Paraneoplastic neurological disorders (PND) may be the first sign of an occult cancer and are often more incapacitating than the cancer itself.1 In addition, PND can mimic other neurological disorders. Therefore, it is important to detect paraneoplastic syndromes early in the disease. Such early detection can lead to prompt clinical treatment and reduce the severity of neurological disability.
PND are syndromes associated with systemic cancers and may affect the peripheral and central nervous systems. These syndromes are not caused by the tumor itself, but by remote effects of the malignancy. While the exact pathogenesis of most paraneoplastic neurologic syndromes is unknown, most are thought to have an immunopathogenesis. One hypothesis suggests that the expression of neuronal antigens by the tumor triggers an immune response against the tumor that affects the nervous system, resulting in the paraneoplastic disorder.
PND are difficult to diagnose
because the neurologic symptoms often appear before the tumor is detected. In fact, studies report that in almost 70% of patients, neurologic symptoms preceded the diagnosis of the tumor.1 Detecting the antibodies that are associated with the specific paraneoplastic disorder helps direct the search for the underlying cancer.2 Furthermore, identification of a paraneoplastic syndrome can assist with early detection of a neoplasm and its treatment, that may potentially reduce the severity of the patient's neurologic disability.2
A recently discovered paraneoplastic associated autoantibody, CV2, recognizes a 66 kDa brain protein, POP66 (paraneoplastic oligodendrocyte protein of 66 kDa molecular weight).3 Antibodies to POP66 specifically label a subpopulation of oligodendrocytes in the adult human brain following an increasing rostral-to-caudal gradient with the greatest number of these cells found in the spinal cord.3 This is in contrast to other PND antigens which are expressed in neurons.
Molecular analysis demonstrates that POP66, the protein recognized by anti-CV2 autoantibodies, may belong to a mammalian protein family called Ulip/CRMP (unc-33-like phosphoprotein/collapsin response mediator protein). This family comprises phosphoproteins that are regulated during development and are involved in axonal growth, guidance, and synaptic organization/development.3-4 Anti-CV2 autoantibodies most closely recognize the family member Ulip4/CRMP3. Ulip/CRMPs are downregulated, in particular Ulip4, in PC12 cells that are differentiated when nerve growth factor is present.4 This down-regulation suggests that cell growth termination may be related to Ulip/CRMP expression levels.4 Therefore, POP66 in oligodendrocytes could be directly or indirectly associated with neuron survival.
In patients with autoantibodies related to PND, the distribution of antigens throughout the brain 
anatomy closely correlates with the type of neurological syndrome.3 Anti-CV2 autoantibodies have been associated with several neurological syndromes, including subacute cerebellar syndrome, limbic encephalitis, encephalomyelitis, sensory neuropathy, and optic neuritis.3-6 Although most commonly observed in patients with small-cell lung cancer, anti-CV2 autoantibodies have been associated with malignant thymoma, uterine sarcoma, and undifferentiated mediastinal cancer.5
Anti-CV2 autoantibodies are associated with similar pathophysiological changes as those observed in other PND associated with anti-neuronal autoantibodies.4 The clinical symptoms and brain lesions seen in patients with anti-CV2 autoantibodies closely resemble those of patients with anti-Hu autoantibodies.4 In addition, patients with anti-Hu and anti-CV2 autoantibodies most commonly present with small-cell lung cancer. The association of two paraneoplastic antibodies, i.e., anti-Hu or anti-Ri, as well as anti-CV2 autoantibodies, has been reported.4 PND can be identified by the neurological syndrome, associated tumor, and autoantibodies circulating in the serum. Table 1 illustrates the findings of eleven patients in a recent study of PND associated with anti-CV2 autoantibodies.
| Patient | Age/Sex | Delay of Tumor (months) | Neurological Syndrome | Tumor | Antibody Titer |
| 1 | 66/F | -24 | Cerebellar ataxia Sensory-motor neuropathy Uveitis and retinopathy |
Undifferentiated carcinoma | 1/15,000 |
| 2 | 58/F | -1 | Limbic encephalitis | Malignant lymphoepithelial thymoma | 1/15,000 |
| 3 | 49/M | -1 | Limbic encephalitis | Small-cell lung carcinoma | 1/1,000 |
| 4 | 53/M | +7 | Myasthenia gravis Encephalopathy |
Malignant lymphoepithelial thymoma | 1/5,000 |
| 5 | 69/M | -6 | Frontal dementia Cerebellar ataxia Sensory neuropathy |
Small-cell lung carcinoma | 1/100,000 |
| 6 | 70/F | +3 | Cerebellar ataxia Sensory neuropathy Loss of vision |
Uterine sarcoma | 1/10,000 |
| 7 | 60/M | -20 | Limbic encephalitis Sensory neuropathy |
Small-cell lung carcinoma | 1/10,000 |
Chart adapted from: Honnorat, J. et al., Antibodies to a subpopulation of glial cells and a 66kDa developmental protein in patients with paraneoplastic neurological syndromes. Journal of Neurology, Neurosurgery, and Psychiatry 1996; 61:270-278
Anti-CV2 autoantibodies are associated with several paraneoplastic syndromes including cerebellar degeneration, sensory neuropathy, and encephalitis, and are most often related to small-cell lung cancer. Patients may have clinical features similar to anti-Hu, anti-Yo, anti-MaTa, anti-CAR, and anti-Ri syndromes. Thus, anti-CV2 autoantibodies are associated with a range of neurological symptoms and a variety of tumor types.
"Clinically, the detection of these
autoantibodies is highly relevant as
this predicts underlying malignancies,
hence allowing early diagnosis of the cancer."4
