RESUMEN
OBJECTIVES: To evaluate prevalence, clinical characteristics, and predictors of pain, depression, and their impact on the quality of life (QoL) in a large neuromyelitis optica spectrum disorder (NMOSD) cohort. METHODS: We included 166 patients with aquaporin-4-seropositive NMOSD from 13 tertiary referral centers. Patients received questionnaires on demographic and clinical characteristics, PainDetect, short form of Brief Pain Inventory, Beck Depression Inventory-II, and Short Form 36 Health Survey. RESULTS: One hundred twenty-five (75.3%) patients suffered from chronic NMOSD-associated pain. Of these, 65.9% had neuropathic pain, 68.8% reported spasticity-associated pain and 26.4% painful tonic spasms. Number of previous myelitis attacks (OR = 1.27, p = 0.018) and involved upper thoracic segments (OR = 1.31, p = 0.018) were the only predictive factors for chronic pain. The latter was specifically associated with spasticity-associated pain (OR = 1.36, p = 0.002). More than a third (39.8%) suffered from depression, which was moderate to severe in 51.5%. Pain severity (OR = 1.81, p < 0.001) and especially neuropathic character (OR = 3.44, p < 0.001) were associated with depression. Pain severity and walking impairment explained 53.9% of the physical QoL variability, while depression and walking impairment 39.7% of the mental QoL variability. No specific medication was given to 70.6% of patients with moderate or severe depression and 42.5% of those with neuropathic pain. Two-thirds (64.2%) of patients with symptomatic treatment still reported moderate to severe pain. CONCLUSIONS: Myelitis episodes involving upper thoracic segments are main drivers of pain in NMOSD. Although pain intensity was lower than in previous studies, pain and depression remain undertreated and strongly affect QoL. Interventional studies on targeted treatment strategies for pain are urgently needed in NMOSD.
Asunto(s)
Acuaporina 4/sangre , Depresión/etiología , Neuromielitis Óptica/complicaciones , Dolor/etiología , Adulto , Anciano , Anciano de 80 o más Años , Acuaporina 4/inmunología , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mielitis/complicaciones , Neuromielitis Óptica/fisiopatología , Prevalencia , Calidad de Vida , Médula Espinal/patología , Encuestas y CuestionariosRESUMEN
Multiple sclerosis and neuromyelitis optica spectrum disorders are autoimmune inflammatory diseases of the central nervous system, which can lead to a multitude of neurological complaints and pain syndromes. Pain may be an acute symptom during disease exacerbation as well as a chronic symptom, whereby the latter sometimes substantially reduces the quality of life. The etiology of pain is very heterogeneous but the rapid differential diagnostic classification is decisive in order to be able to initiate a differentiated treatment strategy. Chronic pain must be differentiated from pain as a possible (early) symptom of an acute disease exacerbation, classified in more detail and individually treated. These include central neuropathic pain, pain associated with spasticity, musculoskeletal pain due to excess loading and pain as a side effect of immunotherapy and in the context of comorbidities. The treatment strategies are often insufficiently evidence-based due to the lack of data.
Asunto(s)
Esclerosis Múltiple , Neuromielitis Óptica , Autoanticuerpos , Humanos , Glicoproteína Mielina-Oligodendrócito , Neuromielitis Óptica/diagnóstico , Neuromielitis Óptica/terapia , Calidad de VidaRESUMEN
BACKGROUND: In the past, multiple sclerosis (MS) medications have been primarily designed to modulate T cell properties. Based on the emerging concept that B cells are equally important for the propagation of MS, we compared the effect of four commonly used, primarily T cell-targeting MS medications on B cells. METHODS: Using flow cytometry, we analyzed peripheral blood mononuclear cells (PBMC) of untreated (n = 19) and dimethyl fumarate (DMF; n = 21)-, fingolimod (FTY; n = 17)-, glatiramer acetate (GA; n = 18)-, and natalizumab (NAT; n = 20)-treated MS patients, focusing on B cell maturation, differentiation, and cytokine production. RESULTS: While GA exerted minor effects on the investigated B cell properties, DMF and FTY robustly inhibited pro-inflammatory B cell function. In contrast, NAT treatment enhanced B cell differentiation, activation, and pro-inflammatory cytokine production when compared to both intraindividual samples collected before NAT treatment initiation as well as untreated MS controls. Our mechanistic in vitro studies confirm this observation. CONCLUSION: Our data indicate that common MS medications have differential, in part opposing effects on B cells. The observed activation of peripheral B cells upon NAT treatment may be instructive to interpret its unfavorable effect in certain B cell-mediated inflammatory conditions and to elucidate the immunological basis of MS relapses after NAT withdrawal. TRIAL REGISTRATION: Protocols were approved by the ethical review committee of the University Medical Center Göttingen (#3/4/14).
