Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Current Treatment Options in Neurology
Published in: Current Treatment Options in Neurology 3/2010

01-05-2010 | Neuroimmunology

Treatment of Paraneoplastic Neurologic Disorders

Author: John E. Greenlee, MD

Published in: Current Treatment Options in Neurology | Issue 3/2010

Login to get access

Opinion statement

Paraneoplastic neurologic disorders are rare, autoimmune disorders, which can be broken down into two groups: those in which antibody response is directed against intracellular neuronal or neuroglial proteins (Group 1) and those in which the immune response is directed against antigens within or subjacent to the neuronal cell membrane (Group 2). In both groups, detection and treatment of the underlying neoplasm is critical and carries the best chance of clinical stabilization or remission.
Syndromes in Group 2 frequently respond to therapy. This may involve corticosteroids, plasma exchange (PE), or intravenous immunoglobulin G (IgG), depending on the specific paraneoplastic syndrome. Cyclophosphamide or rituximab may be helpful in patients who fail to stabilize or improve on less aggressive therapies.
Treatment of syndromes in Group 1 is far more difficult, and proven treatment strategies do not exist. Younger men (< 40 years of age) with limbic or brainstem syndromes, testicular or germ cell tumors, and anti-Ma2 antibodies may respond to specific tumor treatment together with immunotherapy. Patients with paraneoplastic syndromes and anti-Ri antibodies may respond to corticosteroids and/or cyclophosphamide. Evidence-based treatment guidelines do not exist for patients with other central paraneoplastic syndromes such as cerebellar degeneration or encephalomyeloneuritis. Approaches to therapy, apart from treating the underlying tumor, are thus speculative.
In patients with rapidly progressive symptoms classically suggestive of a paraneoplastic neurologic syndrome, time is of the essence in arresting neurologic deterioration. Clinical improvement in patients with longstanding symptoms is unlikely. At the outset, one should move rapidly to define the antibody response involved, as this may also assist tumor diagnosis. Treatment may include prednisone, intravenous IgG, and cyclophosphamide; rituximab plus prednisone may be an alternative, either initially or in the face of continued disease progression despite treatment with intravenous IgG or cyclophosphamide. Although PE is of questionable benefit, a single cycle of PE may be considered before other treatment, to achieve rapid lowering of circulating paraneoplastic autoantibodies.
Literature
1.•
Dalmau J, Rosenfeld MR: Paraneoplastic syndromes of the CNS. Lancet Neurol 2008, 7:327–340. This is one of two excellent reviews of the current understanding of paraneoplastic and related autoimmune conditions. It discusses current concepts of the two groups of paraneoplastic neurologic conditions.
2.
Pellkofer HL, Voltz R, Goebels N, et al.: Cross-reactive T-cell receptors in tumor and paraneoplastic target tissue. Arch Neurol 2009, 66:655–658.CrossRefPubMed
3.
Pellkofer H, Schubart AS, Hoftberger R, et al.: Modelling paraneoplastic CNS disease: T-cells specific for the onconeuronal antigen PNMA1 mediate autoimmune encephalomyelitis in the rat. Brain 2004, 127:1822–1830.CrossRefPubMed
4.
Albert ML, Austin LM, Darnell RB: Detection and treatment of activated T cells in the cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration. Ann Neurol 2000, 47:9–17.CrossRefPubMed
5.•
Graus F, Saiz A, Dalmau J: Antibodies and neuronal autoimmune disorders of the CNS. J Neurol 2009 Dec 25 (Epub ahead of print). This is the second of two excellent reviews of paraneoplastic and related autoimmune conditions and current concepts of pathogenesis.
6.
Butler MH, Hayashi A, Ohkoshi N, et al.: Autoimmunity to gephyrin in stiff-man syndrome. Neuron 2000, 26:307–312.CrossRefPubMed
