RESUMO
Cladribine (Mavenclad®) is an oral treatment for relapsing remitting MS (RRMS), but its mechanism of action and its effects on innate immune responses in unknown. This study is a prospective Phase IV study of 41 patients with RRMS, and aims to investigate the mechanism of action of cladribine on peripheral monocytes, and its impact on the P2X7 receptor. There was a significant reduction in monocyte count in vivo at week 1 post cladribine administration, and the subset of cells being most impacted were the CD14lo CD16+ 'non-classical' monocytes. Of the 14 cytokines measured in serum, CCL2 levels increased at week 1. In vitro, cladrabine induced a reduction in P2X7R pore as well as channel activity. This study demonstrates a novel mechanism of action for cladribine. It calls for studying potential benefits of cladribine in progressive forms of MS and other neurodegenerative diseases where innate immune related inflammation is implicated in disease pathogenesis.
Assuntos
Cladribina , Citocinas , Imunidade Inata , Monócitos , Esclerose Múltipla Recidivante-Remitente , Humanos , Cladribina/uso terapêutico , Cladribina/farmacologia , Imunidade Inata/efeitos dos fármacos , Feminino , Masculino , Adulto , Estudos Prospectivos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/sangue , Monócitos/imunologia , Monócitos/efeitos dos fármacos , Pessoa de Meia-Idade , Citocinas/sangue , Citocinas/imunologia , Receptores Purinérgicos P2X7/imunologia , Imunossupressores/uso terapêutico , Imunossupressores/farmacologia , Adulto JovemRESUMO
OBJECTIVE: To examine the utility of neuroimaging characteristics as biomarkers of prognosis in seropositive autoimmune encephalitis (AE). METHODS: In this multi-center study, we retrospectively analyzed 66 cases of seropositive AE. The MRI and PET imaging was assessed by independent visual inspection. Whole brain and regional volumes were imputed by IcoMetrix, an automated volumetric assessment package. The modified Rankin Scale (mRS) was utilized to assess the patients' follow-up disability. Other outcomes were mortality, first line treatment failure, medial temporal lobe (MTL) atrophy, and clinical relapse. Univariate and multivariable regression analysis was performed. RESULTS: Abnormalities on MRI were detected in 35.1% of patients, while PET was abnormal in 46.4%. Initial median whole brain and hippocampal volumes were below the 5th and 20th percentile respectively compared to an age-matched healthy database. After a median follow-up of 715 days, 85.2% had good functional outcome (mRS ≤ 2). Nine patients developed MTL atrophy during follow-up. On multivariable analysis, inflammatory MTL changes were associated with development of MTL atrophy (HR 19.6, p = 0.007) and initial hippocampal volume had an inverse relationship with mortality (HR 0.04, p = 0.011). Patients who developed MTL atrophy had a reduced chance of good final mRS (HR 0.16, p = 0.015). CONCLUSIONS: Neuroimaging on initial hospital admission may be provide important diagnostic and prognostic information. This study demonstrates that structural and inflammatory changes of the MTL may have importance in clinical and radiological prognosis in seropositive AE.
Assuntos
Doenças Autoimunes do Sistema Nervoso , Neuroimagem , Humanos , Estudos Retrospectivos , Imageamento por Ressonância Magnética/métodos , Prognóstico , AtrofiaRESUMO
OBJECTIVE: To evaluate the utility of electroencephalography (EEG) changes as diagnostic and prognostic biomarkers in acute autoimmune encephalitis (AIE). METHODS: One hundred and thirty-one patients with AIE were recruited retrospectively across 7 hospitals. Clinical data were collected during admission and at 12 months. EEGs were reviewed using a standard reporting proforma. Associations between EEG biomarkers, AIE subtypes, and clinical outcomes were assessed using logistic regression modeling. RESULTS: Presence of superimposed fast activity (OR 34.33; 95% CI 3.90, 4527.27; pâ¯<â¯0.001), fluctuating EEG abnormality (OR 6.60; 95% CI 1.60, 37.59; pâ¯=â¯0.008), and hemispheric focality (OR 28.48; 95% CI 3.14, 3773.14; pâ¯<â¯0.001) were significantly more common in N-methyl-d-aspartate receptor (NMDAR) antibody-associated patients with AIE compared to other AIE subtypes. Abnormal background rhythm was associated with a poor mRS (modified Rankin score) at discharge (OR 0.29; 95% CI 0.10, 0.75; pâ¯=â¯0.01) and improvement in mRS at 12â¯months compared with admission mRS (3.72; 95% CI 1.14, 15.23; pâ¯=â¯0.04). SIGNIFICANCE: We have identified EEG biomarkers that differentiate NMDAR AIE from other subtypes. We have also demonstrated EEG biomarkers that are associated with poor functional outcomes.
Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato , Doença de Hashimoto , Encefalite Antirreceptor de N-Metil-D-Aspartato/complicações , Biomarcadores , Eletroencefalografia , Doença de Hashimoto/complicações , Doença de Hashimoto/diagnóstico , Humanos , Estudos RetrospectivosRESUMO
OBJECTIVE: To evaluate the prevalence and biomarkers of drug-resistant epilepsy (DRE) in patients with autoimmune encephalitis (AIE). METHODS: Sixty-nine patients with AIE were recruited retrospectively and electroencephalographies (EEGs) were reviewed using a standard reporting proforma. Associations between EEG biomarkers and DRE development at 12â¯months were examined using logistic regression modeling and were utilized to create a DRE risk score. RESULTS: Sixteen percent of patients with AIE developed DRE at 12-month follow-up. The presence of status epilepticus (SE) (OR 11.50, 95% CI [2.81, 51.86], p-value <0.001), temporal lobe focality (OR 9.90, 95% CI [2.60, 50.71], p-value 0.001) and periodic discharges (OR 19.12, 95% CI [3.79, 191.10], p-value 0.001) on the admission EEG were associated with the development of DRE at 12â¯months. These variables were utilized to create a clinically applicable risk score for the prediction of DRE development. CONCLUSIONS: Drug-resistant epilepsy is an infrequent complication of AIE. Electroencephalography changes during the acute illness can predict the risk of DRE at 12â¯months post-acute AIE. SIGNIFICANCE: The identified EEG biomarkers provide the basis to generate a clinically applicable prediction tool which could be used to inform treatment, prognosis, and select patients for acute treatment trials.
Assuntos
Epilepsia Resistente a Medicamentos , Encefalite , Biomarcadores , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/epidemiologia , Epilepsia Resistente a Medicamentos/etiologia , Eletroencefalografia/efeitos adversos , Encefalite/complicações , Encefalite/epidemiologia , Doença de Hashimoto , Humanos , Prevalência , Prognóstico , Estudos Retrospectivos , Fatores de RiscoAssuntos
Esclerose Múltipla/complicações , Infecções Oportunistas/prevenção & controle , Guias de Prática Clínica como Assunto , Complicações na Gravidez/prevenção & controle , Vacinação/normas , Austrália , Feminino , Humanos , Hospedeiro Imunocomprometido , Imunogenicidade da Vacina , Fatores Imunológicos/efeitos adversos , Masculino , Esclerose Múltipla/sangue , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Infecções Oportunistas/complicações , Infecções Oportunistas/imunologia , Infecções Oportunistas/microbiologia , Gravidez , Complicações na Gravidez/imunologia , Complicações na Gravidez/microbiologia , Soroconversão , Vacinação/efeitos adversos , Vacinas/administração & dosagem , Vacinas/efeitos adversos , Vacinas/imunologiaRESUMO
Background: In Australia, tixagevimab/cilgavimab 150 mg/150 mg was a government-funded pre-exposure prophylaxis for COVID-19 people with multiple sclerosis (pwMS) and other neuroimmunological conditions (pwNIc) treated with anti-CD20 antibodies or sphingosine-1-phosphate receptor modulators were eligible. Objective: To analyse the roll-out, uptake and real-world efficacy of tixagevimab/cilgavimab in the prevention and severity of COVID-19. To assess compliance with uptake depending on the location of delivery. Methods: We undertook a single-centre study. 440 pwMS and pwNIc were eligible. Logistic regression was used to assess predictors of COVID-19 during follow-up and to assess predictors of uptake among those who consented. Results: Of the eligible pwMS and pwNIc in our service, 52.7% (233/440) requested a consultation and were included in this study. Consultation resulted in 71.7% of people (167/233) receiving the treatment. Of these, 94.0% (157/167) had received three or more COVID-19 vaccines. Among those who received a single dose of tixagevimab/cilgavimab, 19.16% (32/167) tested positive for COVID-19 during the observational window. The majority of these were on ocrelizumab (68.8% (22/32)). None of those with COVID-19 required hospitalisation or supplemental oxygen. There was no difference in odds of COVID-19 during the observation period between those who received and did not receive tixagevimab/cilgavimab (adjusted OR, aOR 2.16 (95% CI 0.82 to 6.85), p=0.43). Uptake of tixagevimab/cilgavimab was highest when offered at the hospital infusion centre (aOR 3.09 (95% CI 1.08 to 9.94) relative to referral to the local pharmacy, p=0.04). Conclusion: Tixagevimab/cilgavimab administration did not protect against subsequent COVID-19 in our cohort. Compliance with uptake was influenced by administration location.