Asunto(s)
Linfocitos B/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Factores Inmunológicos/farmacología , Activación de Linfocitos/efectos de los fármacos , Esclerosis Múltiple Recurrente-Remitente/inmunología , Natalizumab/farmacología , Adulto , Linfocitos B/inmunología , Células Cultivadas , Dimetilfumarato/farmacología , Femenino , Clorhidrato de Fingolimod/farmacología , Acetato de Glatiramer/farmacología , Humanos , Masculino , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológicoRESUMEN
Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by the infiltration of mononuclear cells into the CNS and a subsequent inflammation of the brain. Monocytes are implicated in disease pathogenesis not only in their function as potential antigen-presenting cells involved in the local reactivation of encephalitogenic T cells but also by independent effector functions contributing to structural damage and disease progression. However, monocytes also have beneficial effects as they can exert anti-inflammatory activity and promote tissue repair. Glucocorticoids (GCs) are widely used to treat acute relapses in MS patients. They act on a variety of cell types but their exact mechanisms of action including their modulation of monocyte function are not fully understood. Here we investigated effects of the therapeutically relevant GC methylprednisolone (MP) on monocytes from healthy individuals and MS patients in vitro and in vivo. The monocyte composition in the blood was different in MS patients compared to healthy individuals, but it was only marginally affected by MP treatment. In contrast, application of MP caused a marked shift toward an anti-inflammatory monocyte phenotype in vitro and in vivo as revealed by an altered gene expression profile. Chemotaxis of monocytes toward CCL2, CCL5, and CX3CL1 was increased in MS patients compared to healthy individuals and further enhanced by MP pulse therapy. Both of these migration-promoting effects were more pronounced in MS patients with an acute relapse than in those with a progressive disease. Interestingly, the pro-migratory GC effect was independent of chemokine receptor levels as exemplified by results obtained for CCR2. Collectively, our findings suggest that GCs polarize monocytes toward an anti-inflammatory phenotype and enhance their migration into the inflamed CNS, endowing them with the capacity to suppress the pathogenic immune response.
Asunto(s)
Antiinflamatorios/farmacología , Quimiotaxis de Leucocito/efectos de los fármacos , Metilprednisolona/farmacología , Monocitos/efectos de los fármacos , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adulto , Anciano , Antiinflamatorios/administración & dosificación , Antiinflamatorios/uso terapéutico , Antígenos CD/biosíntesis , Antígenos CD/genética , Antígenos de Diferenciación Mielomonocítica/biosíntesis , Antígenos de Diferenciación Mielomonocítica/genética , Quimiocina CCL2/farmacología , Quimiocina CCL2/fisiología , Femenino , Humanos , Masculino , Metilprednisolona/administración & dosificación , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Monocitos/inmunología , Esclerosis Múltiple Crónica Progresiva/inmunología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Quimioterapia por Pulso , Receptores CCR2/biosíntesis , Receptores CCR2/genética , Receptores de Superficie Celular/biosíntesis , Receptores de Superficie Celular/genética , Receptores de Glucocorticoides/biosíntesis , Receptores de Glucocorticoides/genética , Adulto JovenRESUMEN
