The remote effects of malignant
tumors in most cases of paraneoplastic neurological syndromes(PNS)are mediated by autoimmune processes against
antigens shared by the
tumor cells and the nervous tissue(onconeural
antigens). Onconeural (or paraneoplastic)
antibodies are broadly categorized into two groups according to the location of the corresponding onconeural
antigens, inside or on the surface of neurons.
Antibodies established as clinically relevant diagnostic markers for PNS are designated as well-characterized onconeural
antibodies (or classical
antibodies)that target intracellular
antigens(Hu, Yo, Ri, CV2/CRMP5,Ma2, and
amphiphysin). They also serve as useful markers in detecting primary
tumors. Recent identification of new
antibodies as markers of subtypes of
limbic encephalitis has also expanded the concept of
autoimmune limbic encephalitis. These
autoantibodies are directed to neuronal
cell-surface antigens including
neurotransmitter receptors(
NMDA,
AMPA, and GABAB receptors)and
ion channels(VGKC). They are less frequently associated with
cancer, so that they cannot be used as specific markers for PNS.
Autoimmune limbic encephalitis with anti-neuronal cell surface antobodies and
paraneoplastic limbic encephalitis with classical
antibodies overlap in some clinical features but are pathophysiologically distinct. Classical
antibodies are not simple
tumor markers. They seem to be closely related to the disease mechanisms because specific intrathecal synthesis has been shown in PNS patients. However, attempts to produce an animal model of PNS by passive transfer of these
antibodies have been unsuccessful, and there is no direct evidence demonstrating the pathogenic role of classical
antibodies. Instead, some circumstantial evidence, including pathological studies showing extensive infiltrates of T cells in the CNS of the patients, supports the hypothesis that cytotoxic-T cell mechanisms cause irreversible neuronal damage. On the other hand, humoral immune response is probably the principal mechanism in
autoimmune encephalitis associated with
antibodies against neuronal
cell-surface antigens. Those
antibodies are supposed to mediate neural dysfunction which may be reversed by immunosuppression therapy, while the exact mechanism remains to be elucidated. Further accumulation of the cases and longer observation would be necessary to delineate the clinical spectrum of each type of newly-identified
autoimmune limbic encephalitis. Early diagnosis and optimal oncological treatment is a prerequisite for better prognosis of PNS patients. Detection of the primary
tumor at very early stages including
carcinoma in situ is a challenging issue. Optimization of immunosuppression/
immunomodulation therapy for each patient according to the underlying pathophysiological processes is another important clinical issue.