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Open Access 01-12-2017 | Neurologic Manifestations of Systemic Disease (N Scolding, C Rice and A Wilkins, Section Editors)

Treatment of Cerebellar Ataxia in the Context of Systemic Diseases

Authors: Malcolm Proudfoot, PhD, MRCP, Alastair Wilkins, PhD, FRCP

Published in: Current Treatment Options in Neurology | Issue 12/2017

Abstract

Purpose of review The purpose of this review is to assess the evidence behind treatment regimens for cerebellar ataxias occurring in the context of systemic disease. We will address systemic conditions which are associated with specific involvement of the cerebellum (rather than widespread nervous system involvement) and those conditions for which some degree of evidence of treatment response exists.

Recent findings We have divided systemic disorders affecting the cerebellum into systemic immunological disorders, endocrine and metabolic disorders and paraneoplastic. Recent studies have increased understanding of the range of cerebellar disorders associated with a systemic immunological condition. The identification of newer pathogenic antibodies has improved diagnosis in conditions which would have previously been labelled as idiopathic. However, their rarity and phenotypic variability makes defining optimal immunomodulatory treatment regimens challenging. There is some evidence for beneficial effects of immunomodulation, particularly in anti-GAD ataxia and Hashimoto’s encephalopathy, although, at this time, specific treatment regimens cannot be defined. Immune-mediated paraneoplastic cerebellar disorders show response to therapy dependent, to some extent, on the underlying pathogenic antibody. Much is still to be understood concerning treatment regimens for the ataxic manifestations of metabolic disorders, notably alcohol-induced cerebellar injury, which are common and which are associated with significant disability.

Summary Despite their rarity, cerebellar ataxias occurring in the context of systemic disease cause significant morbidity and better therapies are required to improve outcomes associated with these conditions.

Honnorat J, Trouillas P, Thivolet C, Aguera M, Belin MF. Autoantibodies to glutamate decarboxylase in a patient with cerebellar cortical atrophy, peripheral neuropathy, and slow eye movements. Arch Neurol. 1995;52(5):462–8.CrossRefPubMed

Barova H, Perusicova J, Hill M, Sterzl I, Vondra K, Masek Z. Anti-GAD-positive patients with type 1 diabetes mellitus have higher prevalence of autoimmune thyroiditis than anti-GAD-negative patients with type 1 and type 2 diabetes mellitus. Physiol Res. 2004;53(3):279–86.PubMed

Hadjivassiliou M, Boscolo S, Tongiorgi E, Grunewald RA, Sharrack B, Sanders DS, et al. Cerebellar ataxia as a possible organ-specific autoimmune disease. Mov Disord. 2008;23(10):1370–7. https://doi.org/10.1002/mds.22129.CrossRefPubMed

• Mitoma H, Adhikari K, Aeschlimann D, Chattopadhyay P, Hadjivassiliou M, Hampe CS, et al. Consensus paper: neuroimmune mechanisms of cerebellar ataxias. Cerebellum. 2016;15(2):213–32. https://doi.org/10.1007/s12311-015-0664-x. Useful consensus paper highlighting the recent developments in immune ataxias.CrossRefPubMed

Ishida K, Mitoma H, Wada Y, Oka T, Shibahara J, Saito Y, et al. Selective loss of Purkinje cells in a patient with anti-glutamic acid decarboxylase antibody-associated cerebellar ataxia. J Neurol Neurosurg Psychiatry. 2007;78(2):190–2. https://doi.org/10.1136/jnnp.2006.091116.CrossRefPubMed

Baizabal-Carvallo JF, Jankovic J. Stiff-person syndrome: insights into a complex autoimmune disorder. J Neurol Neurosurg Psychiatry. 2015;86(8):840–8. https://doi.org/10.1136/jnnp-2014-309201.CrossRefPubMed

