Abstract
Raised levels of P/Q type voltage-gated calcium-channel (VGCC) antibodies were found in 16 (41%) of 39 patients with paraneoplastic cerebellar degeneration (PCD) and Hu antibodies were found in nine (23%). Seven of the 16 VGCC antibody-positive patients had Lambert–Eaton myasthenic syndrome (LEMS). Seven of 15 CSF samples had VGCC antibodies, with evidence of intrathecal synthesis in four. VGCC antibodies should be looked for in PCD, even if there are no symptoms of LEMS, and may be related to the cerebellar dysfunction.
The pathologic hallmark of paraneoplastic cerebellar degeneration (PCD) is subacute loss of Purkinje cells of the cerebellum.1 In this and other paraneoplastic conditions, there are often serum and CSF antibodies to antigens that are expressed by the tumor and also by the nervous system.1 Patients with PCD and small cell lung carcinoma (SCLC) may have Hu antibodies in serum and CSF, particularly if there is clinical evidence of neurologic symptoms beyond the cerebellum.2 However, in a substantial number of patients with PCD and SCLC, Hu or other antineuronal antibodies are not detected, but antibodies to P/Q type voltage-gated calcium channels (VGCC) have been reported in some cases.2,3⇓ VGCC antibodies are typically associated with the Lambert–Eaton myasthenic syndrome (LEMS), but not all patients with PCD and VGCC antibodies had clinical evidence of LEMS. VGCC antibodies, in contrast to Hu antibodies, bind to extracellular determinants and alter VGCC expression, and if they are able to access the CNS they could theoretically be directly responsible for the cerebellar dysfunction in PCD.4
To clarify the clinical and pathologic relevance of P/Q type VGCC antibodies, we reviewed 39 patients with PCD and lung cancer and looked for clinical and electrophysiological evidence of LEMS. We compared the prognosis in VGCC antibody-positive and -negative cases and assessed intrathecal synthesis of VGCC antibodies.
Patients and methods.
From our database, we selected patients with the final diagnosis of PCD with lung cancer. These patients presented with an isolated or clearly predominant cerebellar syndrome of unknown cause and had either Hu antibodies or developed lung cancer. Unlike previous work,2 we specifically excluded Hu-positive patients who presented with ataxia but quickly developed symptoms beyond the cerebellum; the purpose was to exclude cases of paraneoplastic encephalomyelitis that, in contrast to PCD, almost always have Hu antibodies.1 All patients were tested retrospectively for VGCC antibodies, and the clinical features were compared between antibody-positive and -negative patients (table).
Table Association between clinical characteristics and the presence of anti-VGCC antibodies in 39 patients with PCD
Serum and CSF, when available, were evaluated for the presence of antineuronal antibodies by immunohistochemistry on frozen sections of rat cerebellum according to standardized techniques previously reported in detail.5 Antibodies to P/Q type VGCC were analyzed in the Oxford laboratory, as previously described,6 using 125I-ω-CmTx-VGCC extracted from human cerebellum. Sera, diluted 1:10, were screened using 2.5 μL, and all positive samples were titrated for accurate determination. CSF samples were screened using 50 μL of undiluted CSF (with 2.5 μL normal human serum as carrier) and diluted further if necessary. CSF results were considered positive if greater than the mean ± 3 SD from 14 CSF from patients with degenerative ataxias. Intrathecal synthesis of VGCC antibodies was calculated in paired samples of serum and CSF by the formula:
A value higher than 1 was considered indicative of intrathecal synthesis.
Results.
Thirty-nine patients (37 men, 2 women) fulfilled the criteria of PCD and had a median age of 63 years. SCLC was diagnosed in 31 patients and other types of lung cancer in five. One patient had x-ray features suggestive of lung cancer, but histology could not be obtained. Two patients with no evidence of tumor were included because they were smokers and had Hu antibodies.
