Small-cell lung cancer, paraneoplastic cerebellar degeneration and the Lambert-Eaton myasthenic syndrome

Several cancers, especially lung, ovarian and breast, can cause paraneoplastic cerebellar degeneration. The presence of different antineuronal antibodies associated with different cancers and paraneoplastic cerebellar degeneration suggests that several immunological mechanisms may result in the same neurological disorder In patients with small-cell lung cancel; paraneoplastic cerebellar degeneration may occur with or without Hu antineuronal antibodies (HuAb), indicating that patients with the same tumour can develop paraneoplastic cerebellar degeneration by different immunological mechanisms. Furthermore, paraneoplastic cerebellar degeneration sometimes occurs in association with the Lambert-Eaton myasthenic syndrome. In order to try to understand the clinical implication of antineuronal antibodies in patients with small-cell lung cancer; we examined the serum of 57 patients with presenting symptoms of paraneoplastic cerebellar degeneration for the presence of HuAb and P/Q- and N-type voltage-gated calcium channel antibodies. Patients with paraneoplastic cerebellar degeneration who were HuAb positive were compared with HuAb negative patients with respect to neurological symptoms, course of the neurological disorder; response to treatment, tumour prognosis, pathological findings, and cause of death. The tumour outcome and serological findings of these patients were also compared with those of 109 small-cell lung cancer patients without paraneoplastic syndromes of the CNS. Titres of HuAb were classified as 'high' (immunoblot titre >1 : 10 000) or 'low' (<1 : 10 000), the latter similar to the antibody titres detected in some small-cell lung cancer patients without paraneoplastic symptoms. Twenty-five patients with paraneoplastic cerebellar degeneration (44%) had high titres of HuAb, four (7%) had low titres of HuAb, and 28 (49%) were HuAb negative; for clinical comparisons with the patients with high titres of HuAb, the four patients with low antibody titres were included in the HuAb negative cohort. None of the 109 small-cell lung cancer patients without paraneoplastic symptoms had high titres of HuAb. The presence of high titres of HuAb defined a subset of patients who differed from the HuAb negative paraneoplastic cerebellar degeneration cohort, HuAb positive patients were more likely to be female (P < 0.01), to have multifocal neurological disease (brainstem encephalopathy and sensory neuropathy being common extracerebellar manifestations) (P < 0.002), and be severely disabled (P < 0.005). A total of nine patients (16%) from both paraneoplastic cerebellar degeneration groups developed electrophysiologically confirmed Lambert-Eaton myasthenic syndrome. Seven of these nine patients had serum available for P/Q-type voltage-gated calcium channel antibody testing and all seven were positive. In addition, 20% of HuAb negative paraneoplastic cerebellar degeneration patients without clinically identified Lambert-Eaton myasthenic syndrome had P/Q-type voltage-gated calcium channel antibodies, while only 2% of small-cell lung cancer patients without paraneoplastic symptoms had these antibodies. Treatment of the tumour and/or immunomodulation did not alter the course of paraneoplastic cerebellar degeneration, but improved Lambert-Eaton myasthenic syndrome symptoms. At the time of death, in 60% of HuAb positive and 20% of HuAb negative paraneoplastic cerebellar degeneration patients, the tumour was either not evident or localized to the chest (P < 0.007): neurological disease was the cause of death of 65% HuAb positive paraneoplastic cerebellar degeneration and 10% HuAb negative paraneoplastic cerebellar degeneration patients (P < 0.001). Irrespective of the serological findings and cause of death, paraneoplastic cerebellar degeneration patients who received standard treatment for the small-cell lung cancer, had shorter survival (1- and 2-year survival after cancer diagnosis of 46% and 28%, respectively) than an age-, tumour-stage- and treatment-matched group of 59 small-cell lung cancer patients without paraneoplastic disease (1- and 2-year survival estimates, 76% and 31%, respectively). The pathological findings of five HuAb positive paraneoplastic cerebellar degeneration patients examined at autopsy included diffuse encephalomyelitis with severe los of Purkinje cells in four patients, but no apparent Purkinje cell loss in one; three patients also had involvement of posterior nerve roots or dorsal root ganglia. By contrast, autopsy studies of three HuAb negative paraneoplastic cerebellar degeneration patients demonstrated severe loss of Purkinje cells without inflammatory infiltrates of the neuraxis (two patients); mild perivascular inflammatory infiltrates involving dentate, brainstem and spinal cord were found in one patient who died within 1 month of symptom development. We conclude that in patients with small-cell lung cancer and paraneoplastic cerebellar degeneration: (i) the HuAb may or may not be present at high titre (>1 : 10 000); (ii) at least 16% of these patients had Lambert-Eaton myasthenic syndrome, irrespective of the HuAb status; (iii) all Lambert-Eaton myasthenic syndrome patients were P/Q-type voltage-gated calcium channel antibody positive, suggesting that they had subclinical Lambert-Eaton myasthenic syndrome; (v) HuAb positive paraneoplastic cerebellar degeneration patients were more likely to be female, to have multifocal neurological disease, to be severely disabled, or to die from neurological causes; (vi) independent of serology and cause of death, paraneoplastic cerebellar degeneration patients receiving standard treatment for small-cell lung cancer died earlier than a matched group of non-paraneoplastic cerebellar degeneration small-cell lung cancer patients; (vii) (pathology) inflammatory infiltrates were far more prominent in HuAb positive compared with HuAb negative paraneoplastic cerebellar degeneration patients, in a small series (n = 8).