RESUMO
BACKGROUND: Serum autoantibodies against the water channel aquaporin-4 (AQP4) are important diagnostic biomarkers and pathogenic factors for neuromyelitis optica (NMO). However, AQP4-IgG are absent in 5-40% of all NMO patients and the target of the autoimmune response in these patients is unknown. Since recent studies indicate that autoimmune responses to myelin oligodendrocyte glycoprotein (MOG) can induce an NMO-like disease in experimental animal models, we speculate that MOG might be an autoantigen in AQP4-IgG seronegative NMO. Although high-titer autoantibodies to human native MOG were mainly detected in a subgroup of pediatric acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) patients, their role in NMO and High-risk NMO (HR-NMO; recurrent optic neuritis-rON or longitudinally extensive transverse myelitis-LETM) remains unresolved. RESULTS: We analyzed patients with definite NMO (n = 45), HR-NMO (n = 53), ADEM (n = 33), clinically isolated syndromes presenting with myelitis or optic neuritis (CIS, n = 32), MS (n = 71) and controls (n = 101; 24 other neurological diseases-OND, 27 systemic lupus erythematosus-SLE and 50 healthy subjects) for serum IgG to MOG and AQP4. Furthermore, we investigated whether these antibodies can mediate complement dependent cytotoxicity (CDC). AQP4-IgG was found in patients with NMO (n = 43, 96%), HR-NMO (n = 32, 60%) and in one CIS patient (3%), but was absent in ADEM, MS and controls. High-titer MOG-IgG was found in patients with ADEM (n = 14, 42%), NMO (n = 3, 7%), HR-NMO (n = 7, 13%, 5 rON and 2 LETM), CIS (n = 2, 6%), MS (n = 2, 3%) and controls (n = 3, 3%, two SLE and one OND). Two of the three MOG-IgG positive NMO patients and all seven MOG-IgG positive HR-NMO patients were negative for AQP4-IgG. Thus, MOG-IgG were found in both AQP4-IgG seronegative NMO patients and seven of 21 (33%) AQP4-IgG negative HR-NMO patients. Antibodies to MOG and AQP4 were predominantly of the IgG1 subtype, and were able to mediate CDC at high-titer levels. CONCLUSIONS: We could show for the first time that a subset of AQP4-IgG seronegative patients with NMO and HR-NMO exhibit a MOG-IgG mediated immune response, whereas MOG is not a target antigen in cases with an AQP4-directed humoral immune response.
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Autoanticorpos/imunologia , Ativação do Complemento/imunologia , Proteínas da Mielina/imunologia , Mielite Transversa/imunologia , Neuromielite Óptica/imunologia , Adolescente , Adulto , Aquaporina 4/imunologia , Autoanticorpos/sangue , Autoantígenos/imunologia , Pré-Escolar , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Glicoproteína Mielina-Oligodendrócito , Mielite Transversa/sangue , Neuromielite Óptica/sangueRESUMO
Multiple sclerosis (MS) is an idiopathic chronic inflammatory demyelinating disease of the central nervous system with variable extent of remyelination. Remyelination originates from oligodendrocyte (OG) precursor cells, which migrate and differentiate into mature OG. Tubulin polymerization promoting protein (TPPP/p25) is located in mature OG and aggregates in oligodendroglial cytoplasmic inclusions in multiple system atrophy. We developed a novel monoclonal anti-TPPP/p25 antibody to quantify OG in different subtypes and disease stages of MS, and possible degenerative changes in OG. We evaluated autopsy material from 25 MS cases, including acute, primary progressive, secondary progressive, relapsing remitting MS, and five controls. Demyelinated lesions revealed loss of TPPP/p25-positive OG within the plaques. In remyelination, TPPP/p25 was first expressed in OG cytoplasms and later became positive in myelin sheaths. We observed increased numbers of TPPP/p25 immunoreactive OG in the normal appearing white matter (NAWM) in MS patients. In MS cases, the cytoplasmic area of TPPP/p25 immunoreactivity in the OG was higher in the periplaque area when compared with NAWM and the plaque, and TPPP/p25 immunoreactive OG cytoplasmic area inversely correlated with the disease duration. There was a lack of phospho-TDP-43, phospho-tau, α-synuclein, and ubiquitin immunoreactivity in OG with enlarged cytoplasm. Our data suggest impaired differentiation, migration, and activation capacity of OG in later disease stages of MS. Upregulation of TPPP/p25 in the periplaque white matter OG without evidence for inclusion body formation might reflect an activation state. Distinct and increased expression of TPPP/p25 in MS renders it a potential prognostic and diagnostic marker of MS.
