Journal of Clinical Neuroscience xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Journal of Clinical Neuroscience journal homepage:

Case Report

Anti-Ri-associated paraneoplastic brainstem cerebellar syndrome with coexisting limbic encephalitis in a patient with mixed large cell neuroendocrine lung carcinoma Amber N. Mitchell a,⇑, Charles T. Bakhos b, Earl A. Zimmerman a a b

Department of Neurology, Albany Medical Center, 47 New Scotland Avenue, Albany, NY 12208, USA Department of Surgery, Section of Thoracic Surgery, Albany Medical Center, Albany, NY, USA

a r t i c l e

i n f o

Article history: Received 22 April 2014 Accepted 12 June 2014 Available online xxxx Keywords: Cerebellum Paraneoplastic syndrome Vertigo

a b s t r a c t Paraneoplastic neurologic syndromes (PNS) can be the first manifestations of occult malignancies. If left untreated, PNS often lead to significant morbidity and mortality. Anti-Ri (anti-neuronal nuclear antibody type 2 [ANNA-2]) autoantibodies are commonly associated with breast and small cell lung cancers. Cases of anti-Ri paraneoplastic cerebellar degeneration are reported, but few describe severe nausea and coexisting limbic encephalitis as the major presenting features. We report a 75-year-old woman with medically-intractable emesis, encephalopathy, diplopia, vertigo, and gait ataxia for 3 months. Examination revealed rotary nystagmus, ocular skew deviation, limb dysmetria, and gait ataxia. After two courses of intravenous immunoglobulin, there was minimal improvement. Anti-Ri antibodies were positive in serum only. CT scan identified a 2.0 cm left lung mass, and histopathology revealed large cell neuroendocrine carcinoma with admixed adenocarcinoma non-small cell lung carcinoma (NCSLC). Though the patient achieved nearly complete clinical recovery after tumor resection, anti-Ri levels remained high at 20 months post-resection. To our knowledge this is the first report of a paraneoplastic brainstem cerebellar syndrome with coexisting limbic encephalitis involving anti-Ri positivity and associated mixed neuroendocrine/NSCLC of the lung with marked improvement after tumor resection. Ó 2014 Elsevier Ltd. All rights reserved.

1. Background

2. Case presentation

Paraneoplastic involvement of the brainstem and cerebellum is rarely reported in the literature compared with other primary neoplastic processes. Early treatment of PNS may result in improvement in morbidity and mortality. Of the cases reported, some have been associated with particular onconeural antibodies. Small cell lung carcinoma (SCLC) is one of the most frequently cited in paraneoplastic disorders [1,2]. Anti-Ri (anti-neuronal nuclear antibody type 2 [ANNA-2]) mediated opsoclonus myoclonus syndrome is a classic paraneoplastic syndrome seen in breast carcinoma [3]. However, we report a unique patient with anti-Ri positive paraneoplastic brainstem and cerebellar syndrome with coexisting limbic encephalitis associated with a mixed adenocarcinoma and neuroendocrine large cell lung neoplasm with atypical features of intractable nausea, vomiting, and encephalopathy.

A 75-year-old woman was admitted to our hospital for acute worsening of vertigo, nausea, vomiting, and gait instability, slowly progressing over the past 3 months. She complained of vertigo that worsened upon sudden movements of the head, diplopia and persistent tinnitus, but denied hearing loss, headache, numbness, weakness, dysphagia, or dysarthria. She was delusional with visual hallucinations. Short-term memory was acutely impaired, while long-term memory remained intact. On examination, the patient demonstrated cachexia and encephalopathy. There was rotary nystagmus in the clockwise direction on primary gaze without opsoclonus. She had diplopia vertically aligned on primary binocular gaze, which extinguished on monocular testing. Skew deviation was apparent with hypertropic left eye position and disconjugate gaze by reflection of the light reflex of the pupil. She had overshoot on horizontal smooth pursuit. Hypophonia, limb dysmetria, and gait ataxia were present. Dix–Hallpike maneuver was positive.

⇑ Corresponding author. Tel.: +1 845 399 6074. E-mail address: [email protected] (A.N. Mitchell). 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Mitchell AN et al. Anti-Ri-associated paraneoplastic brainstem cerebellar syndrome with coexisting limbic encephalitis in a patient with mixed large cell neuroendocrine lung carcinoma. J Clin Neurosci (2014),


