Journal of Neuroimmunology 310 (2017) 66–68 Contents lists available at ScienceDirect Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim Short communication Neuroendocrine tumour metastatic brain disease during immunosuppressive treatment for paraneoplastic GABAB receptor antibodies encephalitis: Is immunosuppression always beneficial? MARK Ana Andréa,⁎, Ana Félixa, Motasem Shamasnaa, Hipólito Nzwalob, Carlos Basílioa a b Neurology Department, Algarve Hospital Center, Portugal Department of Biomedical Sciences and Medicine, University of Algarve, Portugal A R T I C L E I N F O A B S T R A C T Keywords: GABA-B-receptor antibody Paraneoplastic neurological syndrome Immunosuppression Brain metastasis Pulmonary neuroendocrine tumour metastatic disease Background: Limbic autoimmune encephalitis (LE) should be considered in any patient with acute or subacute neuropsychiatric manifestations, without other common causes of encephalitis. Y-Aminobutyric-acid-B-receptor (anti-GABABR) antibodies are rarely encountered in association with LE. Case report: A 74-year-old patient presented with a progressive cognitive degradation and generalized tonicclonic seizures, with positive anti-GABABR. He declined under immunosuppression treatment. Control magnetic resonance revealed brain lesions, which became positive for pulmonary neuroendocrine tumour metastatic disease. Conclusion: The occurrence of diversified neurological manifestations of an underling tumour is difficult to manage. We speculate if in some cases, immunosuppression can itself facilitate tumour progression. 1. Introduction After exclusion of more common causes of encephalitis, limbic autoimmune encephalitis should be considered in any patient with acute or sub-acute neuropsychiatric manifestations and documented central nervous system (CNS) inflammation (Vincent et al., 2011). The diagnosis of paraneoplastic limbic encephalitis (PLE) is in many patients delayed because clinical markers of both primary tumour and incipient PLE are often initially absent (Vincent et al., 2011). Y-Aminobutyricacid-B-receptor (anti-GABABR) antibodies are rarely encountered in association with PLE (Gromadzka et al., 2013). We report a rare and atypical case of metastatic brain disease immediately preceded by antiGABABR PLE, in a patient under immunosuppressive treatment. 2. Case report A 74-year-old man, with previous history of prostatectomy for prostatic adenocarcinoma 3 years before, presented with a three-week history of progressive cognitive deterioration and episodic generalized tonic-clonic seizures. The neurological examination disclosed the presence of spatial-temporal disorientation and marked dysexecutive syndrome. The electroencephalography showed diffuse frontal lobe lentification and subtle inter-ictal right-sided temporal activity. Brain ⁎ Corresponding author. E-mail address: alandre@chalgarve.min-saude.pt (A. André). http://dx.doi.org/10.1016/j.jneuroim.2017.06.009 Received 20 March 2017; Received in revised form 15 June 2017; Accepted 23 June 2017 0165-5728/ © 2017 Elsevier B.V. All rights reserved. Magnetic Resonance Imaging (MRI) revealed the presence of bilateral hippocampal signal change suggestive of limbic encephalitis (Fig. 1A–C). Cerebrospinal fluid (CSF) was not inflammatory. Initial autoimmune, infection and malignancy workup (echography, body tomography, oncological markers and full body PET) yielded negative results. A presumed diagnosis of limbic encephalitis was made. He started antiepileptic treatment, high-dose methylprednisolone and intravenous immunoglobulin. Four-weeks later, the patient became worse, with increased frequency of generalized focal seizures and moderate encephalopathy. The electroencephalography revealed marked epileptiform activity in the left temporal lobe and diffuse slowing waves. The follow up brain MRI at this moment was unchanged (Fig. 1D–F). During this period, anti-GABABR antibodies returned positive (analysis of blood and CSF by indirect immunofluorescence at National Reference Laboratory) and cyclophosphamide was added. A new control brain MRI after 6 weeks of hospitalization revealed the presence of multiple enhancing lesions (Fig. 1G–I) suggestive of brain metastasis, which was confirmed by the biopsy. Repeated search of primary tumour, including body MRI was also negative. Despite treatment optimization, the patient died after progressive encephalopathy with refractory status epilepticus. The immunochemistry that came after the patient death was conclusive for pulmonary neuroendocrine tumour (PNT) metastatic disease. Journal of Neuroimmunology 310 (2017) 66–68 A. André et al. Fig. 1. Brain Magnetic Resonance Imaging (MRI) series, demonstrating typical images of limbic encephalitis (A–C) with imaging recover (D–F), followed by metastatic brain disease (G–I). (A) Symmetric hyperintensity in both mesial temporal lobes – T2 (arrow); (B) shine through in the temporal lobe and hippocampus - diffusion-weighted images (arrow); (C) no enhancement in T1-weighted gadolinium; (D and E) normal densities - FLAIR; (F) no enhancement in T1 weighted gadolinium. (G and H) Multiple lesions with leptomeningeal and parenchymal location - FLAIR; (I) enhancing lesions T1 with gadolinium. 