McKeon A, Robinson MT, McEvoy KM, Matsumoto JY, Lennon VA, Ahlskog JE, et al. Stiff-man syndrome and variants: clinical course, treatments, and outcomes. Arch Neurol. 2012;69(2):230–8. https://doi.org/10.1001/archneurol.2011.991.CrossRefPubMed

Tilikete C, Vighetto A, Trouillas P, Honnorat J. Anti-GAD antibodies and periodic alternating nystagmus. Arch Neurol. 2005;62(8):1300–3. https://doi.org/10.1001/archneur.62.8.1300.CrossRefPubMed

Glasauer S, Strupp M, Kalla R, Buttner U, Brandt T. Effect of 4-aminopyridine on upbeat and downbeat nystagmus elucidates the mechanism of downbeat nystagmus. Ann N Y Acad Sci. 2005;1039:528–31. https://doi.org/10.1196/annals.1325.060.CrossRefPubMed

10.

Strupp M, Teufel J, Habs M, Feuerecker R, Muth C, van de Warrenburg BP, et al. Effects of acetyl-DL-leucine in patients with cerebellar ataxia: a case series. J Neurol. 2013;260(10):2556–61. https://doi.org/10.1007/s00415-013-7016-x.CrossRefPubMedPubMedCentral

11.

Feil K, Adrion C, Teufel J, Bosch S, Claassen J, Giordano I, et al. Effects of acetyl-DL-leucine on cerebellar ataxia (ALCAT trial): study protocol for a multicenter, multinational, randomized, double-blind, placebo-controlled, crossover phase III trial. BMC Neurol. 2017;17(1):7. https://doi.org/10.1186/s12883-016-0786-x. CrossRefPubMedPubMedCentral

12.

Honnorat J, Saiz A, Giometto B, Vincent A, Brieva L, de Andres C, et al. Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol. 2001;58(2):225–30.CrossRefPubMed

13.

Mitoma H, Hadjivassiliou M, Honnorat J. Guidelines for treatment of immune-mediated cerebellar ataxias. Cerebellum Ataxias. 2015;2:14. https://doi.org/10.1186/s40673-015-0034-y.CrossRefPubMedPubMedCentral

14.

•• Jones AL, Flanagan EP, Pittock SJ, Mandrekar JN, Eggers SD, Ahlskog JE, et al. Responses to and outcomes of treatment of autoimmune cerebellar ataxia in adults. JAMA Neurol. 2015;72(11):1304–12. https://doi.org/10.1001/jamaneurol.2015.2378. Study of paraneoplastic and non-paraneoplastic outcomes in autoimmune cerebellar ataxias.CrossRefPubMed

15.

• Arino H, Gresa-Arribas N, Blanco Y, Martinez-Hernandez E, Sabater L, Petit-Pedrol M, et al. Cerebellar ataxia and glutamic acid decarboxylase antibodies: immunologic profile and long-term effect of immunotherapy. JAMA Neurol. 2014;71(8):1009–16. https://doi.org/10.1001/jamaneurol.2014.1011. Long-term follow-up of patietns with anti-GAD cerebellar ataxia.CrossRefPubMedPubMedCentral

16.

Simon NG, Vucic S, Joffe R, Kiernan MC. Cortical dysfunction in cerebellar ataxia with antibodies to glutamic acid decarboxylase. J Neurol. 2014;261(1):238–9. https://doi.org/10.1007/s00415-013-7197-3.CrossRefPubMed

17.

Planche V, Marques A, Ulla M, Ruivard M, Durif F. Intravenous immunoglobulin and rituximab for cerebellar ataxia with glutamic acid decarboxylase autoantibodies. Cerebellum. 2014;13(3):318–22. https://doi.org/10.1007/s12311-013-0534-3.CrossRefPubMed

18.

McFarland NR, Login IS, Vernon S, Burns TM. Improvement with corticosteroids and azathioprine in GAD65-associated cerebellar ataxia. Neurology. 2006;67(7):1308–9. https://doi.org/10.1212/01.wnl.0000238389.83574.be.CrossRefPubMed

19.

