By Bianca D. Santomasso, MD, PhD

Instructor in Neurology, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College

Dr. Santomasso reports no financial relationships relevant to this field of study.

Synopsis: This retrospective case series identifies the clinical and immunologic features of GAD antibody-positive patients who should be screened for an underlying cancer.

Source: Arino H, et al. Paraneoplastic neurological syndromes and glutamic acid decarboxylase antibodies. JAMA Neurol 2015; June 22. doi:10.1001/jamaneurol.2015.0749 [Epub ahead of print].

Autoimmune neurological disorders can be associated with an underlying cancer (in which case they are referred to as paraneoplastic) or they can be idiopathic. High titer antibodies against the intracellular synaptic enzyme glutamic acid decarboxylase (GAD) fall into this latter category and are associated with specific neurologic syndromes including stiff-person syndrome (SPS), cerebellar ataxia, limbic encephalitis, and epilepsy. Rather than a cancer association, GAD antibodies more often occur with organ-specific autoimmune disorders such as diabetes. The clinician faced with a patient with GAD antibodies typically would not embark on a search for an underlying tumor unless the patient also had an additional “onconeural” antibody such as Hu, Yo, Ri, CV2, amphiphysin, or Ma. Nevertheless, there have been case reports of patients with GAD antibodies who have an underlying cancer, suggesting that some cases may be paraneoplastic. This leads to the question: When should we be doing a tumor workup in a patient with GAD-abs and a neurological syndrome?

The authors, who are affiliated with a large center in Barcelona, Spain, for autoimmune neurological disorders, retrospectively examined patients between 1995 and 2013 whose samples were submitted for onconeural antibody analysis. Patients whose samples were sent in for analysis met criteria for definite or possible paraneoplastic neurologic syndrome. Unexpectedly, they found 15 patients who had no onconeural antibodies but who had high titer GAD-abs and an underlying tumor. The tumors included six lung cancers (four of them SCLC), four neuroendocrine tumors (two pancreas and two thymic carcinoid), two thymoma, two breast cancer, and one non-Hodgkin lymphoma. Interestingly, eight of the 15 GAD patients with tumors presented with classical paraneoplastic neurologic syndromes (limbic encephalitis, encephalomyelitis, cerebellar degeneration, or opsoclonus-myoclonus syndrome) rather than the typical GAD-ab-associated syndromes of SPS, cerebellar ataxia, and epilepsy. In most patients, the neurological syndrome preceded the diagnosis of the cancer. Three tumors were examined for GAD protein by immunohistochemistry and all were found to express it, suggesting triggering of the immune response by the tumor.

The authors then compared the 15 paraneoplastic GAD-ab patients to a cohort of 106 patients with nonparaneoplastic GAD-ab disorders. There was no significant difference in the levels of antibody in the serum and CSF between the groups. They found that patients with paraneoplastic GAD-abs were older (median age 60 vs 48 years; P = 0.03), were more frequently male (60% vs 13%; P < 0.001), and more often had coexisting neuronal cell-surface autoantibodies (53% vs 11%; P < 0.001) such as γ-aminobuteric acid B antibodies, γ-aminobutyric acid A receptors antibodies, and glycine receptor antibodies. Eight of 15 patients with paraneoplastic GAD-abs had one of these or other antibodies to unknown targets on the neuronal cell surface. The patients also presented with more classical paraneoplastic syndromes (limbic encephalitis, paraneoplastic cerebellar degeneration, paraneoplastic encephalomyelitis, or opsoclonus-myoclonus syndrome) than SPS or cerebellar ataxia. The authors contrasted their series with reviewed cases of paraneoplastic GAD from the literature where SPS was the most common neurological syndrome (rather than limbic encephalitis) and thymic tumors (rather than lung) were the most common underlying neoplasm. They conclude that there seem to be distinct subgroups of patients with GAD-abs, some of whom have underlying tumors that are likely triggering their neurologic symptoms.

All study patients received immunotherapy with high-dose corticosteroids, intravenous immunoglobulin, intravenous immunoglobulin plus rituximab, or intravenous immunoglobulin plus cyclophosphamide. In addition, 10 (71%) patients received treatment of their underlying cancer with surgery, chemotherapy, radiotherapy alone, or combined therapy. Compared with their series, the previously reported cases were more likely to have clinical improvement and the probability of clinical improvement was greater in patients with thymic tumors.


Commentary

Many neurologists have the ability to order comprehensive antigen test batteries, which allow for the detection of neuronal cell surface antibodies in addition to GAD-abs. Although this study found the risk of cancer to be seven-fold higher in patients with concomitant antibodies against neuronal cell surface antigens, almost half of the patients in this study with an underlying tumor had no other antibodies detected. The clinical presentation, while helpful, is also not 100%; in this study, tumors in two SPS patients would have been missed by relying only on the clinical presentation alone as a way to distinguish paraneoplastic from idiopathic GAD-abs. Importantly, limbic encephalitis can be seen as a neurologic syndrome in both paraneoplastic and non-paraneoplastic cases. Therefore, one reasonable conclusion from this study is that every patient with a high-level GAD-abs should have screening for an underlying cancer, including mammogram and CT chest or PET scan.