Recurrent myelitis is one of the predominant characteristics in patients with neuromyelitis optica (NMO). While paresis, visual loss, sensory deficits, and bladder dysfunction are well known symptoms in NMO patients, pain has been recognized only recently as another key symptom of the disease. Although spinal cord inflammation is a defining aspect of neuromyelitis, there is an almost complete lack of data on altered somatosensory function, including pain. Therefore, eleven consecutive patients with NMO were investigated regarding the presence and clinical characteristics of pain. All patients were examined clinically as well as by Quantitative Sensory Testing (QST) following the protocol of the German Research Network on Neuropathic Pain (DFNS). Additionally, plasma endocannabinoid levels and signs of chronic stress and depression were determined. Almost all patients (10/11) suffered from NMO-associated neuropathic pain for the last three months, and 8 out of 11 patients indicated relevant pain at the time of examination. Symptoms of neuropathic pain were reported in the vast majority of patients with NMO. Psychological testing revealed signs of marked depression. Compared to age and gender-matched healthy controls, QST revealed pronounced mechanical and thermal sensory loss, strongly correlated to ongoing pain suggesting the presence of deafferentation-induced neuropathic pain. Thermal hyperalgesia correlated to MRI-verified signs of spinal cord lesion. Heat hyperalgesia was highly correlated to the time since last relapse of NMO. Patients with NMO exhibited significant mechanical and thermal dysesthesia, namely dynamic mechanical allodynia and paradoxical heat sensation. Moreover, they presented frequently with either abnormal mechanical hypoalgesia or hyperalgesia, which depended significantly on plasma levels of the endogenous cannabinoid 2-arachidonoylglycerole (2-AG). These data emphasize the high prevalence of neuropathic pain and hyperalgesia in patients with NMO. The degree of mechanical hyperalgesia reflecting central sensitization of nociceptive pathways seems to be controlled by the major brain endocannabinoid 2-AG.
Asunto(s)
Ácidos Araquidónicos/sangre , Encéfalo/metabolismo , Depresión/fisiopatología , Endocannabinoides/sangre , Glicéridos/sangre , Hiperalgesia/fisiopatología , Neuralgia/fisiopatología , Neuromielitis Óptica/fisiopatología , Adulto , Anciano , Encéfalo/fisiopatología , Estudios de Casos y Controles , Depresión/sangre , Depresión/complicaciones , Femenino , Humanos , Hiperalgesia/sangre , Hipoestesia/sangre , Hipoestesia/fisiopatología , Masculino , Persona de Mediana Edad , Neuralgia/sangre , Neuromielitis Óptica/sangre , Neuromielitis Óptica/complicaciones , Nervio Óptico/metabolismo , Nervio Óptico/fisiopatología , Dimensión del Dolor , Umbral del Dolor , Pruebas Psicológicas , Médula Espinal/metabolismo , Médula Espinal/fisiopatologíaRESUMEN
BACKGROUND: The oral sphingosine-1-phosphate receptor modulator fingolimod (FTY720) was recently approved for the treatment of relapsing-remitting multiple sclerosis. To date, data about a possible recurrence of disease activity after discontinuation of fingolimod treatment are scarce. OBJECTIVE: To describe a patient who discontinued fingolimod treatment after a local malignant melanoma was diagnosed. Three months after cessation, he had a striking rebound of multiple sclerosis activity. DESIGN: Case report and review of literature. SETTING: Institute of Clinical Neuroimmunology, Ludwig-Maximilians-University, Munich, Germany. PATIENT: A 45-year-old man diagnosed as having relapsing-remitting multiple sclerosis. MAIN OUTCOME MEASURES: Multiple sclerosis disease activity including annual relapse rate, Expanded Disability Status Scale score, and number of gadolinium-enhancing lesions on magnetic resonance imaging before, during, and after treatment with fingolimod. RESULTS: Three months after discontinuation of treatment with fingolimod, the patient experienced a severe relapse, with Expanded Disability Status Scale score progression from 2.5 to 4.5. On brain and spinal magnetic resonance imaging, he showed a rebound of disease activity, with a drastic increase of gadolinium-enhancing lesions (>20). CONCLUSIONS: Two aspects relevant to any newly approved multiple sclerosis treatment with immunomodulatory properties are highlighted with this case: first, possible rebound of disease activity after discontinuation; second, the occurrence of a tumor as a possible treatment-related complication.
