Paraneoplastic encephalomyelitis associated with pancreatic tumor and anti-GAD antibodies.

Glutamic acid decarboxylase (GAD), the enzyme that catalyzes the conversion of glutamate to -aminobutyric acid (GABA), is expressed in GABA-secreting neurons and pancreatic cells.1 Anti-GAD antibodies (GAD Abs) have been described in patients with type 1 diabetes mellitus and patients with two CNS disorders, stiff-person syndrome and cerebellar ataxia associated with polyendocrine autoimmunity.2 We report a patient with paraneoplastic encephalomyelitis associated with a pancreatic tumor and GAD Abs. Case report. A 67-year-old man presented paresthesias and numbness in hands, feet, and perioral region. Over the next 2 weeks, he developed gait instability that required bilateral support for walking. The general examination was unremarkable. The neurologic examination showed gaze-evoked downbeat nystagmus. Deep tendon reflexes were absent in the legs. There was hypoesthesia in glove and stocking distribution, with decreased vibration and joint position sense in the fingers and toes. He showed truncal and gait ataxia and moderate limb dysmetria. Routine hematologic and biochemical analysis were normal. CSF analysis revealed a protein level of 314 mg/dL, 11 lymphocytes/ mm, and negative oligoclonal IgG bands. Serum and CSF serologies and cultures ruled out an infectious etiology. Antineuronal antibodies (Hu, Yo, Ri, Ma 1 and 2, CV2, and amphiphysin antibodies) were negative, but GAD Abs, detected by immunohistochemistry and RIA,2 were present in serum (1/80,000) and CSF (1/800). No other autoantibodies were detected either by immunohistochemistry or immunoblot of neuronal extracts. Nerve conduction studies demonstrated absent sensory nerve action potential in the legs with normal motor nerve and F-wave studies. Brain MRI was normal. A CT scan of the abdomen demonstrated a mass (5.5 3 5 cm) in the body of the pancreas without evidence of metastasis. The patient underwent a resection of the corpus and cauda of the pancreas combined with splenectomy. A histopathologic examination revealed a neoplasm of the pancreatic body, which showed an intense infiltration of inflammatory cells (figure) and a positive immunostaining for synaptophysin and chromogranin A. The tumor was classified as a well-differentiated, nonfunctioning pancreatic endocrine neoplasm. Symptoms worsened over the ensuing months. He also developed painful spasms in the left leg with fixed dorsiflexion posture of the foot. A new electromyogram demonstrated persistent motor activity in the left leg. Symptoms did not improve after several courses of IV immunoglobulins; he developed confusion and agitation and died from aspiration bronchopneumonia. The expression of GAD antigen by the patient’s tumor was demonstrated by the characteristic immunoreactivity of the tumor cells after incubation with GAD-6 monoclonal antibody (Hybrioma Bank, Iowa City, IA) (see figure) or biotinylated IgG of a patient with high titers of GAD Abs. Specificity of staining for GAD antigen was confirmed by competition experiments in which binding of the GAD-6 monoclonal antibody was blocked by preincubation of tumor sections with a human serum with high titers of GAD Abs (see figure) but not with serum from a normal individual (not shown). At brain autopsy, the CNS appeared grossly normal. Microscopically, there was an extensive loss of Purkinje cells in the cerebellum and proliferation of Bergmann astrocytes. A vacuolization in the posterior columns of the spinal cord was also noticeable. Inflammatory infiltrates were not detected in the cerebellum or other areas of the nervous system. Discussion. The current study shows that GAD Ab response can be associated with tumors other than thymoma.3 This finding is important because the presence of GAD Abs is usually associated with the nonparaneoplastic form of the stiff-person syndrome and in the cerebellar ataxia associated with polyendocrine autoimmunity, which are unrelated to malignancies with the exception of thymoma.1,2,4,5 The detection of high titers of GAD Abs in a patient with a neurologic syndrome usually indicates that the probable cause is nonparaneoplastic autoimmunity, and the search for an underlying cancer is unnecessary. Although this statement is probably correct when the patient has a stiff-person or cerebellar syndrome,1,2 in the clinical setting of a possible encephalomyelitis, a possible paraneoplastic origin should be considered even if the patient has GAD Abs.6 The pathogenic role of GAD Abs in the two characteristic neurologic disorders, stiff-person and cerebellar ataxia, has been questioned because GAD is a cytoplasmic antigen.7 In our patient, the massive infiltration of the tumor by T lymphocytes suggests that the GAD expression by the tumor could induce a complex (humoral and cellular) immune response, initially driven to control the tumor growth and later misdirected to the nervous system. The final mechanisms of neuronal damage are unclear, but it was probably caused by a T cell–mediated immune attack against GAD-positive neurons.6