The cerebrospinal fluid in multiple sclerosis: far beyond the bands / O líquido cefalorraquidiano na esclerose múltipla: muito além das bandas

ABSTRACT The cerebrospinal fluid analysis has been employed for supporting multiple sclerosis diagnosis and ruling out the differential diagnoses. The most classical findings reflect the inflammatory nature of the disease, including mild pleocytosis, mild protein increase, intrathecal synthesis of immunoglobulin G, and, most typically, the presence of oligoclonal bands. In recent years, new biomarkers have emerged in the context of multiple sclerosis. The search for new biomarkers reflect the need of a better evaluation of disease activity, disease progression, and treatment efficiency. A more refined evaluation of disease and therapy status can contribute to better therapeutic choices, particularly in escalation of therapies. This is very relevant taking into account the availability of a greater number of drugs for multiple sclerosis treatment in recent years. In this review, we critically evaluate the current literature regarding the most important cerebrospinal fluid biomarkers in multiple sclerosis. The determination of biomarkers levels, such as chemokine ligand 13, fetuin A, and mainly light neurofilament has shown promising results in the evaluation of this disease, providing information that along with clinical and neuroimaging data may contribute to better therapeutic decisions.

RESUMO A análise do líquido cefalorraquidiano tem sido empregada para avaliação diagnóstica da esclerose múltipla e a exclusão dos diagnósticos diferenciais. Os achados clássicos refletem a natureza inflamatória da doença, incluindo discreta pleocitose, leve hiperproteinorraquia, aumento da síntese intratecal de imunoglobulina G e, mais tipicamente, a presença de bandas oligoclonais. Nos últimos anos, surgiram novos biomarcadores para esclerose múltipla, e esta busca por marcadores reflete a necessidade de melhor avaliar a atividade e a progressão da doença, bem como a eficácia terapêutica. Uma avaliação mais refinada da atividade da doença e da resposta aos medicamentos pode contribuir para melhores decisões terapêuticas, particularmente no que se refere à troca de medicação. Isto é muito importante nos dias de hoje, quando surgem novas opções medicamentosas. Neste artigo de revisão, avaliamos criticamente a literatura atual referente aos novos marcadores liquóricos na esclerose múltipla. A mensuração destes marcadores, como a quimiocina CXCL13, fetuína A e, principalmente, o neurofilamento de cadeia leve, demonstrou resultados promissores na avaliação da doença, provendo informações que, em conjunto com dados clínicos e de neuroimagem, podem contribuir para melhores decisões terapêuticas.

Cytokines and intrathecal IgG synthesis in multiple sclerosis patients during clinical remission

Os níveis de citocinas e síntese intratecal de IgG foram dosados no líquido cefalorraquidiano (LCR) e soro, com o objetivo de avaliar a atividade inflamatória em pacientes com esclerose múltipla durante remissão clínica. Foram detectados níveis elevados de citocinas pró-inflamatórias (TNFa e IFNg) no LCR e soro, sem alterações significativas na produção de IL12 e IL10. O perfil de produção das citocinas pró-inflamatórias estava associado ao aumento de leucócitos no LCR, assim como a presença de bandas oligoclonais IgG sugerindo síntese intratecal de IgG. Estes resultados sugerem que mesmo quando a doença está clinicamente silenciosa, a atividade inflamatória está presente nestes pacientes.

Cytokine Levels in Cerebrospinal Fluid and Delayed Ischemic Deficits in Patients with Aneurysmal Subarachnoid Hemorrhage