Virgilio R, Corti S, Agazzi P, Santoro D, Lanfranconi S, Candelise L, et al. Effect of steroid treatment in cerebellar ataxia associated with anti-glutamic acid decarboxylase antibodies. J Neurol Neurosurg Psychiatry. 2009;80(1):95–6. https://doi.org/10.1136/jnnp.2007.142745.CrossRefPubMed

20.

Nanri K, Niwa H, Mitoma H, Takei A, Ikeda J, Harada T, et al. Low-titer anti-GAD-antibody-positive cerebellar ataxia. Cerebellum. 2013;12(2):171–5. https://doi.org/10.1007/s12311-012-0411-5.CrossRefPubMed

21.

Guasp M, Sola-Valls N, Martinez-Hernandez E, Gil MP, Gonzalez C, Brieva L, et al. Cerebellar ataxia and autoantibodies restricted to glutamic acid decarboxylase 67 (GAD67). J Neuroimmunol. 2016;300:15–7. https://doi.org/10.1016/j.jneuroim.2016.09.019.CrossRefPubMed

22.

Baizabal-Carvallo JF, Alonso-Juarez M. Cerebellar disease associated with anti-glutamic acid decarboxylase antibodies: review. J Neural Transm (Vienna). 2017;124(10):1171–1182. https://doi.org/10.1007/s00702-017-1754-3.

23.

Hadjivassiliou M, Aeschlimann D, Grunewald RA, Sanders DS, Sharrack B, Woodroofe N. GAD antibody-associated neurological illness and its relationship to gluten sensitivity. Acta Neurol Scand. 2011;123(3):175–80. https://doi.org/10.1111/j.1600-0404.2010.01356.x.CrossRefPubMed

24.

Hadjivassiliou M, Sanders DS, Grunewald RA, Woodroofe N, Boscolo S, Aeschlimann D. Gluten sensitivity: from gut to brain. Lancet Neurol. 2010;9(3):318–30. https://doi.org/10.1016/S1474-4422(09)70290-X.CrossRefPubMed

25.

Thawani SP, Brannagan TH 3rd, Lebwohl B, Green PH, Ludvigsson JF. Risk of neuropathy among 28,232 patients with biopsy-verified celiac disease. JAMA Neurol. 2015;72(7):806–11. https://doi.org/10.1001/jamaneurol.2015.0475.CrossRefPubMed

26.

Currie S, Hoggard N, Sanders D, Wilkinson I, Griffiths P, Hadjivassiliou M. Coeliac disease and neurological dysfunction: a case-control study. Lancet. 2014;383:39.CrossRef

27.

Ludvigsson JF, Bai JC, Biagi F, Card TR, Ciacci C, Ciclitira PJ, et al. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut. 2014;63(8):1210–28. https://doi.org/10.1136/gutjnl-2013-306578.CrossRefPubMedPubMedCentral

28.

Hadjivassiliou M, Davies-Jones GA, Sanders DS, Grunewald RA. Dietary treatment of gluten ataxia. J Neurol Neurosurg Psychiatry. 2003;74(9):1221–4.CrossRefPubMedPubMedCentral

29.

Hadjivassiliou M, Grunewald RA, Sanders DS, Shanmugarajah P, Hoggard N. Effect of gluten-free diet on cerebellar MR spectroscopy in gluten ataxia. Neurology. 2017;89(7):705–709. https://doi.org/10.1212/WNL.0000000000004237.

30.

Nanri K, Okuma M, Sato S, Yoneda M, Taguchi T, Mitoma H, et al. Prevalence of autoantibodies and the efficacy of immunotherapy for autoimmune cerebellar ataxia. Intern Med. 2016;55(5):449–54. https://doi.org/10.2169/internalmedicine.55.5156.CrossRefPubMed

31.

Souayah N, Chin RL, Brannagan TH, Latov N, Green PH, Kokoszka A, et al. Effect of intravenous immunoglobulin on cerebellar ataxia and neuropathic pain associated with celiac disease. Eur J Neurol. 2008;15(12):1300–3. https://doi.org/10.1111/j.1468-1331.2008.02305.x.CrossRefPubMed

32.