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Esclerose Múltipla/classificação , Esclerose Múltipla/patologia , Bainha de Mielina/patologia , Proteínas do Tecido Nervoso/metabolismo , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores/metabolismo , Movimento Celular/fisiologia , Proteínas de Ligação a DNA/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteína Básica da Mielina/metabolismo , Proteína Proteolipídica de Mielina/metabolismo , Bainha de Mielina/metabolismo , Índice de Gravidade de Doença , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismoRESUMO
PURPOSE: Penetrating keratoplasty has been the mainstay for the treatment of blindness and is the most common form of tissue transplantation worldwide. Due to significant rates of rejection, treatment of immunological transplant reactions is of wide interest. Recently in a mouse model, the overexpression of indoeleamine 2,3 dioxigenase (IDO) was led to an extension in corneal allograft survival. L-kynurenine is a tryptophan metabolite, which may render activated T-cells apoptotic and therefore might modulate an allogenous transplant reaction. The function of L-kynurenine in the human cornea remains unclear. We analyzed the expression levels of IDO in human corneal endothelial cells (HCECs) and downstream tryptophan/kynurenine mechanisms in cell culture. METHODS: An immunological activation profile was determined in proliferation assays of monocytes from healthy donors. Reversed-phase high pressure liquid chromatography (HPLC), western blot, real time polymerase chain reaction (PCR), and microarray analyses were used. The expression of IDO and immunological infiltration of rejected human corneal allografts (n=12) were analyzed by immunohistochemistry. RESULTS: We found IDO and an associated tryptophan/kynurenine transporter protein exchange mechanism upregulated by inflammatory cytokines in HCECs. The inhibition of T-cell proliferation might depend on rapid delivery of the tryptophan metabolite, L-kynurenine, to the local corneal environment. Microarray analysis gives evidence that the large amino acid transporter 1 (LAT1) transporter protein is responsible for this mechanism. CONCLUSIONS: Our data support that adequate levels of functional L-kynurenine might contribute to the maintenance of a relative immune privilege in the ocular anterior chamber, thereby contributing to the preservation of corneal allogeneic cells.
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Endotélio Corneano/citologia , Endotélio Corneano/metabolismo , Cinurenina/metabolismo , Triptofano/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Meios de Cultivo Condicionados , Citocinas/farmacologia , Endotélio Corneano/enzimologia , Endotélio Corneano/patologia , Ensaio de Imunoadsorção Enzimática , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Antígenos HLA-DR/genética , Antígenos HLA-DR/metabolismo , Cadeias HLA-DRB1 , Humanos , Imuno-Histoquímica , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Inflamação/patologia , Transportador 1 de Aminoácidos Neutros Grandes/genética , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/metabolismo , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Técnicas de Cultura de Tecidos , Fator de Crescimento Transformador beta2/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Neuromyelitis optica (NMO) is characterised by a particular pattern of the optic nerves and the spinal cord. Long-term MRI follow-up studies of spinal NMO lesions are rare, or limited by short observation periods. In nine patients with definite NMO or recurrent longitudinally extensive transverse myelitis (LETM) with NMO-IgG serum antibodies, repeated MRI examinations of the spine were carried out over a period of up to 11 years and evaluated regarding the changes over time in this retrospective study. In eight patients spinal cord lesions were located centrally, involving the grey and white matter. In the first examination after clinical onset changes resembled a stroke of the anterior spinal artery in two patients. Symmetrical signal alterations within the grey matter were observed. In one patient this pattern was transient, but it remained in the other. During the chronic stage, either a variable degree of spinal cord atrophy and high signal alterations, or almost complete remission of the lesions, was observed. Spinal MRI of patients with NMO myelitis can resemble a stroke. MRI of acute NMO stages did not allow a prediction of the clinical outcome. To a variable degree, NMO left behind typical defects which correlated with the clinical outcome.
Assuntos
Imageamento por Ressonância Magnética/métodos , Neuromielite Óptica/patologia , Medula Espinal/patologia , Doenças da Coluna Vertebral/patologia , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
A 34-year-old oligophrenic woman was admitted in comatose state with marked tachypnea. History revealed the oral ingestion of a large amount of acetylsalicylate to attenuate ear pain within the preceding 3 days. Laboratory investigations showed a toxic concentration of serum salicylate (668 mg/l, toxic range above 200 mg/l) and metabolic acidosis. Oxygenation, blood pressure, electrocardiography, echocardiography and CT of thorax and brain were normal. The patient was intubated, fluid and bicarbonate was given intravenously. Six hours after admission asystolia refractory to resuscitation led to death. Autopsy showed venous congestion of the brain, cardiac dilatation and pulmonary edema. Brain histopathology showed myelin disintegration and caspase-3 activation in glial cells, whereas, grey matter changes were sparse. Acute white matter damage is suggested to be the substrate of cerebral dysfunction in salicylate intoxication and possible mechanisms are discussed.
