18 Patients producing NSAbs generally show a good response to immunotherapy and have a better overall prognosis. 8, 17 Several sources of evidence support the theory that the pathogenesis of encephalitis is mainly antibody-mediated in AEs associated with this group of antibodies. Unlike encephalitis with antibodies to intracellular antigens, the frequency of cancer in cases involving antibodies targeting cell-surface antigens is, to a varying degree dependent upon the particular type of antibody, lower. 7 – 10 The contactin-associated protein like 2 (Caspr2), 11 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), 12 gamma-aminobutyric acid (GABA)-A and -B receptors, 13, 14 dipeptidyl-peptidase-like protein-6 (DPPX), 15 and glycine receptor (GlyR) 16 antibodies are other examples of recently identified NSAbs. Anti-NMDAR antibodies are most common, followed by antibodies against leucine-rich glioma inactivated-1 (LGI1). NSAbs target an extracellular epitope, and their corresponding antigens are often synaptic receptors or components of synaptic protein complexes. Neuronal cell-surface antibodies (NSAbs) are another group of antibodies detected in AE. 4 – 6 The intracellular location of the antigens, and the evidence for CD8 + cytotoxic T-cell-mediated neuronal cell damage in encephalitis coincident with these antibodies, raise the possibility that the humoral immune response could be a nonpathogenic ‘epiphenomenon.’ 6
Antibodies targeting nuclear and cytoplasmic proteins (onconeuronal antibodies) such as Hu, Ma, and Ri usually accompany malignancy, 3, 4 and LE coincident with the detection of these antibodies is termed ‘paraneoplastic LE.’ Patients producing these antibodies respond poorly to immunotherapy, but treatment of the cancer often results in neurological improvements. These autoantibodies often affect not only limbic structures but also other cerebral regions, and the term autoimmune encephalitis (AE), rather than autoimmune LE, is used with growing frequency to refer to this disease entity.ĪE is classified according to the location of the antigen, either intracellular or on the cell surface, because each classification is associated with different clinical features, especially pertaining to cancer association and immune therapy responsiveness. Autoimmune etiology is increasingly recognized as a major cause of LE along with the finding of the high prevalence of anti- N-methyl-d-aspartate receptor (NMDAR) antibody-associated encephalitis after the discovery of the antibody 2 and the continued identification of additional novel antibodies in LE. The existence of autoantibodies and a response to immunotherapy in these patients suggests that an aberrant immune reaction is involved in the disease pathogenesis. Infectious agents such as herpes simplex virus cause inflammation in the central nervous system (CNS) including the limbic area of the brain, but a substantial number of patients with LE are without clear evidence of CNS infection. Limbic encephalitis (LE), first described in 1960, 1 is characterized by a subacute onset of episodic memory loss and confusion frequently accompanied by seizures, psychiatric symptoms, and lesion involving the medial temporal lobe and hippocampus. In this review, the agents used for first- and second-line immunotherapy are discussed and recent attempts at finding new treatment options are introduced. Although several investigations have shown promising alternatives, the low absolute number of patients involved necessitates more evidence to establish further treatment strategies.
A small but significant proportion of patients are refractory to all first- and second-line therapies and require further treatment. Immune response to first-line immunotherapeutic agents (corticosteroids, intravenous immunoglobulin, plasma exchange, and immunoadsorption) is fair, but approximately half or more of patients are administered second-line immunotherapy (rituximab and cyclophosphamide). Retrospective observations indicate that early aggressive treatment is associated with better functional outcomes and fewer relapses. Along with discoveries of novel antibodies associated with the disease, clinical experience and outcomes with diverse immunotherapeutic agents in the treatment of autoimmune encephalitis are accumulating. Autoimmune encephalitis is one of the most rapidly growing research topics in neurology.
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