Victor M, Adams RD. On the etiology of the alcoholic neurologic diseases with special reference to the role of nutrition. Am J Clin Nutr. 1961;9:379–97.PubMed

33.

Diener HC, Dichgans J, Bacher M, Guschlbauer B. Improvement of ataxia in alcoholic cerebellar atrophy through alcohol abstinence. J Neurol. 1984;231(5):258–62.CrossRefPubMed

34.

Rosenbloom MJ, Rohlfing T, O'Reilly AW, Sassoon SA, Pfefferbaum A, Sullivan EV. Improvement in memory and static balance with abstinence in alcoholic men and women: selective relations with change in brain structure. Psychiatry Res. 2007;155(2):91–102. https://doi.org/10.1016/j.pscychresns.2006.12.019.CrossRefPubMedPubMedCentral

35.

Smith S, Fein G. Persistent but less severe ataxia in long-term versus short-term abstinent alcoholic men and women: a cross-sectional analysis. Alcohol Clin Exp Res. 2011;35(12):2184–92. https://doi.org/10.1111/j.1530-0277.2011.01567.x.CrossRefPubMedPubMedCentral

36.

•• Day E, Bentham PW, Callaghan R, Kuruvilla T, George S. Thiamine for prevention and treatment of Wernicke-Korsakoff Syndrome in people who abuse alcohol. Cochrane Database Syst Rev. 2013 Jul 1;(7):CD004033. https://doi.org/10.1002/14651858.CD004033.pub3. Cochrane database review on studies of thiamine in WE.

37.

Galvin R, Brathen G, Ivashynka A, Hillbom M, Tanasescu R, Leone MA, et al. EFNS guidelines for diagnosis, therapy and prevention of Wernicke encephalopathy. Eur J Neurol. 2010;17(12):1408–18. https://doi.org/10.1111/j.1468-1331.2010.03153.x.CrossRefPubMed

38.

Sandyk R. Cerebellar dysfunction in hypothyroidism. S Afr Med J. 1982;62(14):468.PubMed

39.

Quinn N, Barnard RO, Kelly RE. Cerebellar syndrome in myxoedema revisited: a published case with carcinomatosis and multiple system atrophy at necropsy. J Neurol Neurosurg Psychiatry. 1992;55(7):616–8.CrossRefPubMedPubMedCentral

40.

Shaw PJ, Walls TJ, Newman PK, Cleland PG, Cartlidge NE. Hashimoto's encephalopathy: a steroid-responsive disorder associated with high anti-thyroid antibody titers—report of 5 cases. Neurology. 1991;41(2 ( Pt 1)):228–33.CrossRefPubMed

41.

Yoneda M, Fujii A, Ito A, Yokoyama H, Nakagawa H, Kuriyama M. High prevalence of serum autoantibodies against the amino terminal of alpha-enolase in Hashimoto’s encephalopathy. J Neuroimmunol. 2007;185(1–2):195–200. https://doi.org/10.1016/j.jneuroim.2007.01.018.CrossRefPubMed

42.

Matsunaga A, Ikawa M, Fujii A, Nakamoto Y, Kuriyama M, Yoneda M. Hashimoto’s encephalopathy as a treatable adult-onset cerebellar ataxia mimicking spinocerebellar degeneration. Eur Neurol. 2013;69(1):14–20. https://doi.org/10.1159/000342217.CrossRefPubMed

43.

Kishitani T, Matsunaga A, Ikawa M, Hayashi K, Yamamura O, Hamano T, et al. Limbic encephalitis associated with anti-NH2-terminal of alpha-enolase antibodies: a clinical subtype of Hashimoto encephalopathy. Medicine (Baltimore). 2017;96(10):e6181. https://doi.org/10.1097/MD.0000000000006181.CrossRef

44.