Assuntos
Anti-Inflamatórios não Esteroides/intoxicação , Aspirina/intoxicação , Encéfalo/patologia , Adulto , Autopsia , Biomarcadores , Química Encefálica/efeitos dos fármacos , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Veias Cerebrais/patologia , Evolução Fatal , Feminino , Humanos , Imuno-Histoquímica , Bainha de Mielina/patologia , Neuroglia/patologia , Neurônios/patologia , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/patologia , Fixação de TecidosRESUMO
Destruction of myelin and oligodendrocytes leading to the formation of large demyelinated plaques is the hallmark of multiple sclerosis (MS) pathology. In a subset of MS patients termed pattern III, actively demyelinating lesions show preferential loss of myelin-associated glycoprotein (MAG) and apoptotic-like oligodendrocyte destruction, whereas other myelin proteins remain well preserved. MAG is located in the most distal periaxonal oligodendrocyte processes and primary "dying back" oligodendrogliopathy may be the initial step of myelin degeneration in pattern III lesions. In the present study, various human white matter pathologies, including acute and chronic white matter stroke, virus encephalitis, metabolic encephalopathy, and MS were studied. In addition to a subset of MS cases, a similar pattern of demyelination was found in some cases of virus encephalitis as well as in all lesions of acute white matter stroke. Brain white matter lesions presenting with MAG loss and apoptotic-like oligodendrocyte destruction, irrespective of their primary disease cause, revealed a prominent nuclear expression of hypoxia inducible factor-1alpha in various cell types, including oligodendrocytes. Our data suggest that a hypoxia-like tissue injury may play a pathogenetic role in a subset of inflammatory demyelinating brain lesions.
Assuntos
Encefalite/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Glicoproteína Associada a Mielina/metabolismo , Oligodendroglia/metabolismo , Acidente Vascular Cerebral/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Encefalopatias/metabolismo , Encefalopatias/patologia , Criança , Encefalite/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Hipóxia-Isquemia Encefálica/patologia , Pessoa de Meia-Idade , Glicoproteína Associada a Mielina/análise , Oligodendroglia/química , Oligodendroglia/patologia , Acidente Vascular Cerebral/patologia , Fatores de Transcrição/biossínteseRESUMO
Damage to myelin sheath or oligodendrocytes may precede or even provoke inflammation of the central nervous system (CNS), but the extent to which these degenerative changes affect inflammation remains largely undefined. To study these processes in more detail, we used CNS antigen-specific T cells in the presence or absence of anti-myelin antibodies to induce experimental autoimmune encephalomyelitis (EAE) in transgenic Lewis rats with low-grade subclinical myelin degeneration and associated microglia cell activation, and in wild-type Lewis rats with an intact CNS. We found that myelin degeneration affects the localization of inflammatory lesions, the numbers of T cells recruited to these lesions, and the severity of the resulting clinical disease. In addition, myelin degeneration and associated microglia cell activation jointly enhance the susceptibility of the CNS to the action of anti-myelin antibodies. Our data show that even subtle alterations of myelin and oligodendrocytes may massively amplify the extent of demyelination and tissue damage, involving different immune effector mechanisms. A similar causal relationship might also operate in human patients with multiple sclerosis, where T cell-mediated inflammation and antibody-mediated demyelination have been documented, and where genetic factors might determine the susceptibility of the target tissue for immune-mediated injury.
Assuntos
Antígenos/imunologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/imunologia , Encefalomielite Autoimune Experimental/imunologia , Animais , Animais Geneticamente Modificados/genética , Anticorpos/imunologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/patologia , Epitopos , Feminino , Ativação Linfocitária , Contagem de Linfócitos , Proteína Proteolipídica de Mielina/genética , Bainha de Mielina/imunologia , Ratos , Ratos Endogâmicos Lew , Ratos Endogâmicos , Índice de Gravidade de Doença , Linfócitos T/imunologiaRESUMO
We investigated the role of the CD134 (also named OX40) molecule in experimental allergic encephalomyelitis (EAE) and multiple sclerosis (MS). We examined the susceptibility of Cd134(-/-) mice to EAE, an autoimmune murine model that is dependent on infiltrating CD4+ T lymphocytes reactive to myelin proteins. EAE induced by myelin oligodendrocyte glycoprotein (MOG) injection in Cd134(-/-) mice showed less severe clinical signs of disease and markedly reduced inflammatory infiltrates within the central nervous system (CNS). Resistance was associated with a strong reduction of pathogenic IFNgamma-producing T cells infiltrating the CNS of Cd134(-/-) mice. Furthermore, analysis of CNS tissue sections from EAE animals and MS patients revealed the presence of CD134+ cells that were localized in active lesions, mainly in perivascular infiltrates. The presence of CD134-expressing T cells in brain tissue of MS patients and EAE affected mice, together with the functional evidence provided by the significant decrease in disease score obtained in Cd134(-/-) mice, indicate that interfering with the CD134 molecule in T cells may be an appropriate target for therapeutic intervention in active MS.