Asunto(s)
Factores Inmunológicos/uso terapéutico , Melanoma/complicaciones , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Glicoles de Propileno/uso terapéutico , Esfingosina/análogos & derivados , Encéfalo/patología , Evaluación de la Discapacidad , Progresión de la Enfermedad , Clorhidrato de Fingolimod , Humanos , Interferón beta/uso terapéutico , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Esclerosis Múltiple Recurrente-Remitente/patología , Recurrencia , Esfingosina/uso terapéutico , Resultado del TratamientoAsunto(s)
Evaluación de la Discapacidad , Esclerosis Múltiple/rehabilitación , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Encéfalo/efectos de los fármacos , Encéfalo/patología , Progresión de la Enfermedad , Acetato de Glatiramer , Humanos , Inmunosupresores/uso terapéutico , Interferones/uso terapéutico , Imagen por Resonancia Magnética , Esclerosis Múltiple/clasificación , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/psicología , Natalizumab , Examen Neurológico/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Péptidos/uso terapéutico , Calidad de Vida/psicología , Silla de RuedasAsunto(s)
Autoanticuerpos/sangre , Encefalitis Límbica/inmunología , Canales de Potasio con Entrada de Voltaje/inmunología , Receptores de N-Metil-D-Aspartato/inmunología , Antiinflamatorios/administración & dosificación , Esquema de Medicación , Electroencefalografía , Epilepsias Parciales/diagnóstico , Epilepsias Parciales/inmunología , Humanos , Encefalitis Límbica/diagnóstico , Encefalitis Límbica/tratamiento farmacológico , Imagen por Resonancia Magnética , Masculino , Metilprednisolona/administración & dosificación , Persona de Mediana Edad , Pruebas Neuropsicológicas , Lóbulo Temporal/patologíaRESUMEN
In about 40% of patients LEMS is not a paraneoplastic phenomenon (NT-LEMS). Several clinical aspects important to these patients remain open, especially the question when a LEMS can definitely be diagnosed as NT-LEMS. Here we describe a series of 25 German NT-LEMS patients regarding their clinical characteristics, duration of symptoms, value of serological markers, paraneoplastic antibodies and FDG-PET/CT. Furthermore, we discuss the current diagnostic criteria of NT-LEMS.
Asunto(s)
Síndrome Miasténico de Lambert-Eaton/diagnóstico , Síndrome Miasténico de Lambert-Eaton/terapia , Adolescente , Adulto , Anciano , Niño , Diagnóstico Diferencial , Femenino , Fluorodesoxiglucosa F18 , Alemania , Humanos , Síndrome Miasténico de Lambert-Eaton/diagnóstico por imagen , Síndrome Miasténico de Lambert-Eaton/fisiopatología , Masculino , Persona de Mediana Edad , Fosfopiruvato Hidratasa/metabolismo , Tomografía de Emisión de Positrones/métodos , Adulto JovenRESUMEN
Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease that is characterized by impaired transmission across the neuromuscular junction due to autoantibodies directed against the presynaptic voltage-gated calcium channels (VGCC-ab). Clinical symptoms are usually characterized by proximal muscle weakness and mild dysautonomia. In some patients there are signs of cerebellar dysfunction as well, usually associated with cancer. Here we report the long-term follow-up of a patient with VGCC-ab-positive LEMS and a severe cerebellar syndrome but without evidence of cancer over 5 years. While conventional immunosuppressive therapy (steroids, azathioprine) failed, he improved with plasma exchange and consecutive treatment with rituximab. Muscle Nerve 40: 305-308, 2009.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Enfermedades Cerebelosas/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Síndrome Miasténico de Lambert-Eaton/tratamiento farmacológico , Anticuerpos Monoclonales de Origen Murino , Canales de Calcio/inmunología , Enfermedades Cerebelosas/complicaciones , Humanos , Síndrome Miasténico de Lambert-Eaton/complicaciones , Masculino , Persona de Mediana Edad , Intercambio Plasmático/métodos , RituximabRESUMEN