Case Report / Journal of Clinical Neuroscience xxx (2014) xxx–xxx

2.1. Investigations MRI of the brain showed non-enhancing T2-weighted hyperintensity of the white matter of the right temporal lobe (Fig. 1a), which was unchanged from prior scans performed 3 months earlier. Despite MRI resolution of the lesion 6 months later, the clinical syndrome persisted. Mild atrophy of the cerebellar vermis was evident on T1-weighted sagittal imaging (Fig. 1b). Anti-Ri antibodies were positive in serum (titer 1:30,720, Western blot analysis, Mayo Clinic, Rochester, MN, USA), but undetectable in cerebrospinal fluid. While the search for the occult malignancy ensued, she was empirically treated for paraneoplastic syndrome with 5 days of intravenous immunoglobulin, but did not improve. Two weeks later, she underwent a second course of intravenous immunoglobulin again with no effect as was expected given putative anti-Ri intracellular pathophysiology. CT scan of the chest revealed a 2 cm left lower lobe lung nodule in the para-aortic area. The nodule was fluorodeoxyglucose avid on positron emission tomography scan (Supp. Fig. 1a). The patient then underwent a CT guided biopsy which showed the tumor to be consistent with a poorlydifferentiated (high-grade) large cell neuroendocrine carcinoma and small component of adenocarcinoma (Supp. Fig. 1b). 2.2. Treatment The patient was malnourished due to poor oral intake and underwent a laparoscopic jejunostomy feeding tube placement, followed three weeks later by a video-assisted thoracoscopic left lower lobectomy and thoracic lymphadenectomy. Pathologic examination revealed a combined large cell neuroendocrine carcinoma (90%) and foci of adenocarcinoma, with the tumor measuring 2.5 cm by 2.2 cm by 1.8 cm. Seventeen lymph nodes were removed and were negative for malignancy, but lympho-vascular invasion was present. All margins were negative (R0 resection) and pathologic staging was T2a N0 M0. Two weeks after surgical resection, plasmapheresis was undertaken for its immunosuppressive activity given her complex clinical presentation (encephalopathy, nausea, ataxia, diplopia) and concern for hybrid tumor (anti-Ri antibodies with bystander, innominate antibodies). No chemoradiation was necessary. 2.3. Outcome and follow-up Within 12 months, nausea, vertigo, diplopia, and ataxia resolved. Repeat CT scans of the chest at 12 and 24 months

revealed no tumor recurrence or any new lung primary malignancy. Although the patient achieved nearly complete clinical recovery, anti-Ri antibodies remained positive at 20 months postresection of tumor with anti-Ri positivity based on >1:10 titer detected in serum (Western blot, LabCorp, Raritan, NJ, USA). Anti-Ri testing was conducted at two different laboratories, and levels cannot be directly compared.

3. Discussion Paraneoplastic neurologic syndromes occur secondary to autoimmune mechanisms whereby autoantibodies originally targeting oncogenic proteins cross-react with neuronal cell surface and intracellular antigens [1,2]. Paraneoplastic cerebellar degeneration (PCD) is one such PNS characterized by dizziness, nausea, and vomiting due to degeneration of Purkinje cells. These symptoms are followed by gait instability, limb ataxia, dysarthria, dysphagia, nystagmus, diplopia, ocular dysmetria, abnormalities of pursuit, and skew deviation [4,5]. Whereas anti-Yo, anti-Hu, and anti-Tr have been linked to PCD in the setting of breast, ovarian, small cell lung, or Hodgkin malignancies, only half of suspected PCD patients ultimately test positive in serum or cerebrospinal fluid analyses [4,6–8]. Anti-Ri has also been reported in a woman with breast cancer and PCD [8]. Left untreated, the immune effects of most paraneoplastic diseases ultimately lead to neuronal death. Studies have shown greater response rates when PNS is treated within 3 to 6 months [9]. After treatment of the underlying malignancy and immunotherapy, few patients with PCD show improvement [7,10,11]. Our patient was less typical of pure PCD given the presence of anti-Ri antibodies, intractable nausea, and prompt improvement after resection of the lung mass, suggesting a reversible process. Involvement of the brainstem and limbic system suggests a complex paraneoplastic process involving more than one onconeuronal target. Anti-Ri antibodies, also known as ANNA2, target the NOVA-1 and NOVA-2 antigens expressed dually in tumor cells and neurons. Anti-Ri is associated with breast cancer in half of all cases [3]. AntiRi antibodies were initially reported as markers of paraneoplastic opsoclonus-myoclonus and ataxia in association with breast, lung, and gynecological cancers [12,13]. There have been cases of PCD and brainstem encephalitis in association with anti-Ri and SCLC or neuroendocrine SCLC [3,14]. However, more recent studies show a more diverse association of anti-Ri with other paraneoplastic neurologic syndromes of the brainstem, cerebellum, and spinal cord

Fig. 1. MRI of the brain showing limbic encephalitis. (a) Axial fluid attenuated inversion recovery showing increased T2-weighted signal in the white matter of the right temporal lobe without enhancement or diffusion restriction. (b) Sagittal T1-weighted MRI showing mild atrophy of the cerebellar vermis.