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(4):479–482.CrossRefPubMed
8.
Vedeler CA, Antoine JC, Giometto B, et al.: Management of paraneoplastic neurological syndromes: report of an EFNS Task Force. Eur J Neurol 2006, 13:682–690.CrossRefPubMed
9.
Candler PM, Hart PE, Barnett M, et al.: A follow up study of patients with paraneoplastic neurological disease in the United Kingdom. J Neurol Neurosurg Psychiatry 2004, 75:1411–1415.CrossRefPubMed
10.
Vernino S, O’Neill BP, Marks RS, et al.: Immunomodulatory treatment trial for paraneoplastic neurological disorders. Neuro Oncol 2004, 6(1):55–62.CrossRefPubMed
11.
Shams’ili S, Grefkens J, De Leeuw B, et al.: Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain 2003, 126:1409–1418.CrossRefPubMed
12.
Graus F, Abos J, Roquer J, et al.: Effect of plasmapheresis on serum and CSF autoantibody levels in CNS paraneoplastic syndromes. Neurology 1990, 40:1621–1623.PubMed
13.
Elovaara I, Apostolski S, van Doorn P, et al.: EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases: EFNS task force on the use of intravenous immunoglobulin in treatment of neurological diseases. Eur J Neurol 2008, 15(9):893–908.CrossRefPubMed
14.
Skeie GO, Apostolski S, Evoli A, et al.: Guidelines for the treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol 2006, 13:691–699.CrossRefPubMed
15.
Hammack J, Kotanides H, Rosenblum MK, Posner JB: Paraneoplastic cerebellar degeneration. II. Clinical and immunologic findings in 21 patients with Hodgkin’s disease. Neurology 1992, 42(10):1938–1943.PubMed
16.
17.
Punga AR, Stalberg E: Acetylcholinesterase inhibitors in MG: to be or not to be? Muscle Nerve 2009, 39:724–728.CrossRefPubMed
18.
Jani-Acsadi A, Lisak RP: Myasthenia Gravis. Curr Treat Options Neurol 2010 (in press).
19.
Kirsch GE, Narahashi T: 3, 4-diaminopyridine. A potent new potassium channel blocker. Biophys J 1978, 22:507–512.CrossRefPubMed
20.
Thomsen RH, Wilson DF: Effects of 4-aminopyridine and 3, 4-diaminopyridine on transmitter release at the neuromuscular junction. J Pharmacol Exp Ther 1983, 227:260–265.PubMed
21.
Lundh H, Nilsson O, Rosen I: Treatment of Lambert-Eaton syndrome: 3, 4-diaminopyridine and pyridostigmine. Neurology 1984, 34:1324–1330.PubMed
22.
McEvoy KM, Windebank AJ, Daube JR, et al.: 3, 4-Diaminopyridine in the treatment of Lambert-Eaton myasthenic syndrome. N Engl J Med 1989, 321:1567–1571.PubMedCrossRef
23.
Oh SJ, Claussen GG, Hatanaka Y, et al.: 3, 4-Diaminopyridine is more effective than placebo in a randomized, double-blind, cross-over drug study in LEMS. Muscle Nerve 2009, 40:795–800.CrossRefPubMed
24.
Wirtz PW, Verschuuren JJ, van Dijk JG, et al.: Efficacy of 3, 4-diaminopyridine and pyridostigmine in the treatment of Lambert-Eaton myasthenic syndrome: a randomized, double-blind, placebo-controlled, crossover study. Clin Pharmacol Ther 2009, 86:44–48.CrossRefPubMed
25.
Sanders DB, Massey JM, Sanders LL, et al.: A randomized trial of 3, 4-diaminopyridine in Lambert-Eaton myasthenic syndrome. Neurology 2000, 54:603–607.PubMed
26.
Lundh H, Nilsson O, Rosen I, et al.: Practical aspects of 3, 4-diaminopyridine treatment of the Lambert-Eaton myasthenic syndrome. Acta Neurol Scand 1993, 88:136–140.PubMed
27.
28.
29.••
Poepel A, Jarius S, Heukamp LC, et al.: Neurological course of long-term surviving patients with SCLC and anti-Hu syndrome. J Neurol Sci 2007, 263:145–148. This is a valuable article concerning neurologic outcome and effect of therapy over time in this group of patients.
30.
Voltz R: Intravenous immunoglobulin therapy in paraneoplastic neurological syndromes. J Neurol 2006, 253(Suppl 5):V33–V38.CrossRefPubMed
31.
Uchuya M, Graus F, Vega F, et al.: Intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with antineuronal autoantibodies. J Neurol Neurosurg Psychiatry 1996, 60:388–392.CrossRefPubMed