Assuntos
Encéfalo/imunologia , Encéfalo/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Esclerose Múltipla/imunologia , Receptores do Fator de Necrose Tumoral/fisiologia , Medula Espinal/imunologia , Medula Espinal/metabolismo , Regulação para Cima/imunologia , Sequência de Aminoácidos , Animais , Encéfalo/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Divisão Celular/genética , Divisão Celular/imunologia , Movimento Celular/genética , Movimento Celular/imunologia , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Encefalomielite Autoimune Experimental/genética , Feminino , Humanos , Interferon gama/antagonistas & inibidores , Interferon gama/biossíntese , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Esclerose Múltipla/patologia , Bainha de Mielina/patologia , Receptores OX40 , Receptores do Fator de Necrose Tumoral/biossíntese , Receptores do Fator de Necrose Tumoral/deficiência , Receptores do Fator de Necrose Tumoral/genética , Medula Espinal/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/patologia , Regulação para Cima/genéticaRESUMO
INTRODUCTION: Our aim is to examine the clinical value of spectral-domain optical coherence tomography (Spectralis OCT) to detect retinal nerve fibre layer defects in patients with clinically defined Alzheimer's disease (AD). MATERIAL AND METHODS: This cross-sectional study included 22 patients with AD (mean age: 75.9 ± 6.1 years) and 22 healthy age- and sex-matched controls. Neuro-ophthalmologic examinations and a series of high-resolution OCT examinations of the peripapillary retinal nerve fiber layer (RNFL) thickness using the Spectralis 3.5-mm circle scan protocol with ART-Modus and eye tracking were obtained, and compared to age- and sex-matched healthy control subjects. RESULTS: Patients with AD showed a significant decrease in RNFL thickness in the nasal superior sector compared to the control group (101.0 ± 18.18 µm versus 122.8 ± 28.08 µm; P < 0.0001). In all other sectors, independently of disease duration, no significant difference in RNFL thickness compared to controls was detected. Using the advanced age- and gender-matched measurement model, 32 out of 42 eyes (76.19%) as pathologic with 67 abnormal sectors were detected. DISCUSSION: As examined by spectral-domain OCT, patients with mild to moderate stages of AD showed a significant reduction of RNFL thickness in the nasal superior sector. Nevertheless, successive studies are needed.
RESUMO
BACKGROUND: Recent studies investigating the use of optical coherence tomography (OCT) in multiple sclerosis (MS) patients have resulted in wide-ranging and often contradictory outcomes. This is mainly due to the complex etiology and heterogeneity of MS, physiological variations in the retinal nerve fiber layer (RNFL) and/or total macular volume (TMV), and limitations in methodology. It remains to be discovered whether any retinal changes in MS develop continuously or in a stepwise fashion, and whether these changes occur in all or a subset of patients. High-resolution spectral domain-OCT devices (SD-OCT) would be required to detect subtle retinal changes and longitudinal studies would have to be carried out to investigate retinal changes over time. In addition, if the hypothesis is correct, then retinal and global brain tissue changes should be detected in a substantial majority of MS patients and detection should be possible with a high degree of disease activity and/or long disease course. METHODOLOGY: In order to address the factors above, 37 MS patients (relapsing-remitting, n = 27; secondary progressive, n = 10) were examined prospectively on two occasions with a median interval of 22.4 ± 0.5 months [range 19-27]. SD-OCT was utilized with the Spectralis 3.5 mm circle scan protocol (with locked reference images and eye-tracking mode). None of the patients had optic neuritis 12 months prior to study entry or during the observation period. PRINCIPAL FINDINGS: The initial TMV pattern differed between study participants, but remained relatively unchanged over the 2-year observation period despite high disease activity or long disease course. The TMV correlated well with the RNFL. CONCLUSION: The significance of differences in TMV (and RNFL) between study participants remains unclear. Until these differences have been explored further, OCT data in MS patients should be interpreted with caution.