Please cite this article in press as: Mitchell AN et al. Anti-Ri-associated paraneoplastic brainstem cerebellar syndrome with coexisting limbic encephalitis in a patient with mixed large cell neuroendocrine lung carcinoma. J Clin Neurosci (2014),

Case Report / Journal of Clinical Neuroscience xxx (2014) xxx–xxx

with underlying breast, lung (SCLC and non-SCLC), cervical, bladder or neuroendocrine gastric carcinomas [3]. Our patient’s anti-Ri titre remained high 2 years after treatment, and in the setting of clinical stability, may represent a marker of a hybrid malignancy with the pathogenic onconeuronal antibodies eradicated by aggressive treatment. Alternatively, anti-Ri persistence may be due to an occult secondary tumor distal from the lung. Anti-Ri positivity carries a more favorable prognosis in PNS patients treated with tumor resection and adjuvant immunotherapy [13]. Given the rarity of mixed non-SCLC-neuroendocrine-associated paraneoplastic syndromes, this presentation of coexisting cerebellar, brainstem, and limbic pathology brings into question the presence of multiple onconeuronal antigens, both cell surface and intracellular antigens, which remain to be characterized. 4. Conclusion Current treatment of PNS involves tumor identification and resection with chemoradiation and adjuvant immunotherapy (intravenous immunoglobulin or plasmapheresis). Prompt oncologic treatment of PNS within 6 months of presentation may avert irreversible neuronal destruction, though residual impairment often occurs. The clinician should suspect paraneoplastic syndromes when symptoms and signs cannot be explained by other causes. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements Jiang Qian, MD (Department of Pathology, Albany Medical College, Albany, NY) performed the pathological and histological examination of the lung tumor, and contributed to the histological data in the manuscript.


Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at References [1] Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med 2003;349:1543–54. [2] Choi KD, Kim JS, Park SH, et al. Cerebellar hypermetabolism in paraneoplastic cerebellar degeneration. J Neurol Neurosurg Psychiatry 2006;77:525–8. [3] Pittock SJ, Lucchinetti CF, Lennon VA. Anti-neuronal nuclear autoantibody type-2: paraneoplastic accompaniments. Ann Neurol 2003;53:580–7. [4] Kaltsas G, Androulakis II, de Herder WW, et al. Paraneoplastic syndromes secondary to neuroendocrine tumours. Endoc Relat Cancer 2010;17:R173–93. [5] Alabduljalil T, Behbehani R. Paraneoplastic syndromes in neuroophthalmology. Curr Opin Ophthalmol 2007;18:463–9. [6] Braik T, Evans AT, Telfer M, et al. Paraneoplastic neurologic syndromes: unusual presentations of cancer. A practical review. Am J Med Sci 2010;340: 301–8. [7] Keime-Guibert F, Graus F, Fleury A, et al. Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (Anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry 2000;68:479–82. [8] Brieva-Ruíz L, Diaz-Hurtado M, Matias-Guiu X, et al. Anti-Ri-associated paraneoplastic cerebellar degeneration and breast cancer: an autopsy case study. Clin Neurol Neurosurg 2008;110:1044–6. [9] Greenlee JE. Treatment of paraneoplastic neurologic disorders. Curr Treat Options Neurol 2010;12:212–30. [10] Cocconi G, Ceci G, Juvarra G, et al. Successful treatment of subacute cerebellar degeneration in ovarian carcinoma with plasmapheresis. A case report. Cancer 1985;56:2318–20. [11] Graus F, Vega F, Delattre JY, et al. Plasmapheresis and antineoplastic treatment in CNS paraneoplastic syndromes and antineuronal autoantibodies. Neurology 1992;42:536–40. [12] Bataller L, Sabater L, Saiz A, et al. Carbonic anhydrase-related protein, VIII autoantigen in paraneoplastic cerebellar degeneration. Ann Neurol 2004;56: 575–9. [13] Luque FA, Furneaux HM, Ferziger R, et al. Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer. Ann Neurol 1991;29: 241–51. [14] Veilleux M, Bernier JP, Lamarche JB. Paraneoplastic encephalomyelitis and subacute dysautonomia due to an occult atypical carcinoid tumour of the lung. Can J Neurol Sci 1990;17:324–8.

Please cite this article in press as: Mitchell AN et al. Anti-Ri-associated paraneoplastic brainstem cerebellar syndrome with coexisting limbic encephalitis in a patient with mixed large cell neuroendocrine lung carcinoma. J Clin Neurosci (2014),

Anti-Ri-associated paraneoplastic brainstem cerebellar syndrome with coexisting limbic encephalitis in a patient with mixed large cell neuroendocrine lung carcinoma.

Paraneoplastic neurologic syndromes (PNS) can be the first manifestations of occult malignancies. If left untreated, PNS often lead to significant mor...
373KB Sizes 0 Downloads 7 Views