RESUMO
Ocrelizumab is an anti-CD20 monoclonal antibody (mAb) that has been shown in phase 3 clinical trials to reduce relapses and disease progression in multiple sclerosis (MS) patients. Prior to the approval of ocrelizumab, rituximab, a chimeric anti-CD20 mAb was used to treat MS. Rituximab is still used to treat MS in many countries outside of Australia and remains mainstay of treatment of many non-MS neuroimmunological and systemic inflammatory diseases. Rituximab is currently used in neuromyelitis optica spectrum disorder (NMOSD) and autoimmune encephalitis, in addition to its widespread usage in hematological malignancies and systemic inflammatory diseases. Ocrelizumab is currently approved in Australia for treatment of relapsing-remitting MS (RRMS). Neutropaenia is a rare complication of both ocrelizumab and rituximab treatment. This case series reports 12 patients who have experienced neutropaenia following ocrelizumab or rituximab treatment and aims to characterize the clinical parameters of neutropaenia experienced by these patients, including the severity and duration of neutropaenia, length of hospital admission, the types of subsequent infections experienced and types of treatment necessary before patients reached count recovery. The unpredictability of neutropaenia and potential for serious infections highlight the need for continued hematological monitoring for patients on B-cell depleting therapies and calls for careful patient counselling to provide guidance on whether to continue such therapies in patients who have experienced related neutropaenia.
Assuntos
Antineoplásicos , Esclerose Múltipla , Neutropenia , Humanos , Rituximab/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neutropenia/tratamento farmacológicoRESUMO
OBJECTIVE: To examine the prognostic value of CSF abnormalities in seropositive autoimmune encephalitis (AE). METHODS: We retrospectively studied 57 cases of seropositive AE. Primary outcomes were mortality and modified Rankin Scale, while secondary outcomes were first line treatment failure, ICU admission and relapse. Regression analysis was performed. RESULTS: CSF white cell count (WCC) was higher in the NMDAR group, while elevated protein was more common amongst other subtypes. We found an association between WCC >5 cells/mm3 and treatment failure (OR 16.0, p = 0.006)), and between WCC >20 cells/mm3 and ICU admission (OR 19.3, p = 0.026). CONCLUSIONS: Different subsets of AE have characteristic CSF abnormalities, which may aid recognition during early evaluation. CSF WCC had prognostic significance in our study.
Assuntos
Doenças Autoimunes/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Encefalite/líquido cefalorraquidiano , Linfocitose/líquido cefalorraquidiano , Adulto , Autoanticorpos/imunologia , Doenças Autoimunes/tratamento farmacológico , Líquido Cefalorraquidiano/citologia , Encefalite/tratamento farmacológico , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Masculino , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: People with multiple sclerosis and neuroimmunologic disorders (herein referred to as patients) are increasingly treated with infusible monoclonal antibodies. This rise in demand has placed increased loads on current infusion services and mandates careful strategic planning. This study examined patient preferences for the timing and location of infusions and their association with demographic and disease variables to facilitate patient-focused strategic planning. METHODS: Ninety-one patients receiving an infusible therapy at an infusion service during March 2019 were asked to complete a questionnaire exploring eight domains, including preferences for time of infusions and location of infusion centers. Potential access to home-based treatment was included as an option. Unstructured (free-text) feedback on current service was also obtained. RESULTS: Eighty-three patients completed the survey (mean age, 42 years; 75% women). Infusions were predominantly natalizumab (66%) and ocrelizumab (25%). Of these patients, 71% were engaged in some form of work or study, and 83% of this group had to arrange time off from work or study to attend treatment. Seventy percent of patients would prefer their infusion before noon, and 60% would consider home-based infusions. Most used a car as their transport to the infusion service. CONCLUSIONS: These results suggest that patients are more likely to prefer infusible treatment in the morning and are open to home-based infusions. This study provides information for health services to target service delivery at peak preference times and consider alternate ways of delivering infusible treatments.
RESUMO
BACKGROUND AND OBJECTIVE: The global COVID-19 pandemic creates an obvious acute health care resourcing and response problem. The different timing of pandemic peak in geographically distinct locations creates a short window of response opportunity. Rapid dissemination of medical information from early affected areas to later ones is therefore crucial to optimise planning. Formulating the best system response for at-risk patient populations is especially complex. People with multiple sclerosis (pwMS) are exposed to long-term immunosuppressive disease modifying treatments (DMTs) and, in theory, could be at increased risk of contracting the virus and developing complications. Social media, such as Twitter, can provide a global platform to rapidly share information and individual experiences. METHODS AND RESULTS: This report summarizes the case experience of pwMS with COVID-19 infection in the first month of the pandemic as reported on Twitter using the #MSCOVID19 hashtag. 26 individual cases of COVID-19 in pwMS were reported from Europe and the United States of America. The cases involved a combination of relapsing and progressive MS phenotypes treated with a range of DMT (5 anti CD20 therapy, 4 cladribine, 4 fingolimod, 4 injectables, 3 alemtuzumab, 2 dimethyl fumarate, 2 untreated, 1 teriflunomide, 1 natalizumab). The cases shared present the earliest reported data on outcomes of COVID-19 infection in pwMS. Whilst limited, the cautiously reassuring nature of these early cases assisted in clinical management by allowing neurologists to continuously reassess their approach to DMT management.