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Cell-based assays (CBA) have increased the sensitivity of the neuromyelitis optica (NMO)-IgG/aquaporin-4-antibody detection compared to classical tissue-based indirect assays. We describe the sensitivity of an optimized immunohistochemistry (IHC-o) to detect NMO-IgG/aquaporin-4-antibody in comparison with that of two CBA: an in-house (CBA-ih) and a commercial (CBA-c) assay (Euroimmun, Germany). Coded serum from 103 patients with definite NMO and 122 inflammatory controls were studied by IHC-o, CBA-ih, and CBA-c. IHC-o used the same protocol described to detect antibodies against cell surface antigens. CBA-ih used live cells transfected with the aquaporin-4-M23-isoform. The sensitivity of the IHC-o was 74.8% (95% confidence interval [CI] 65-83) and was similar to that of the CBA-ih 75.7% (95% CI 66-84) and the CBA-c 73.8% (95% CI 64-82). The specificity of the three assays was 100% (95% CI 97-100). Interassay concordance was high, 100 of 103 samples were coincident in all techniques. The optimized immunohistochemistry proves to be as sensitive and specific as the cell-based assays. This assay extends the available tools for NMO-IgG/aquaporin-4-antibody detection.
Assuntos
Técnica Indireta de Fluorescência para Anticorpo/métodos , Imunoglobulina G/análise , Imuno-Histoquímica/métodos , Neuromielite Óptica/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Aquaporina 4/imunologia , Autoanticorpos/análise , Autoanticorpos/imunologia , Criança , Feminino , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/imunologia , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto JovemRESUMO
IMPORTANCE: Given the high frequency of failure of first-line therapies, there is an urgent need for second-line treatment strategies for pediatric patients with multiple sclerosis (MS). OBJECTIVE: To report the use of natalizumab in pediatric MS. Natalizumab, a humanized monoclonal antibody targeting α4 integrin, is effective against active relapsing-remitting MS in adults. DESIGN: Retrospective study. SETTING: Eleven centers for neurology and pediatric neurology in Germany and Austria. PARTICIPANTS: A total of 20 pediatric patients with MS who started treatment with natalizumab prior to 18 years of age. These patients underwent magnetic resonance imaging as clinically indicated, despite the fact that 19 of these 20 patients were undergoing first-line disease-modifying therapy. The mean (SD) age at initiation of natalizumab therapy was 16.7 (1.1) years, and the mean (SD) pretreatment period was 18 (10) months. INTERVENTION: Natalizumab, 300 mg every 4 weeks. MAIN OUTCOME MEASURES: Annualized relapse rates, Expanded Disability Status Scale scores, number of new T2/fluid-attenuated inversion recovery lesions and contrast-enhancing lesions on magnetic resonance imaging, number of adverse events, the prevalence of neutralizing antibodies against natalizumab, and serum JC virus-antibody status. RESULTS Treatment with natalizumab was associated with reductions in mean annualized relapse rates (3.7 without treatment vs 0.4 with treatment; P < .001), median Expanded Disability Status Scale scores (2 without treatment vs 1 with treatment; P < .02), and mean number of new T2/fluid-attenuated inversion recovery lesions per year (7.8 without treatment vs 0.5 with treatment; P < .001). Two patients developed high-titer neutralizing antibodies against natalizumab and had to stop therapy. Adverse events included headaches, asthenia, infections, and hypersensitivity. Abnormal laboratory results were found for 8 patients. JC virus antibodies were found in 5 of 13 patients. After the discontinuation of natalizumab therapy, relapse activity occurred in 6 of 8 patients within 6 months. CONCLUSIONS AND RELEVANCE: Our data indicate that natalizumab may be safe and effective against MS in pediatric patients with breakthrough disease.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Adolescente , Anemia/induzido quimicamente , Anti-Inflamatórios/uso terapêutico , Áustria , Avaliação da Deficiência , Feminino , Seguimentos , Alemanha , Humanos , Fatores Imunológicos/uso terapêutico , Integrina alfa4/imunologia , Interferon beta/uso terapêutico , Contagem de Leucócitos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Imageamento por Ressonância Magnética , Masculino , Metilprednisolona/uso terapêutico , Esclerose Múltipla/sangue , Natalizumab , Estudos Retrospectivos , Prevenção SecundáriaRESUMO
BACKGROUND: In 2008 the Austrian Task Force for Neuromyelitis Optica (NMO) started a nation-wide network for information exchange and multi-centre collaboration. Their aim was to detect all patients with NMO or NMO spectrum disorders (NMO-SD) in Austria and to analyse their disease courses and response to treatment. METHODS: (1) As of March 2008, 1957 serum samples (of 1557 patients) have been tested with an established cell based immunofluorescence aquaporin-4 antibody (AQP4-ab) assay with a high sensitivity and specificity (both >95%). All tests were performed in a single reference laboratory (Clinical Dept. of Neurology of the Innsbruck Medical University). (2) A nation-wide survey with several calls for participation (via email newsletters, articles in the official journal of the Austrian Society of Neurology, and workshops) was initiated in 2008. All collected data will be presented in a way that allows that every individual patient can be traced back in order to ensure transparency and to avoid any data distortion in future meta-analyses. The careful and detailed presentation allows the visualization and comparison of the different disease courses in real time span. Failure and response to treatment are made visible at one glance. Database closure was 31 December 2011. All co-operators were offered co-authorship. RESULTS: All 71 NMO- or NMO-SD patients with AQP4-ab positivity (age range 12.3 to 79.6 years) were analysed in detail. Sex ratio (m:f = 1:7) and the proportion of patients without oligoclonal bands in cerebrospinal fluid (86.6%) were in line with previously published results. All identified patients were Caucasians. CONCLUSIONS: A nationwide collaboration amongst Austrian neurologists with good network communications made it possible to establish a database of 71 AQP4-ab positive patients with NMO/NMO-SD. This database is presented in detail and provides the basis for further studies and international cooperation in order to investigate this rare disease.