Subarachnoid hemorrhage (SAH) induces an inflammatory reaction and may lead to ischemic brain damage. The pathogenesis of brain dysfunction and delayed ischemic symptoms remain difficult to understand despite extensive surveys of such reactions. Cytokine production in the central nervous system following SAH and its relation with clinical outcome have hardly been studied. This study was aimed to determine whether the levels of IL-1 beta, IL-6 and TNF-alpha in the initial cerebrospinal fluid would increase following aneurysmal SAH, and be related with development of delayed ischemic deficit and clinical outcome. Nineteen patients suffering from aneurysmal SAH and 12 control volunteers were the subjects in this study. Cerebrospinal fluid samples were obtained on admission and the levels of each cytokine were determined with enzyme-linked immunosorbent assay. Patients with aneurysmal subarachnoid hemorrhage showed elevated levels of IL-1 beta, and TNF-alpha on admission. The patients with poor neurological status showed high levels of IL-1 beta, and IL-6. The patients who developed delayed ischemic deficit had high level of IL-6. We suggest that elevated level of IL-6 in cerebrospinal fluid of patients with aneurysmal SAH on admission can predict the high risk of delayed ischemic deficit.

Interleukin-5 and interleukin-10 are major cytokines in cerebrospinal fluid from patients with active neurocysticercosis

Neurocysticercosis (NCC) is a common neurological disorder especially in developing countries, caused by infection of the brain with encysted larvae of the tapeworm Taenia solium. Seizures are a common finding associated with this disease. The objective of the present study was to evaluate the correlation between the levels of various cytokines present in the cerebrospinal fluid (CSF) of patients with NCC and the severity of the disease. The levels of the cytokines IL-1î, TNF-alpha, IL-5, IL-10 and IFN-gamma were determined in the CSF of 22 patients with active NCC, 13 patients with inactive NCC and 15 control subjects. CSF from patients with active NCC presented significantly higher IL-5 levels compared to control subjects. IL-5 and IL-10 levels in CSF from NCC patients with inflammatory CSF were significantly higher than those detected in non-inflammatory CSF. These results show a predominant Th2 lymphocyte activation in human NCC and also indicate the possible use of cytokines in the CSF as a marker for the differential diagnosis between inactive disease and the active form of NCC

Cytokines and zinc levels in serum and cerebrospinal fluid of children with febrile seizures and encephalitis

The present study was proposed in an attempt to understand the role of serum and cerebrospinal fluid [CSF] levels of proinflammatory cytokines [TNF-alpha, IL-1beta and IL-6] and zinc in children with febrile convulsions and cases with encephalitis in comparison with normal ranges. Fifty patients were enrolled in the study, 15 with febrile convulsions, 15 patients with acute encephalitis and a control group of 20 patients with febrile illness but no convulsions. Serum and CSF levels of TNF-alpha, IL1-Beta and IL-6 were significantly higher in cases with encephalitis than in cases with febrile convulsions and control. There were no significant differences between cases with febrile convulsions and controls. On comparing cases with febrile convulsions and cases with encephalitis, serum and CSF levels of pro-inflammatory cytokines were significantly higher in cases with encephalitis. It was also found that children with febrile convulsions had decreased serum and CSF levels of zinc much less than in both cases with encephalitis and control groups. The correlation between serum and CSF levels of pro-inflammatory cytokines was significantly positive for cases with febrile convulsions and encephalitis, while there was no correlation between serum and CSF zinc levels in both groups

CSF cytokines, nitric oxide and prostaglandins in diagnosis and pathophysiology of childhood CNS leukemia and lymphoma

To clarify the role of cytokines, nitric oxide [NO] and prostaglandin- E2 [PG-E2] in diagnosis and pathogenesis of infiltration of central nervous system [CNS] in cases with leukemia and lymphoma, the levels of these indices in the cerebrospinal fluid [CSF] of those children were determined. Their levels were correlated with other laboratory studies of CSF and clinical criteria. This study included twenty- seven children with acute leukemia [twenty with acute lymphoblastic leukemia [ALL] and seven with acute myeloid leukemia [AML]] and fifteen with non- Hodgkin's lymphoma [NHL]. Clinical evidence of CNS involvement was present in seventeen patients with acute leukemia and seven cases with NHL. The study revealed significantly elevated levels of two types of cytokines [TNF-alpha, IL-6] NO and PG-E2 in CSF of children with acute leukemias and lymphoma compared with control group [children with tension headache or meningism]