We review the neuronal
antibodies described in CNS disorders in order to clarify their diagnostic value, emphasize potentials pitfalls and limitations in the diagnosis of paraneoplastic neurological syndromes (PNS), and examine the current evidence for a possible pathogenic role. We propose to classify the neuronal
antibodies associated with syndromes resulting from CNS neuronal dysfunction into two groups according to the location of the
antigen: inside the neuron or in the cell membrane. Group I includes
antibodies which target intracellular
antigens and probably are not pathogenic. They are further subdivided into three groups. Group Ia comprises well-characterized onconeural
antibodies (Hu (ANNA1), Yo (PCA1), Ri (ANNA2), CV2 (CRMP5),
amphiphysin, Ma2) that are useful for the diagnosis of PNS. Group Ib
antibodies (SOX and ZIC) are
cancer-specific but there is no evidence that the immune response is in any way pathogenically related to the PNS.
Antibodies in group Ic (
glutamic acid decarboxylase (GAD),
adenylate kinase 5 and
Homer 3) identify non-PNS:
stiff-person syndrome (SPS),
cerebellar ataxia, and
limbic encephalitis (LE). Group II
antibodies recognize neuronal
surface antigens.
Antibodies in group IIa associate with characteristic CNS syndromes but their detection does not indicate that the disorder is paraneoplastic.
Antibodies to
potassium channels,
AMPA and
GABA(B) receptors are associated with LE,
NMDA receptor antibodies identify a well-defined
encephalitis, and
antibodies against
glycine receptors associate with SPS with
encephalitis. A pathogenic role of the
antibodies is suggested by the response of symptoms to
immunotherapy and the correlation between antibody titers and neurological outcome. Lastly, Group IIb includes
antibodies that are found in patients with paraneoplastic
cerebellar ataxia associated with
lung cancer (P/
Q type calcium channels antibodies) or
Hodgkin disease (
metabotropic glutamate receptor type 1 antibodies).