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Projetos de Pesquisa Epidemiológica , Neuromielite Óptica/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Áustria/epidemiologia , Demografia , Diagnóstico Diferencial , Humanos , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/sangue , Neuromielite Óptica/diagnóstico , Adulto JovemRESUMO
BACKGROUND: "Non-invasive, faster and less expensive than MRI" and "the eye is a window to the brain" are recent slogans promoting optical coherence tomography (OCT) as a new surrogate marker in multiple sclerosis (MS). Indeed, OCT allows for the first time a non-invasive visualization of axons of the central nervous system (CNS). Reduction of retina nerve fibre layer (RNFL) thickness was suggested to correlate with disease activity and duration. However, several issues are unclear: Do a few million axons, which build up both optic nerves, really resemble billions of CNS neurons? Does global CNS damage really result in global RNFL reduction? And if so, does global RNFL reduction really exist in all MS patients, and follow a slowly but steadily ongoing pattern? How can these (hypothesized) subtle global RNFL changes be reliably measured and separated from the rather gross RNFL changes caused by optic neuritis? Before generally being accepted, this interpretation needs further critical and objective validation. METHODOLOGY: We prospectively studied 37 MS patients with relapsing remitting (nâ=â27) and secondary progressive (nâ=â10) course on two occasions with a median interval of 22.4±0.5 months [range 19-27]. We used the high resolution spectral domain (SD-)OCT with the Spectralis 3.5 mm circle scan protocol with locked reference images and eye tracking mode. Patients with an attack of optic neuritis within 12 months prior to the onset of the study were excluded. PRINCIPAL FINDINGS: Although the disease was highly active over the observation period in more than half of the included relapsing remitting MS patients (19 patients/32 relapses) and the initial RNFL pattern showed a broad range, from normal to markedly reduced thickness, no significant changes between baseline and follow-up examinations could be detected. CONCLUSIONS: These results show that caution is required when using OCT for monitoring disease activity and global axonal injury in MS.
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Esclerose Múltipla/diagnóstico , Tomografia de Coerência Óptica/métodos , Adolescente , Adulto , Demografia , Seguimentos , Humanos , Pessoa de Meia-Idade , Fibras Nervosas/patologia , Retina/patologia , Adulto JovemRESUMO
BACKGROUND: Reduced N-acetyl-aspartate (NAA) levels in magnetic resonance spectroscopy (MRS) may visualize axonal damage even in the normal appearing white matter (NAWM). Demyelination and axonal degeneration are a hallmark in multiple sclerosis (MS). OBJECTIVE: To define the extent of axonal degeneration in the NAWM in the remote from focal lesions in patients with relapsing-remitting (RRMS) and secondary progressive MS (SPMS). MATERIAL AND METHODS: 37 patients with clinical definite MS (27 with RRMS, 10 with SPMS) and 8 controls were included. We used 2D (1)H-MR-chemical shift imaging (TR = 1500ms, TE = 135ms, nominal resolution 1ccm) operating at 3Tesla to assess the metabolic pattern in the fronto-parietal NAWM. Ratios of NAA to creatine (Cr) and choline (Cho) and absolute concentrations of the metabolites in the NAWM were measured in each voxel matching exclusively white matter on the anatomical T2 weighted MR images. RESULTS: No significant difference of absolute concentrations for NAA, Cr and Cho or metabolite ratios were found between RRMS and controls. In SPMS, the NAA/Cr ratio and absolute concentrations for NAA and Cr were significantly reduced compared to RRMS and to controls. CONCLUSIONS: In our study SPMS patients, but not RRMS patients were characterized by low NAA levels. Reduced NAA-levels in the NAWM of patients with MS is a feature of progression.