Olmez I, Moses H, Sriram S, Kirshner H, Lagrange AH, Pawate S. Diagnostic and therapeutic aspects of Hashimoto’s encephalopathy. J Neurol Sci. 2013;331(1–2):67–71. https://doi.org/10.1016/j.jns.2013.05.009.CrossRefPubMed

45.

Marshall GA, Doyle JJ. Long-term treatment of Hashimoto’s encephalopathy. J Neuropsychiatry Clin Neurosci. 2006;18(1):14–20. https://doi.org/10.1176/jnp.18.1.14.CrossRefPubMed

46.

Laurent C, Capron J, Quillerou B, Thomas G, Alamowitch S, Fain O, et al. Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT): characteristics, treatment and outcome in 251 cases from the literature. Autoimmun Rev. 2016;15(12):1129–33. https://doi.org/10.1016/j.autrev.2016.09.008.CrossRefPubMed

47.

Hoftberger R, Rosenfeld MR, Dalmau J. Update on neurological paraneoplastic syndromes. Curr Opin Oncol. 2015;27(6):489–95. https://doi.org/10.1097/CCO.0000000000000222.CrossRefPubMedPubMedCentral

48.

Venkatraman A, Opal P. Paraneoplastic cerebellar degeneration with anti-Yo antibodies—a review. Ann Clin Transl Neurol. 2016;3(8):655–63. https://doi.org/10.1002/acn3.328.CrossRefPubMedPubMedCentral

49.

Greene M, Lai Y, Baella N, Dalmau J, Lancaster E. Antibodies to Delta/notch-like epidermal growth factor-related receptor in patients with anti-Tr, paraneoplastic cerebellar degeneration, and Hodgkin lymphoma. JAMA Neurol. 2014;71(8):1003–8. https://doi.org/10.1001/jamaneurol.2014.999.CrossRefPubMedPubMedCentral

50.

Shams'ili S, Grefkens J, de Leeuw B, van den Bent M, Hooijkaas H, van der Holt B, et al. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain. 2003;126(Pt 6):1409–18.CrossRefPubMed

51.

Pittock SJ, Lucchinetti CF, Lennon VA. Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments. Ann Neurol. 2003;53(5):580–7. https://doi.org/10.1002/ana.10518.CrossRefPubMed

52.

Bataller L, Sabater L, Saiz A, Serra C, Claramonte B, Graus F. Carbonic anhydrase-related protein VIII: autoantigen in paraneoplastic cerebellar degeneration. Ann Neurol. 2004;56(4):575–9. https://doi.org/10.1002/ana.20238.CrossRefPubMed

53.

Sabater L, Bataller L, Carpentier AF, Aguirre-Cruz ML, Saiz A, Benyahia B, et al. Protein kinase Cgamma autoimmunity in paraneoplastic cerebellar degeneration and non-small-cell lung cancer. J Neurol Neurosurg Psychiatry. 2006;77(12):1359–62. https://doi.org/10.1136/jnnp.2006.097188.CrossRefPubMedPubMedCentral

54.

Rojas I, Graus F, Keime-Guibert F, Rene R, Delattre JY, Ramon JM, et al. Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology. 2000;55(5):713–5.CrossRefPubMed

55.

Giometto B, Grisold W, Vitaliani R, Graus F, Honnorat J, Bertolini G, et al. Paraneoplastic neurologic syndrome in the PNS Euronetwork database: a European study from 20 centers. Arch Neurol. 2010;67(3):330–5. https://doi.org/10.1001/archneurol.2009.341.CrossRefPubMed

56.

Briani C, Vitaliani R, Grisold W, Honnorat J, Graus F, Antoine JC, et al. Spectrum of paraneoplastic disease associated with lymphoma. Neurology. 2011;76(8):705–10. https://doi.org/10.1212/WNL.0b013e31820d62eb.CrossRefPubMed

57.

Peterson K, Rosenblum MK, Kotanides H, Posner JB. Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients. Neurology. 1992;42(10):1931–7.CrossRefPubMed

58.

