Intravenous immunoglobulins in paraneoplastic ...

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Sirs: We report the case of a. 71 year old man who developed over 2 days severe cerebellar ataxia, dysarthria, dysphagia, opsoclonus-myoclonus, nausea.
J Neurol (2006) 253 : 1360–1361 DOI 10.1007/s00415-006-0199-7

Arnaud Fumal Jerome Jobe Jean-Louis Pepin Valerie Delvaux Jean-Marc Senterre Sandrine Bonaventure Alain Maertens de Noordhout

Intravenous immunoglobulins in paraneoplastic brainstem encephalitis with anti-Ri antibodies

JON 2199

Received: 25 November 2005 Revised: 1 February 2006 Accepted: 21 February 2006 Published online: 27 September 2006

Sirs: We report the case of a 71 year old man who developed over 2 days severe cerebellar ataxia, dysarthria, dysphagia, opsoclonus-myoclonus, nausea and vomiting. Brain MRI was normal. The cerebrospinal fluid (CSF) contained 39 lymphocytes/ mm3 with normal protein and glucose levels. An extensive biological investigation remained negative except for the presence of anti-Ri antibodies. These anti-Ri antibodies were demonstrated by a combination of immunofluorescence analysis and Western blot (anti-neuronal antibody Western blot immunoassay, Immco Diagnostics Inc., Buffalo, NY). Serial dilutions revealed a specific antibody titre of 1 : 320. Thoracic CT revealed a suspect nodular mass in the right lung (middle lobe). Bronchoscopy with broncho-alveolar wash was normal. A full-body PET was planned but due to the severity of dysphagia and the fact that patient became bedridden, intravenous immunoglobulins (IVIg, 400 mg/kg/day for 5 days) were administered 4 weeks after

LETTER TO THE EDITORS

symptom onset. This treatment induced a clear-cut clinical improvement after 1 week, allowing removal of the nasogastric tube and a restart of oral feeding. The patient could walk with some aid. Retest for anti-Ri antibodies was negative. The PET scan was in favour of a right lung neoplasm. Unfortunately, the patient developed a pyelonephritis with septicaemia and died 8 weeks after the onset of symptoms. Autopsy confirmed a diagnosis of lung adenocarcinoma. In paraneoplastic neurological disorders (PNDs), the most frequently found antineuronal antibodies are anti-Hu, anti-Yo and anti-CRMP5; anti-Ri antibodies are rare. In 1988 and 1991, BuddeSteffen et al. [2] and Luque et al. [6] described a subpopulation of patients with opsoclonus and a history of breast cancer, in sera and CSF in whom they identified an antibody they named Anti-Ri. After those seminal reports, anti-Ri antibodies have subsequently been associated with a broad spectrum of malignancies, the most frequent being breast, gynaecological and lung cancers [8] and their spectrum of associated neurological symptoms has also expanded considerably. In patients with anti-Ri antibodies, antitumour treatment is recommended as it can also act on paraneoplastic symptoms [10]. Few data are available over efficacy of immunotherapy in anti-Ri syndromes. Shams’ili et al. [10], Rajabally et al. [9] and Martinaud et al. [7] reported some experience with the use of IVIg (3 patients treated) with opposite issues. Our case illustrates the possibility of rapid onset of PNDs. A paraneoplastic syndrome should be considered in cases of subacute brainstem encephalitis. Moreover, despite the fatal outcome, this observation highlights the thera-

peutic potential of IVIg in neurological paraneoplastic disorders, with clinical improvement, albeit transient and the hypothesis of a neutralization of anti-Ri antibodies (of which this is the first case report). One could postulate that any immunotherapy might have had the same efficacy as IVIg in our patient. Indeed, various immunomodulatory approaches used so far in PND have brought striking improvement but only in single patients (See Voltz [14] for a review). For example, treatment options that have been tried include protein A absorption [3], intravenous immunoglobulin [1, 12], cyclophosphamide [5, 11, 13], methylprednisolone [5, 15] and plasma exchanges [4, 13]. Owing to the equivocal efficacy of such treatments, it seems up to now difficult to outline general guidelines in PND for the use of immunotherapy which should probably be adapted to the individual patient’s situation. Further studies are needed to determine which patients with PND (characterized by antineuronal antibodies and clinical syndromes) could benefit from which immunotherapy. One must keep in mind that the earlier immunotherapy is started the better the chances of improvement [1, 5]. We thank ZLB Belgium for providing SandoglobulineÒ as compassionate treatment for this patient.

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9. Rajabally YA, Naz S, Farrell D, Abbott RJ (2004) Paraneoplastic brainstem encephalitis with tetraparesis in a patient with anti-Ri antibodies. J Neurol 251:1528–9 10. Shams’ili S, Grefkens J, de Leeuw B, et al. (2003) Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain 126:1409–1418 11. Stark E, Wurster U, Patzold U, et al. (1995) Immunological and clinical response to immunosuppressive treatment in paraneoplastic cerebellar degeneration. Arch Neurol 52:814–8 12. Uchuya M, Graus F, Vega F, et al. (1996) Intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with antineuronal autoantibodies. J Neurol Neurosurg Psychiatry 60:388–92 13. Vernino S, O’Neill BP, Marks RS, et al. (2004) Immunomodulatory treatment trial for paraneoplastic neurological disorders. Neurooncol 6:55–62 14. Voltz R (2002) Paraneoplastic neurological syndromes: an update on diagnosis, pathogenesis, and therapy. Lancet Neurol 1:294–305

15. Widdess-Walsh P, Tavee JO, Schuele S, Stevens GH (2003) Response to intravenous immunoglobulin in anti-Yo associated Paraneoplastic cerebellar degeneration: case report and review of the literature. J Neurooncol 63:187–90 A. Fumal (&) Æ J. Jobe Æ J.-L. Pepin Æ V. Delvaux Æ A. M. de Noordhout University Dept. of Neurology CHR Hospital Bvld du 12e`me de Ligne 1 4000 Lie`ge, Belgium Tel: +32-42/298170 Fax: +32-42/262939 E-Mail: [email protected] J.-M. Senterre Clinical biology Laboratory CHR Citadelle 4000 Liege, Belgium S. Bonaventure Pathology University of Liege 4000 Liege, Belgium