Assuntos
Ácido Aspártico/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Adulto , Colina/metabolismo , Creatina/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Peritumoral brain edema (PTBE) may be crucial in the clinical outcome of meningioma patients. The underlying pathogenetic key mechanism has so far not been determined. Sex, age, tumor size, location, involvement of other structures, or the histological appearance was not found to sufficiently explain PTBE formation in meningiomas. OBJECTIVE: As PTBE formation is widely accepted to be vasogenic, we investigated the role of vascular endothelial growth factor (VEGF) and pial supplying vessels in a series of World Health Organization (WHO) grade I meningiomas. METHODS: A total of 79 patients with WHO grade I meningiomas were immunohistochemically studied for VEGF and MIB-1. Pre- and postoperative magnetic resonance imaging including 3-dimensional reconstruction of 1.3-mm thick layers, with calculation of tumor and edema volume, was performed. Intraoperatively, the vascular supply and arachnoidal state were noted by the neurosurgeon. RESULTS: VEGF was found to be exclusively confined to meningioma tumor cells. We identified 4 different patterns. VEGF and supplying pial vessels were found in 14 meningioma patients, pial vascular supply only in 3, VEGF expression only in 46, and neither VEGF expression nor supplying pial vessels in 16. Only the occurrence of both pial vascular supply and tumor VEGF expression was found to be correlated with PTBE formation (P<.002). CONCLUSION: Our data suggest that VEGF may be crucial in angiogenesis and therefore indirectly in PTBE formation in World Health Organization grade I meningiomas.
Assuntos
Edema Encefálico/etiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Neoplasias Meníngeas/complicações , Meningioma/complicações , Neovascularização Patológica/etiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Edema Encefálico/diagnóstico , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/diagnóstico , Análise de Regressão , Estatísticas não Paramétricas , Adulto JovemRESUMO
The peptide hormones ACTH, MSHs, ß-lipotropin (ß-LPH), and ß-endorphin are all derived from the precursor molecule proopiomelanocortin (POMC). Using confocal laser microscopy and immunoelectron microscopy in human pituitary gland, we demonstrate a peroxisomal localization of ß-endorphin and ß-LPH in cells expressing the peroxisomal ATP-binding cassette-transporter adrenoleukodystrophy protein (ALDP). The peroxisomal localization of ß-LPH and ß-endorphin was not restricted to the pituitary gland but was additionally found in other human tissues that express high levels of ALDP, such as dorsal root ganglia, adrenal cortex, distal tubules of kidney, and skin. In contrast to the peptide hormones ß-LPH and ß-endorphin, which are derived from the C terminus of POMC, the N-terminal peptides ACTH, α-MSH, and γ-MSH were never detected in peroxisomes. This novel peroxisomal localization of ß-endorphin and ß-LPH in ALDP-positive cells was confirmed by costaining with ALDP and the peroxisomal marker catalase. Moreover, peroxisomal sorting of ß-LPH could be modeled in HeLa cells by ectopic expression of a POMC variant, modified to allow cleavage and release of ß-LPH within the secretory pathway. Although ß-LPH and ß-endorphin were only associated with peroxisomes in cells that normally express ALDP, the transporter activity of ALDP is not necessary for the peroxisomal localization, as demonstrated in tissues of X-linked adrenoleukodystrophy patients lacking functional ALDP. It remains to be elucidated whether and how the peroxisomal localization of POMC-derived hormones has a role in the endocrine dysfunction of peroxisomal disease.
