuronal damage in neurodegenerative diseases (NDDs). The best analytical approaches to measure pNfH levels and whether serum levels correlate with cerebrospinal fluid (CSF) levels in NDDs remain to be determined. Methods We here compared analytical sensitivity and reliability of three novel analytical approaches (homebrew Simoa, commercial Simoa and ELISA) for quantifying pNfH in both CSF and serum in samples of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and control subjects. Results While all three assays showed highly correlated CSF measurements, Simoa assays also yielded high between-assay correlations for serum measurements (ϱ = 0.95). Serum levels also correlated strongly with CSF levels for Simoa-based measurements (both ϱ = 0.62). All three assays allowed distinguishing ALS from controls by increased CSF pNfH levels, and Simoa assays also by increased serum pNfH levels. pNfH levels were also increased in FTD. Conclusions pNfH concentrations in CSF and, if measured by Simoa assays, in blood might provide a sensitive and reliable biomarker of neuronal damage, with good between-assay correlations. Serum pNfH levels measured by Simoa assays closely reflect CSF levels, rendering serum pNfH an easily accessible blood biomarker of neuronal damage in NDDs.


Assuntos
Técnicas de Laboratório Clínico/métodos , Proteínas de Neurofilamentos/análise , Reprodutibilidade dos Testes , Adulto , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Esclerose Amiotrófica Lateral/sangue , Esclerose Amiotrófica Lateral/líquido cefalorraquidiano , Biomarcadores/sangue , Progressão da Doença , Feminino , Demência Frontotemporal/sangue , Demência Frontotemporal/líquido cefalorraquidiano , Humanos , Doença de Huntington/sangue , Doença de Huntington/líquido cefalorraquidiano , Filamentos Intermediários , Masculino , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Fosforilação , Soro/metabolismo
18.
J Peripher Nerv Syst ; 24(2): 187-194, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30973667

RESUMO

Axonal damage in chronic inflammatory demyelinating polyneuropathy (CIDP) is the main predictor of poor outcome. We hypothesized that serum neurofilament light chain (sNfL) reflects disease activity by detecting ongoing neuro-axonal damage in CIDP. Three prospective cohorts of CIDP patients were studied: (a) patients starting induction treatment (IT cohort, N = 29) measured at baseline and 6 months after starting treatment; (b) patients on maintenance treatment (MT) starting intravenous immunoglobuline (IVIg) withdrawal (MT cohort, N = 24) measured at baseline and 6 months after IVIg withdrawal or at time of relapse; and (c) patients in long-term remission without treatment (N = 27). A single molecule array assay was used to measure sNfL. Age-matched healthy controls (N = 30) and age-specific reference values were used for comparison. At baseline, sNfL was higher in patients starting IT compared to healthy controls. Ten out of 29 IT (34%) patients have sNfL levels above the 95th percentile of age-specific cut-off values. In the MT and remission cohort, elevated sNfL levels were infrequent and not different from healthy controls. sNfL levels were correlated with electrophysiological markers of axonal damage. At follow-up assessment, patients with active disease (non-responders and patients who relapsed after IVIg withdrawal) had higher sNfL levels compared with patients with stable disease (responders and patients who were successfully withdrawn from IVIg treatment). sNfL levels were increased in a third of CIDP patients starting IT and reflected axonal damage. sNfL levels might be usable as biomarker of disease activity in a subset of CIDP patients.


Assuntos
Proteínas de Neurofilamentos/sangue , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/sangue , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Condução Nervosa/fisiologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/fisiopatologia , Estudos Prospectivos
19.
Ann Clin Transl Neurol ; 5(12): 1478-1491, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30564615

RESUMO

Objective: To assess the value of annual serum neurofilament light (NfL) measures in predicting 10-year clinical and MRI outcomes in multiple sclerosis (MS). Methods: We identified patients in our center's Comprehensive Longitudinal Investigations in MS at Brigham and Women's Hospital (CLIMB) study enrolled within 5 years of disease onset, and with annual blood samples up to 10 years (n = 122). Serum NfL was measured using a single molecule array (SIMOA) assay. An automated pipeline quantified brain T2 hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) from year 10 high-resolution 3T MRI scans. Correlations between averaged annual NfL and 10-year clinical/MRI outcomes were assessed using Spearman's correlation, univariate, and multivariate linear regression models. Results: Averaged annual NfL values were negatively associated with year 10 BPF, which included averaged year 1-5 NfL values (unadjusted P < 0.01; adjusted analysis P < 0.01), and averaged values through year 10. Linear regression analyses of averaged annual NfL values showed multiple associations with T2LV, specifically averaged year 1-5 NfL (unadjusted P < 0.01; adjusted analysis P < 0.01). Approximately 15-20% of the BPF variance and T2LV could be predicted from early averaged annual NfL levels. Also, averaged annual NfL levels with fatigue score worsening between years 1 and 10 showed statistically significant associations. However, averaged NfL measurements were not associated with year 10 EDSS, SDMT or T25FW in this cohort. Interpretation: Serum NfL measured during the first few years after the clinical onset of MS contributed to the prediction of 10-year MRI brain lesion load and atrophy.

20.
Neurology ; 91(22): e2078-e2088, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30413629

RESUMO

OBJECTIVE: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype-phenotype correlation. METHODS: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations. RESULTS: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype-phenotype correlation did not emerge. CONCLUSION: COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.


Assuntos
Colágeno Tipo IV/genética , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Epilepsia/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Mutação , Adulto Jovem
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