3. Discussion particular type of tumour, which generally spreads through endoneural or perineural pathways to the leptomeninges (Rhun et al., 2013). Furthermore, in our case the rapid and concomitant spread of parenchymal and leptomeningeal metastases suggest haematogenous dissemination (Kokkoris, 1983; Rhun et al., 2013), increasing the speculation of immune system failure to control the PNT expansion. In conclusion, this case raises the question if in particular patients with PLE, immunosuppression can itself facilitate tumour progression. The unusual occurrence of a neuroendocrine tumour metastatic brain disease during immunosuppressive treatment for PLE makes our case unique. Our patient showed the clinical and imaging characteristics consistent with limbic encephalitis (LE) (Boronat et al., 2011). Early empiric immunosuppressive treatment improves the outcome (Darnell and Posner, 2005), particularly when LE is associated with surface antibodies (Kim et al., 2014) as in our case. However, despite progressive escalation of immunosuppressive treatment, the patient got worse, and PNT metastatic brain disease developed rapidly. PNT can be very small and located anywhere along the respiratory or digestive tract. Therefore, the most advanced investigation tools potentially fail to reveal it (Yao et al., 2008). The brain is an uncommon site of PNT metastases, and its presence indicates poor outcome (Pavel et al., 2010). PNT can abnormally express synaptic proteins including GABAB receptors (Kazarian et al., 2011) that can trigger an immune response with production of anti-GABABR IgG antibodies (Lancaster et al., 2010). This immune response may help control tumour growth, either by antibody-dependent cell-mediated cytotoxicity or by complement-mediated toxicity (Lancaster et al., 2010). Unfortunately, we were unable to document the expression of GABAB receptor in the biopsied tissue. In this case, it is reasonable to consider that the aggressive suppression of the immune system may have contributed to the rapid spread in this References Boronat, A., Sabater, L., Saiz, A., Dalmau, J., Graus, F., 2011. GABA(B) receptor antibodies in limbic encephalitis and anti-GAD-associated neurologic disorders. Neurology 76 (9), 795–800 (Mar 1). Darnell, R.B., Posner, J.B., 2005. A new case of limbic encephalopathy. Brain 128, 1745. Gromadzka, G., Karlińska, A.G., et al., 2013. Positivity of serum “classical” onconeural antibodies in a series of 2063 consecutive patients with suspicion of paraneoplastic neurological syndrome. J. Neuroimmunol. 259 (1–2), 75–80 (Jun 15). Kazarian, M., Laird-Offringa, I.A., et al., 2011. Small-cell lung cancer-associated autoantibodies: potential applications to cancer diagnosis, early detection, and therapy. Mol. Cancer 10, 33 (Mar 30). Kim, T.J., Lee, S.T., Shin, J.W., Moon, J., et al., 2014. Clinical manifestations and outcomes of the treatment of patients with GABAB encephalitis. J. Neuroimmunol. 270, 45–50. Kokkoris, C.P., 1983. Leptomeningeal carcinomatosis. How does cancer reach the piaarachnoid? Cancer 51 (1), 154–160 (Jan 1). Lancaster, E., Lai, M., et al., 2010. Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterization of the antigen. Lancet 67 Journal of Neuroimmunology 310 (2017) 66–68 A. André et al. Vincent, A., Bien, C.G., Irani, S.R., Waters, P., 2011. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol. 10 (8), 759–772 (Aug). Yao, J.C., Hassan, M., Phan, A., Dagohoy, C., et al., 2008. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J. Clin. Oncol. 26 (18), 3063. Neurol. 9 (1), 67–76 (Jan). Pavel, M., Grossman, A., Arnold, R., et al., 2010. ENETS consensus guidelines for the management of brain, cardiac and ovarian metastases from neuroendocrine tumors. Neuroendocrinology 91, 326–332. Rhun, E., Taillibert, S., Chamberlain, M., 2013. Carcinomatous meningitis: leptomeningeal metastases in solid tumors. Surg. Neurol. Int. 4 (Suppl. 4), S265–S288. 68