Assuntos
Peroxissomos/metabolismo , beta-Endorfina/metabolismo , beta-Lipotropina/metabolismo , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/fisiologia , Técnicas de Cultura de Células , Células HeLa , Humanos , Especificidade de Órgãos/genética , Hipófise/metabolismo , Pró-Opiomelanocortina/química , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Transporte Proteico , Distribuição Tecidual , beta-Endorfina/genética , beta-Lipotropina/genéticaRESUMO
BACKGROUND: Recently the reduction of the retinal nerve fibre layer (RNFL) was suggested to be associated with diffuse axonal damage in the whole CNS of multiple sclerosis (MS) patients. However, several points are still under discussion. (1) Is high resolution optical coherence tomography (OCT) required to detect the partly very subtle RNFL changes seen in MS patients? (2) Can a reduction of RNFL be detected in all MS patients, even in early disease courses and in all MS subtypes? (3) Does an optic neuritis (ON) or focal lesions along the visual pathways, which are both very common in MS, limit the predication of diffuse axonal degeneration in the whole CNS? The purpose of our study was to determine the baseline characteristics of clinical definite relapsing-remitting (RRMS) and secondary progressive (SPMS) MS patients with high resolution OCT technique. METHODOLOGY: Forty-two RRMS and 17 SPMS patients with and without history of uni- or bilateral ON, and 59 age- and sex-matched healthy controls were analysed prospectively with the high resolution spectral-domain OCT device (SD-OCT) using the Spectralis 3.5mm circle scan protocol with locked reference images and eye tracking mode. Furthermore we performed tests for visual and contrast acuity and sensitivity (ETDRS, Sloan and Pelli-Robson-charts), for color vision (Lanthony D-15), the Humphrey visual field and visual evoked potential testing (VEP). PRINCIPAL FINDINGS: All 4 groups (RRMS and SPMS with or without ON) showed significantly reduced RNFL globally, or at least in one of the peripapillary sectors compared to age-/sex-matched healthy controls. In patients with previous ON additional RNFL reduction was found. However, in many RRMS patients the RNFL was found within normal range. We found no correlation between RNFL reduction and disease duration (range 9-540 months). CONCLUSIONS: RNFL baseline characteristics of RRMS and SPMS are heterogeneous (range from normal to markedly reduced levels).
Assuntos
Esclerose Múltipla/patologia , Fibras Nervosas/patologia , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica/métodos , Adulto , Idoso , Potenciais Evocados Visuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/fisiopatologia , Neurite Óptica/diagnóstico , Neurite Óptica/fisiopatologia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Testes de Campo Visual , Vias Visuais/patologia , Vias Visuais/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: Neuromyelitis optica (NMO), a severe demyelinating disease, represents itself with optic neuritis and longitudinally extensive transverse myelitis. Serum NMO-IgG autoantibodies (Abs), a specific finding in NMO patients, target the water channel protein aquaporin-4 (AQP4), which is expressed as a long (M-1) or a short (M-23) isoform. METHODOLOGY/PRINCIPAL FINDINGS: The aim of this study was to analyze serum samples from patients with NMO and controls for the presence and epitope specificity of IgG and IgM anti-AQP4 Abs using an immunofluorescence assay with HEK293 cells expressing M-1 or M-23 human AQP4. We included 56 patients with definite NMO (n = 30) and high risk NMO (n = 26), 101 patients with multiple sclerosis, 27 patients with clinically isolated syndromes (CIS), 30 patients with systemic lupus erythematosus (SLE) or Sjögren's syndrome, 29 patients with other neurological diseases and 47 healthy controls. Serum anti-AQP4 M-23 IgG Abs were specifically detected in 29 NMO patients, 17 patients with high risk NMO and two patients with myelitis due to demyelination (CIS) and SLE. In contrast, IgM anti-AQP4 Abs were not only found in some NMO and high risk patients, but also in controls. The sensitivity of the M-23 AQP4 IgG assay was 97% for NMO and 65% for high risk NMO, with a specificity of 100% compared to the controls. Sensitivity with M-1 AQP4 transfected cells was lower for NMO (70%) and high risk NMO (39%). The conformational epitopes of M-23 AQP4 are the primary targets of NMO-IgG Abs, whereas M-1 AQP4 Abs are developed with increasing disease duration and number of relapses. CONCLUSIONS: Our results confirm M-23 AQP4-IgG Abs as reliable biomarkers in patients with NMO and high risk syndromes. M-1 and M-23 AQP4-IgG Abs are significantly associated with a higher number of relapses and longer disease duration.
Assuntos
Aquaporina 4/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Neuromielite Óptica/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular , Feminino , Proteínas de Fluorescência Verde/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/classificação , Isoformas de Proteínas/imunologia , Fatores de Risco , Coloração e Rotulagem , Transfecção , Adulto JovemRESUMO
BACKGROUND: An 80-year-old woman presented with progressive cognitive decline and with a 6-month history of gait ataxia. Brain MRI depicted enlarged ventricles and periventricular lesions. Clinical improvement after CSF spinal tap test suggested a normal pressure hydrocephalus syndrome. But CSF pleocytosis with activated lymphocytes and plasma cells and intrathecal Borrelia burgdorferi specific antibody production led to the diagnosis of active Lyme neuroborreliosis. Clinical symptoms of NPH resolved after a course of ceftriaxone. METHODS: Neurological examination, MMSE, brain MRI, lumbar puncture, spinal tap test. RESULTS: Dementia due Borrelia burgdorferi infection with chronic meningitis was reversible after treatment with iv.2 g ceftriaxone per day for 4 weeks. CONCLUSIONS: Rare but treatable dementias must be diagnosed promptly to slow down or even reverse cognitive decline.