Assuntos
Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Hospedeiro Imunocomprometido , Esclerose Múltipla/complicações , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Mídias Sociais , Adulto , Betacoronavirus , COVID-19 , Infecções por Coronavirus/mortalidade , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/mortalidade , Pandemias , Pneumonia Viral/mortalidade , SARS-CoV-2RESUMO
Objective: To examine the utility of the peripheral blood neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) as biomarkers of prognosis in seropositive autoimmune encephalitis (AE). Methods: In this multicenter study, we retrospectively analyzed 57 cases of seropositive AE with hospital admissions between January 2008 and June 2019. The initial full blood examination was used to determine each patients' NLR and MLR. The modified Rankin Scale (mRS) was utilized to assess the patients' follow-up disability at 12 months and then at final follow-up. Primary outcomes were mortality and mRS, while secondary outcomes were failure of first line treatment, ICU admission, and clinical relapse. Univariate and multivariable regression analysis was performed. Results: During initial hospital admission 44.7% of patients had unsuccessful first line treatment. After a median follow-up of 700 days, 82.7% had good functional outcome (mRS ≤2) while five patients had died. On multivariable analysis, high NLR was associated with higher odds of first line treatment failure (OR 1.32, 95% CI 1.03-1.69, p = 0.029). Increased MLR was not associated with any short or long-term outcome. Conclusions: NLR on initial hospital admission blood tests may be provide important prognostic information for cases of seropositive AE. This study demonstrates the potential use of NLR as a prognostic marker in the clinical evaluation of patients with seropositive AE.
Assuntos
Biomarcadores , Encefalite/sangue , Encefalite/epidemiologia , Doença de Hashimoto/sangue , Doença de Hashimoto/epidemiologia , Contagem de Leucócitos , Contagem de Linfócitos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Gerenciamento Clínico , Encefalite/diagnóstico , Encefalite/terapia , Feminino , Doença de Hashimoto/diagnóstico , Doença de Hashimoto/terapia , Humanos , Linfócitos , Masculino , Pessoa de Meia-Idade , Monócitos , Morbidade , Mortalidade , Neutrófilos , Prognóstico , Vigilância em Saúde Pública , Adulto JovemRESUMO
A 74-year-old man presented with a subacute severe thoracic polyradiculopathy affecting the T4-T8 dermatomes bilaterally. Extensive investigation demonstrated markedly raised triglyceride levels of 44â mmol/L (<1.7). The patient's unique presentation is discussed alongside a review of triglyceride-induced neurotoxicity and therapeutic management.
Assuntos
Analgésicos/uso terapêutico , Hipertrigliceridemia/complicações , Hipertrigliceridemia/diagnóstico , Polirradiculopatia/etiologia , Triglicerídeos/sangue , Idoso , Humanos , Hipertrigliceridemia/sangue , Ketamina/uso terapêutico , Masculino , Polirradiculopatia/sangue , Polirradiculopatia/tratamento farmacológico , Pregabalina/uso terapêutico , Índice de Gravidade de Doença , Resultado do Tratamento , Triglicerídeos/efeitos adversosRESUMO
Epidural blood patching (EBP) is an important therapeutic approach in managing spontaneous cerebrospinal fluid leaks. The mechanism of action of blood patching is likely to be twofold; fluid replacement having an immediate tamponade effect and the proximal flow of blood products having a 'plug' effect. The negative pressure gradient within the epidural space may be important to the rostral flow of injected blood and is possibly increased in intracranial hypotension.
Assuntos
Placa de Sangue Epidural , Vazamento de Líquido Cefalorraquidiano/terapia , Cefaleia/prevenção & controle , Acidentes de Trânsito , Adulto , Placa de Sangue Epidural/métodos , Vazamento de Líquido Cefalorraquidiano/diagnóstico , Vazamento de Líquido Cefalorraquidiano/etiologia , Espaço Epidural/diagnóstico por imagem , Feminino , Humanos , Região Lombossacral , Imageamento por Ressonância Magnética , Fatores de Risco , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
A 67-year-old woman presented with recurrent transient ischaemic attack-like episodes over a 2 year period. Nodular enhancing leptomeningeal changes were detected on MRI and were consistent with meningeal rheumatoid nodules on biopsy. The patient's nodular disease continued to progress and regress clinically and radiologically irrespective of disease modifying agents and peripheral and serological rheumatoid arthritis control. This patient's unique presentation and diagnostic work-up is discussed alongside the dilemma of therapeutic management of meningeal rheumatoid nodules.