32.
Hoffmann LA, Jarius S, Pellkofer HL, et al.: Anti-Ma and anti-Ta associated paraneoplastic neurological syndromes: 22 newly diagnosed patients and review of previous cases. J Neurol Neurosurg Psychiatry 2008, 79:767–773.CrossRefPubMed
33.
Dalmau J, Graus F, Villarejo A, et al.: Clinical analysis of anti-Ma2-associated encephalitis. Brain 2004, 127:1831–1844.CrossRefPubMed
34.
Pittock SJ, Lucchinetti CF, Lennon VA: Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments. Ann Neurol 2003, 53:580–587.CrossRefPubMed
35.
Luque FA, Furneaux HM, Ferziger R, et al.: Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer. Ann Neurol 1991, 29:241–251.CrossRefPubMed
36.
Bataller L, Graus F, Saiz A, et al.: Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus. Brain 2001, 124:437–443.CrossRefPubMed
37.
Murinson BB, Guarnaccia JB: Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease. Neurology 2008, 71:1955–1958.CrossRefPubMed
38.
Widdess-Walsh P, Tavee JO, Schuele S, et al.: Response to intravenous immunoglobulin in anti-Yo associated paraneoplastic cerebellar degeneration: case report and review of the literature. J Neurooncol 2003, 63:187–190.CrossRefPubMed
39.
Phuphanich S, Brock C: Neurologic improvement after high-dose intravenous immunoglobulin therapy in patients with paraneoplastic cerebellar degeneration associated with anti-Purkinje cell antibody. J Neurooncol 2007, 81:67–69.CrossRefPubMed
40.
Coret F, Bosca I, Fratalia L, et al.: Long-lasting remission after rituximab treatment in a case of anti-Hu-associated sensory neuronopathy and gastric pseudoobstruction. J Neurooncol 2009, 93:421–423.CrossRefPubMed
41.
Esposito M, Penza P, Orefice G, et al.: Successful treatment of paraneoplastic cerebellar degeneration with rituximab. J Neurooncol 2008, 86:363–364.CrossRefPubMed
42.
Shams’ili S, de Beukelaar J, Gratama JW, et al.: An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes. J Neurol 2006, 253(1):16–20.CrossRefPubMed
43.
Dalakas MC, Fujii M, Li M, et al.: High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med 2001, 345:1870–1876.CrossRefPubMed
44.
Lehmann HC, Hartung HP, Hetzel GR, et al.: Plasma exchange in neuroimmunological disorders: part 2. Treatment of neuromuscular disorders. Arch Neurol 2006, 63:1066–1071.CrossRefPubMed
45.••
Graus F, Saiz A, Lai M, et al.: Neuronal surface antigen antibodies in limbic encephalitis: clinical-immunologic associations. Neurology 2008, 71:930–936. This is an excellent discussion of limbic encephalitis and its associated autoantibodies.
46.
Bataller L, Galiano R, Garcia-Escrig M, et al.: Reversible paraneoplastic limbic encephalitis associated with antibodies to the AMPA receptor. Neurology 2010, 74:265–267.CrossRefPubMed
47.
Lai M, Hughes EG, Peng X, et al.: AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 2009, 65:424–434.CrossRefPubMed
48.
Sekul EA, Cupler EJ, Dalakas MC: Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med 1994, 121:259–262.PubMed
49.
Jayabose S, Mahmoud M, Levendoglu-Tugal O, et al.: Corticosteroid prophylaxis for neurologic complications of intravenous immunoglobulin G therapy in childhood immune thrombocytopenic purpura. J Pediatr Hematol Oncol 1999, 21:514–517.CrossRefPubMed
50.
Evangelou N, Littlewood T, Anslow P, et al.: Transverse sinus thrombosis and IVIg treatment: a case report and discussion of risk-benefit assessment for immunoglobulin treatment. J Clin Pathol 2003, 56:308–309.CrossRefPubMed
51.
Dalakas MC: High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994, 44:223–226.PubMed
52.••
Pranzatelli MR, Tate ED, Travelstead AL, Colliver JA: Long-term cerebrospinal fluid and blood lymphocyte dynamics after rituximab for pediatric opsoclonus-myoclonus. J Clin Immunol 2010, 30(1):106–113. This paper and the paper by Petereit et al. [53] give important data concerning the ability of rituximab to alter B-cell populations over time within the blood-brain barrier and point out that recovery of B cells occurs more slowly within the CNS than within blood.
