Paraneoplastic encephalomyelitis associated with pancreatic tumor and anti-GAD antibodies

Abstract

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 3 , 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 ϫ 3 ϫ 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 anti...

GABA B receptor antibodies in limbic encephalitis and anti-GAD–associated neurologic disorders

“…The other 5 GAD-ab-positive patients without GABA B R-ab presented with paraneoplastic encephalomyelitis associated with pancreatic cancer 11 and cerebellar ataxia with breast cancer (2 patients), non-SCLC, and neuroendocrine thymic carcinoma. 12 To see if GABA B R-ab associate with other cases of paraneoplastic cerebellar degeneration (PCD), we analyzed the serum or CSF of a series of 45 patients with PCD and lung cancer (35 with SCLC).…”

Paraneoplastic Neurological Syndromes and Glutamic Acid Decarboxylase Antibodies

“…However, there are case reports of patients with GAD-abs whose cancer was identified by the time of the neurological diagnosis, suggesting a paraneoplastic mechanism. 4,5 Whether these cases represent a casual association or a true GAD-ab–associated paraneoplastic neurological syndrome (PNS) is unclear.…”

Unusual paraneoplastic neurological syndrome secondary to a well differentiated pancreatic neuroendocrine tumor: a case report and review of the literature

“…The tumors more commonly involved are small cell lung cancer, gynecological cancers, breast cancers, and Hodgkin’s lymphoma [3]. Only few cases of PNS associated with pancreatic WDNET are reported (Table 1) [6–8]. In these cases the treatment of the underling cancer was followed by marked improvement of neurological symptoms.…”

“…Only few cases of PNS associated with pancreatic WDNET are reported (Table 1) [6–8]. In these cases the treatment of the underling cancer was followed by marked improvement of neurological symptoms.…”