Moll JW, Henzen-Logmans SC, Van der Meche FG, Vecht CH. Early diagnosis and intravenous immune globulin therapy in paraneoplastic cerebellar degeneration. J Neurol Neurosurg Psychiatry. 1993;56(1):112.CrossRefPubMedPubMedCentral

59.

Counsell CE, McLeod M, Grant R. Reversal of subacute paraneoplastic cerebellar syndrome with intravenous immunoglobulin. Neurology. 1994;44(6):1184–5.CrossRefPubMed

60.

Uchuya M, Graus F, Vega F, Rene R, Delattre JY. Intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with antineuronal autoantibodies. J Neurol Neurosurg Psychiatry. 1996;60(4):388–92.CrossRefPubMedPubMedCentral

61.

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 Neuro-Oncol. 2007;81(1):67–9. https://doi.org/10.1007/s11060-006-9198-x. CrossRef

62.

Schessl J, Schuberth M, Reilich P, Schneiderat P, Strigl-Pill N, Walter MC, et al. Long-term efficiency of intravenously administered immunoglobulin in anti-Yo syndrome with paraneoplastic cerebellar degeneration. J Neurol. 2011;258(5):946–7. https://doi.org/10.1007/s00415-010-5859-y.CrossRefPubMed

63.

Thone J, Hohaus A, Lamprecht S, Bickel A, Erbguth F. Effective immunosuppressant therapy with cyclophosphamide and corticosteroids in paraneoplastic cerebellar degeneration. J Neurol Sci. 2008;272(1–2):171–3. https://doi.org/10.1016/j.jns.2008.04.020.CrossRefPubMed

64.

Stark E, Wurster U, Patzold U, Sailer M, Haas J. Immunological and clinical response to immunosuppressive treatment in paraneoplastic cerebellar degeneration. Arch Neurol. 1995;52(8):814–8.CrossRefPubMed

65.

Mowzoon N, Bradley WG. Successful immunosuppressant therapy of severe progressive cerebellar degeneration and sensory neuropathy: a case report. J Neurol Sci. 2000;178(1):63–5.CrossRefPubMed

66.

Keime-Guibert F, Graus F, Fleury A, Rene R, Honnorat J, Broet P, 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):479–82.

67.

Esposito M, Penza P, Orefice G, Pagano A, Parente E, Abbadessa A, et al. Successful treatment of paraneoplastic cerebellar degeneration with rituximab. J Neuro-Oncol. 2008;86(3):363–4. https://doi.org/10.1007/s11060-007-9479-z.CrossRef

68.

Shams'ili S, de Beukelaar J, Gratama JW, Hooijkaas H, van den Bent M, van 't Veer M, et al. An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes. J Neurol. 2006;253(1):16–20. https://doi.org/10.1007/s00415-005-0882-0.CrossRefPubMed

69.

Yeo KK, Walter AW, Miller RE, Dalmau J. Rituximab as potential therapy for paraneoplastic cerebellar degeneration in pediatric Hodgkin disease. Pediatr Blood Cancer. 2012;58(6):986–7.CrossRefPubMed

70.

Orange D, Frank M, Tian S, Dousmanis A, Marmur R, Buckley N, et al. Cellular immune suppression in paraneoplastic neurologic syndromes targeting intracellular antigens. Arch Neurol. 2012;69(9):1132–40. https://doi.org/10.1001/archneurol.2012.595. CrossRefPubMedPubMedCentral

Title: Treatment of Cerebellar Ataxia in the Context of Systemic Diseases
Authors: Malcolm Proudfoot, PhD, MRCP
Alastair Wilkins, PhD, FRCP
Publication date: 01-12-2017
Publisher: Springer US
Published in: Current Treatment Options in Neurology / Issue 12/2017
Print ISSN: 1092-8480
Electronic ISSN: 1534-3138
DOI: https://doi.org/10.1007/s11940-017-0485-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Treatment of Cerebellar Ataxia in the Context of Systemic Diseases

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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