53.
Petereit HF, Moeller-Hartmann W, Reske D, et al.: Rituximab in a patient with multiple sclerosis—effect on B cells, plasma cells and intrathecal IgG synthesis. Acta Neurol Scand 2008, 117:399–403.CrossRefPubMed
54.
Baker MR, Das M, Isaacs J, et al.: Treatment of stiff person syndrome with rituximab. J Neurol Neurosurg Psychiatry 2005, 76:999–1001.CrossRefPubMed
55.
Dupond JL, Essalmi L, Gil H, et al.: Rituximab treatment of stiff-person syndrome in a patient with thymoma, diabetes mellitus and autoimmune thyroiditis. J Clin Neurosci 2010, 17(3):389–391.CrossRefPubMed
56.
Carson KR, Evens AM, Richey EA, et al.: Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 2009, 113:4834–4840.CrossRefPubMed
57.
Sharma M, Moore J, Nguyen V, et al.: Fatal CMV pneumonitis in a lymphoma patient treated with rituximab. Am J Hematol 2009, 84:614–616.CrossRefPubMed
58.
Levi ME, Quan D, Ho JT, et al.: Impact of rituximab-associated B-cell defects on West Nile virus meningoencephalitis in solid organ transplant recipients. Clin Transplant 2009 Aug 3 (Epub ahead of print).
59.
Batchelor TT, Platten M, Hochberg FH: Immunoadsorption therapy for paraneoplastic syndromes. J Neurooncol 1998, 40:131–136.CrossRefPubMed
60.
Cher LM, Hochberg FH, Teruya J, et al.: Therapy for paraneoplastic neurologic syndromes in six patients with protein A column immunoadsorption. Cancer 1995, 75:1678–1683.CrossRefPubMed
61.
Lehmann HC, Hartung HP, Hetzel GR, et al.: Plasma exchange in neuroimmunological disorders: Part 1: Rationale and treatment of inflammatory central nervous system disorders. Arch Neurol 2006, 63:930–935.CrossRefPubMed
62.
Weinstein R: Therapeutic apheresis in neurological disorders: a survey of the evidence in support of current category I and II indications for therapeutic plasma exchange. J Clin Apher 2008, 23:196–201.CrossRefPubMed
63.
Schroder A, Linker RA, Gold R: Plasmapheresis for neurological disorders. Expert Rev Neurother 2009, 9:1331–1339.CrossRefPubMed
64.
Peterson K, Rosenblum MK, Kotanides H, et al.: Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients. Neurology 1992, 42:1931–1937.PubMed
65.
66.
Shemin D, Briggs D, Greenan M: Complications of therapeutic plasma exchange: a prospective study of 1, 727 procedures. J Clin Apher 2007, 22:270–276.CrossRefPubMed
67.
Rojas I, Graus F, Keime-Guibert F, et al.: Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology 2000, 55:713–715.PubMed
68.
Graus F, Keime-Guibert F, Reñe R, et al.: Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001, 124(Pt 6):1138–1148.CrossRefPubMed
69.
Schlake HP, Husstedt IW, Grotemeyer KH, et al.: Paraneoplastic subacute cerebellar degeneration in Hodgkin’s disease. Report of three cases and review of the literature. Clin Neurol Neurosurg 1989, 91:329–335.CrossRefPubMed
70.
de la Sayette V, Bertran F, Honnorat J, et al.: Paraneoplastic cerebellar syndrome and optic neuritis with anti-CV2 antibodies: clinical response to excision of the primary tumor. Arch Neurol 1998, 55:405–408.CrossRefPubMed
Metadata
Title
Treatment of Paraneoplastic Neurologic Disorders
Author
John E. Greenlee, MD
Publication date
01-05-2010
Publisher
Current Science Inc.
Published in
Current Treatment Options in Neurology / Issue 3/2010
Print ISSN: 1092-8480
Electronic ISSN: 1534-3138
DOI
https://doi.org/10.1007/s11940-010-0066-9

Other articles of this Issue 3/2010

Current Treatment Options in Neurology 3/2010 Go to the issue

Headache

Treatment of Acute Migraine in the Pediatric Population

Neuroimmunology

Neuromyelitis Optica

CNS Infections

Tick Paralysis

Movement Disorders

Parkinson’s Psychosis

Neuroimmunology

Myasthenia Gravis

Movement Disorders

Parkinson’s Disease and Motor Fluctuations