Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma

Abstract

We report four young women who developed acute psychiatric symptoms, seizures, memory deficits, decreased level of consciousness, and central hypoventilation associated with ovarian teratoma (OT) and cerebrospinal fluid (CSF) inflammatory abnormalities. Three patients recovered with treatment of the tumor or immunosuppression and one died of the disorder. Five other OT patients with a similar syndrome and response to treatment have been reported. Our patients' serum or CSF showed immunolabeling of antigens that were expressed at the cytoplasmic membrane of hippocampal neurons and processes and readily accessed by antibodies in live neurons. Immunoprobing of a hippocampal-expression library resulted in the isolation of EFA6A, a protein that interacts with a member of the two-pore-domain potassium channel family and is involved in the regulation of the dendritic development of hippocampal neurons. EFA6A-purified antibodies reproduced the hippocampal immunolabeling of all patients' antibodies and colocalized with them at the plasma membrane. These findings indicate that in a young woman with acute psychiatric symptoms, seizures, and central hypoventilation, a paraneoplastic immune-mediated syndrome should be considered. Recognition of this disorder is important because despite the severity of the symptoms, patients usually recover. The location and function of the isolated antigen suggest that the disorder is directly mediated by antibodies.

Figures

Fig 1

Brain magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) of Patient 1. A brain MRI obtained 6 weeks after symptom presentation showed fluid-attenuated inversion recovery and T2 hyperintensities over the left cerebral cortex and cerebellum; mild contrast enhancement was noted in the cerebellum (data not shown). FDG-PET demonstrated increased FDG activity in the left temporal lobe, brainstem and cerebellum, and hypoactivity in the occipital lobes. A follow-up MRI obtained 14 weeks later was normal; the FDG-PET showed minimal decreased activity in the left temporoparietal region.

Fig 2

Sera and cerebrospinal fluid (CSF) of patients with teratoma-associated encephalitis react with hippocampal antigens. Top two rows of panels demonstrate the reactivity of serum antibodies of Patient 1 (Patient 1 ab) and CSF antibodies of Patients 2 and 3 (Patient 2 ab and Patient 3 ab) with rat hippocampus. The pattern of reactivity is identical for the three patients' antibodies, but different from that seen in a patient with voltage-gated potassium channel (VGKC) antibodies (Human VGKC ab). Note that the antibodies of the three patients with teratoma-associated encephalitis predominantly react with the inner aspect of the molecular layer adjacent to the dentate gyrus; in contrast, the serum of the patient with VGKC antibodies predominantly reacts with the outer aspect of the molecular layer. These differences are emphasized in a double immunolabeling assay shown in the bottom row panels, and in the higher magnifications shown in Figure 3. Asterisks are shown in the inner aspect of the molecular layer to allow comparison among all panels. The arrow points to the hilum of hippocampus, which is spared by the three patients' antibodies but is immunolabeled by VGKC antibodies. Bottom row panels compare the reactivity of antibodies from Patient 3 (Patient 3 ab; green) with that of a monoclonal antibody to the Kv1.2 VGKC (red). Note that the immunolabeling of Patient 3 antibodies predominates in the inner aspect of the molecular layer (asterisks), whereas the immunolabeling of the Kv1.2 VGKC antibody predominates in the outer aspect of the molecular layer. Of note, this monoclonal antibody also reacts with some neurons of the dentate gyrus, a feature not seen with human antibodies to the Kv1.2 VGKC (see magnifications using human antibodies in Fig 3). Magnfication: top two row panels ×50; bottom panels ×200.

Fig 3

Pattern of reactivity of teratoma-associated encephalitis antibodies compared with voltage-gated potassium channel (VGKC) antibodies. Panel A shows that antibodies from Patient 3 predominantly react with the inner aspect of the molecular layer of hippocampus, whereas human VGKC antibodies (B) predominantly react with the outer aspect (asterisk shown in the same area as in Fig 2). Note that for both antibodies the reactivity spares cytoplasm and nuclei of neurons. Panel C shows that antibodies from Patient 3 (as well as from Patients 1 and 2, not shown here) have minimal reactivity with cerebellum, whereas human VGKC antibodies (D) have intense reactivity with the molecular layer. Panel E shows double immunolabeling of neuronal cultures with teratoma-associated encephalitis antibodies (red) and Kv1.2 VGKC antibodies (green); note the lack of colocalization. Magnification: panels A–D ×400; panel E ×800 oil objective.

Fig 4

Teratoma-associated encephalitis antibodies readily recognize membrane antigens in live neuronal cultures. Panels A and C show neuronal cultures that have been incubated for 30 minutes with media containing antibodies from Patients 1 (A) and 3 (C) followed by fixation with paraformaldehyde. Neurons similarly incubated with anti–Hu antibodies (B) and normal IgG (D) serve as controls. Note that the antibodies of patients with teratoma-associated encephalitis produce intense immunolabeling of the neuronal cell membrane and processes, whereas antibodies to intracellular antigens or normal IgG do not bind to the cell surface. To visualize neurons, we labeled nuclei with 4,6-diamidino-2-phenylindole-2-HCl. All panels ×800 oil objective.

Fig 5

EFA6A, a brain-specific protein, colocalizes with the target antigen of teratoma-associated encephalitis. Immunoprobing a cDNA hippocampus expression library with patients' sera resulted in the isolation of EFA6A. (A) nitrocellulose filter with EFA6A-expressing bacteriophage plaques incubated with serum from Patient 3 and normal human serum (sera from Patients 1, 2, and 4 did not react with EFA6A protein expressed in plaques). Panel B shows that affinity-purified antibodies eluted from EFA6A reproduce the same pattern of hippocampal immunolabeling as that of all patients' antibodies. Panel C confirms that EFA6A colocalizes with the antigen targeted by patients' antibodies (Patient 2 shown in the figure). All panels ×800 oil objective.