Only eight (20.5%) patients had clinical features consistent with LEMS (see table). One patient was VGCC antibody-negative at the time of diagnosis of ataxia, and 2 years later he developed electromyographic (EMG) features of LEMS (serum was not available at this time). In the other seven patients, LEMS was present at the first neurologic evaluation. An EMG was also performed in the nine patients with positive VGCC antibodies without clinical evidence of LEMS and was negative in all of them. EMG was done specifically to rule out LEMS in five of the nine patients. In the other four, the EMG repetitive stimulation was not done, but the compound muscle action potential was reported to be of normal amplitude.
Serum VGCC antibodies were identified in 16 (41%) patients (median of positive titers 648 pM/L; figure). No major differences were observed between patients with and without VGCC antibodies except for the higher occurrence of LEMS in the positive group (see table). In the three patients with both PCD and LEMS who underwent immunotherapy, there was improvement in the LEMS without any apparent beneficial effect on PCD.
Figure. Voltage-gated calcium channel (VGCC) antibody levels in patients with paraneoplastic cerebellar degeneration and lung cancer. The serum values relate to the left vertical axis and the CSF values to the right vertical axis.
Paired serum/CSF samples were available in 15 patients. Positive CSF VGCC antibodies were found in seven (47%) of these, with a median titer of 81 pM/L (see figure). Measurement of CSF:serum VGCC antibody/IgG ratios was performed in these seven patients; four had values >1 (range, 1.5 to 4.8), compatible with intrathecal synthesis of the antibody.
Discussion.
VGCC antibodies were present in 41% of patients tested, including those without clinical or EMG features of LEMS, and were more frequent than Hu antibodies. This indicates that VGCC antibodies provide a more useful marker for PCD associated with lung cancer than Hu antibodies. Moreover, VGCC antibodies were found in the CSF and there was some evidence of intrathecal synthesis; thus they could well play a pathogenic role in the evolution of the disease.
The frequency of P/Q type VGCC antibodies in patients with particular paraneoplastic neurologic disorders is not clear. An initial study found low titers of VGCC antibodies in 40% of 70 patients with different types of paraneoplastic neurologic disorders.7 By contrast, other studies suggest that VGCC antibodies are found only in patients with either LEMS or PCD with SCLC and in some of those with paraneoplastic encephalomyelitis and Hu antibodies.2,3⇓ In the latter group, the incidence of VGCC antibodies is less than 13%,2,3⇓ whereas in patients with PCD and lung cancer without Hu antibodies, the frequency of VGCC antibodies in the current and previous study2 was higher than 36%. Therefore, VGCC antibodies represent the most useful antibody as a marker of lung cancer associated with PCD. Because some of the patients with VGCC antibodies did not have either clinical or EMG evidence of LEMS, this antibody should be looked for regardless of the presence of LEMS.
VGCC antibodies are known to be pathogenic in LEMS.8 The absence of LEMS in some PCD patients with high titers of VGCC antibodies is, therefore, surprising. It may be that the specificity of the antibodies differs from those in patients with typical LEMS; for instance, it is possible that the antibodies bind to intracellular epitopes that are not expressed on the cell surface. This will require further investigation. Alternatively, the motor nerve terminal may be able to upregulate other subtypes of VGCC to overcome the peripheral dysfunction. Some evidence of modulation of VGCC expression has already been demonstrated in model systems.9
Finally, our results suggest that the VGCC antibodies can gain access to the CNS and could, therefore, bind to the P type VGCC on Purkinje cells.4 Conversely, we failed to show a better response to treatment in antibody-positive patients, and, as described in a previous report,10 PCD did not improve in our patients whose LEMS got better after treatment. It may be that the Purkinje cells have already been irreversibly damaged by the VGCC antibodies or that the immunotherapies used were unable to remove the antibodies from the CSF. We cannot exclude the presence of other coexisting immune mechanisms, e.g., cytotoxic T cells, that are responsible for the cerebellar dysfunction and that the VGCC antibodies, like Hu antibodies, are a secondary marker.
Acknowledgments
Supported in part by grant SGR 9500027 Generalitat de Catalunya, Spain (F.G.).
Acknowledgment
The authors thank all the neurologists who provided clinical information of their patients.
- Received February 20, 2002.
- Accepted May 3, 2002.
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