Paraneoplastic chorea caused by anti-CRMP5 antibodies associated with small-cell lung cancer

Dear Editor:

The appearance of subacute choreic symptoms often poses a diagnostic challenge. Many entities cause these symptoms, and they may be hereditary or secondary to drugs, toxic metabolic disorders, or structural lesions (vascular, oncological, or inflammatory). It is also possible, albeit extremely rare, for symptoms to be caused by a paraneoplastic syndrome. This would generally be associated with other neurological symptoms suggesting encephalitis, polyneuropathy, or cerebellar disorder.^1,2

Male patient aged 69 with a history of arterial hypertension, hypercholesterolaemia, benign hypertrophy of the prostate, and a 2 pack/day smoking habit spanning 40 years. He visited the neurology clinic due to choreic symptoms that had first appeared 5 weeks before. Choreic movements began in the right limbs, where they were the most prominent, but subsequently extended to the orolingual and cervical muscles. The patient had no history of taking dopaminergic drugs. The neurological examination found no changes in cortical functions or cranial nerves, with no sensorimotor deficits or obvious cerebellar impairment. General examination yielded normal results.

Laboratory analyses, including complete blood count, coagulation study, vitamin B₁₂, folic acid, renal function, tumour markers, total protein test, thyroid hormones, rheumatoid factor tests, antinuclear antibodies, copper, and ceruloplasmin tests showed no abnormalities. Serology testing for borreliosis and neurotropic viruses yielded negative results. Blood smear did not show acanthocytosis and the genetic study for Huntington disease was also negative. Cerebrospinal fluid study showed elevated protein at 68 mg/dL, normal glucose levels, and absence of lymphocytes and cancer cells. Likewise, brain MRI with and without gadolinium contrast revealed no significant changes. The study of antineuronal antibodies (anti-Hu, anti-Ri, anti-Yo, anti-CRMP5/CV2, anti-Ma1, anti-Ma2) yielded a positive result for CRMP5/CV2. Chest, abdomen, and pelvis CT showed a small nodule measuring 0.5 cm at the level of the right middle lobe. The nodule was removed and found to be a small-cell lung carcinoma. Prior to surgery, the patient was treated with prednisone dosed at 1 mg/kg body weight concomitantly with gamma globulin dosed at 0.4 g/kg body weight per day over 5 days, with no signs of improvement. After surgery, the patient's symptoms have improved somewhat, but noticeable choreic movements persist and they have not lessened with pimozide or tetrabenazine.

To date, some 30 cases of paraneoplastic chorea have been described.³ Most are associated with small-cell lung cancer, while others are associated with lymphoma or with breast, testicular, or kidney cancer. The most frequently detected antineuronal antibodies are anti-Hu and anti-CRMP5 or CV2. Generally speaking, anti-Hu antibodies are found in paraneoplastic chorea syndromes associated with small-cell lung cancer, whereas anti-CRMP5 tends to be associated with lymphomas.⁴ This makes our case even more uncommon.⁵

Anti-CRMP5 antibodies tend to provoke the appearance of a myasthenic syndrome that is frequently associated with thymoma, or paraneoplastic polyneuropathy associated with small-cell lung cancer.⁶ Other less common syndromes include cerebellar ataxia and eye disorders.⁷

The role played by antineuronal antibodies in the pathogenesis of paraneoplastic syndromes is yet to be fully understood. The most plausible theory points to a cross response between central nervous system antigens and onconeural antigens. Most paraneoplastic antigens are found in cytoplasm (anti-Yo) or the nucleus (anti-CRMP5). Scientists believe that the cell's immunological response to these antigens would harm neural structures and therefore cause neurological symptoms. This hypothesis is founded on the response elicited by immunomodulatory drugs in different paraneoplastic syndromes. As such, in paraneoplastic syndromes in which antigens are located on the cell surface, immunomodulatory treatment (corticosteroids, plasmapheresis, gamma globulin, etc.) is generally effective, but patients with syndromes in which the antigen is intracellular typically do not respond. Chorea in our patient did not respond to treatment with corticosteroids or gamma globulin because the CRMP5 antigen is intracellular.

In conclusion, patients displaying subacute choreic symptoms should be screened to rule out paraneoplastic syndrome. Since paraneoplastic syndrome occasionally appears in early stages of tumour development,^8,9 diagnosing paraneoplastic chorea may result in an earlier diagnosis of cancer, which in turn could improve patient prognosis.