BACKGROUND: According to established criteria, paraneoplastic encephalomyelitis with adrenal neuroblastoma comprises a definite paraneoplastic neurologic syndrome. OBJECTIVE: To detect T-cell clones that cross-react against antigens shared between tumor and nervous system. DESIGN: Case study. SETTING: Academic research. Patient A 22-year-old woman having paraneoplastic encephalomyelitis with adrenal neuroblastoma. MAIN OUTCOME MEASURES: We compared the T-cell receptor repertoires expressed in blood, cerebrospinal fluid, and neuroblastoma tumor tissue using complementary determining region 3 (CDR3) spectratyping and clone-specific polymerase chain reaction. RESULTS: The T-cell receptor repertoire in cerebrospinal fluid was narrow compared with that in tumor and blood. Four T-cell clones from different tissues had identical T-cell receptor beta chains. Remarkably, the chains showed identical amino acid sequences but different nucleotide sequences. CONCLUSIONS: These T cells represent ontogenetically distinct clones but share functionally identical receptors. They recognize the same antigen in nervous system and tumor tissue and represent an attractive target for selective therapy.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/inmunología , Neuroblastoma/inmunología , Síndromes Paraneoplásicos del Sistema Nervioso/inmunología , Receptores de Antígenos de Linfocitos T/análisis , Neoplasias de las Glándulas Suprarrenales/sangre , Neoplasias de las Glándulas Suprarrenales/líquido cefalorraquídeo , Antígenos de Neoplasias/análisis , Antígenos de Neoplasias/clasificación , Biomarcadores/análisis , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Linaje de la Célula/inmunología , Células Clonales/inmunología , Reacciones Cruzadas/inmunología , Femenino , Humanos , Inmunofenotipificación , Activación de Linfocitos/inmunología , Neuroblastoma/diagnóstico , Neuroblastoma/fisiopatología , Síndromes Paraneoplásicos del Sistema Nervioso/sangre , Síndromes Paraneoplásicos del Sistema Nervioso/líquido cefalorraquídeo , Receptores de Antígenos de Linfocitos T/clasificación , Receptores de Antígenos de Linfocitos T alfa-beta/análisis , Subgrupos de Linfocitos T/inmunología , Linfocitos T/clasificación , Linfocitos T/inmunología , Adulto JovenRESUMEN
OBJECTIVE: Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease in which the transmission across the neuromuscular junction is disturbed by autoantibodies directed against the presynaptic P/Q-type voltage-gated calcium channels (VGCC). LEMS is paraneoplastic (T-LEMS) in about 60% of patients mostly associated with a small cellular lung carcinoma (SCLC), but occurs spontaneously without a tumor in 40% (NT-LEMS). In most cases neurologic symptoms appear before tumor diagnosis, but there is as yet no clear specific serologic marker to distinguish between NT- and T-LEMS. METHODS: To see whether antibodies from patients with NT- and T-LEMS differentially recognize antigenic sites of the alpha 1A subunit of P/Q-type VGCC, we studied serum samples from 22 T-LEMS and 24 NT-LEMS patients. Sera reactivity was tested by Western blot analysis to recombinant proteins corresponding to the extracellular S5-S6 linker region of three out of four domains forming the alpha 1 subunit of P/Q-type VGCC. RESULTS: Sera from 9/24 (37,5%) NT-LEMS patients, but only 1/22 (4,6%) T-LEMS patients recognized domain IV (p=0,011). Seroreactivity to domains I and III was similar for NT-LEMS and T-LEMS patients (domain I: 8%/14%; domain III: 46%/41%, not significant). CONCLUSIONS: These data suggest that an antibody response to domain IV is more common in LEMS without tumor than in paraneoplastic LEMS. This may have implications for diagnostic workup in LEMS patients without previously established diagnosis of a tumor. Additionally this could point towards a differential autoimmune pathogenesis between T-LEMS and NT-LEMS.