Stiff Person Syndrome and Other Anti-GAD–Associated Neurologic Disorders

Praveen Dayalu; James W. Teener

doi:10.1055/s-0033-1334477

Seminars in Neurology, Inhaltsverzeichnis

Semin Neurol 2012; 32(05): 544-549
DOI: 10.1055/s-0033-1334477

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Stiff Person Syndrome and Other Anti-GAD–Associated Neurologic Disorders

Praveen Dayalu

¹Department of Neurology, University of Michigan Health System, Ann Arbor, Michigan

,

James W. Teener

¹Department of Neurology, University of Michigan Health System, Ann Arbor, Michigan

› Institutsangaben

Abstract

Antibodies directed against glutamic acid decarboxylase (GAD) are present in many patients with stiff person syndrome and increasingly found in patients with other symptoms indicative of central nervous system (CNS) dysfunction, such as ataxia. The classic clinical features of stiff person syndrome include muscular stiffness with superimposed painful muscular spasms. Gait is often impaired. Other CNS disorders associated with GAD antibodies include progressive encephalomyelitis with rigidity and myoclonus (PERM), limbic encephalitis, and even epilepsy. Glutamic acid decarboxylase is the rate-limiting enzyme in the production of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter. Presumably, antibodies directed against GAD impair GABA production, but the precise pathogenic mechanism of GAD-antibody-related neurologic disorders is uncertain. Many patients respond to treatment with immunomodulating therapy. Symptomatic treatment with agents that enhance GABA activity, such as benzodiazepines and baclofen, is also helpful for many patients.

Keywords

GAD antibodies - stiff person syndrome - muscle stiffness - cerebellar ataxia - progressive encephalomyelitis with rigidity and myoclonus - limbic encephalitis

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Referenzen

Reference
1 Honnorat J, Saiz A, Giometto B , et al. Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol 2001; 58 (2) 225-230
2 Saiz A, Arpa J, Sagasta A , et al. Autoantibodies to glutamic acid decarboxylase in three patients with cerebellar ataxia, late-onset insulin-dependent diabetes mellitus, and polyendocrine autoimmunity. Neurology 1997; 49 (4) 1026-1030
3 Saiz A, Blanco Y, Sabater L , et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain 2008; 131 (Pt 10) 2553-2563
4 Kono S, Miyajima H, Sugimoto M, Suzuki Y, Takahashi Y, Hishida A. Stiff-person syndrome associated with cerebellar ataxia and high glutamic acid decarboxylase antibody titer. Intern Med 2001; 40 (9) 968-971
5 Hadjivassiliou M, Boscolo S, Tongiorgi E , et al. Cerebellar ataxia as a possible organ-specific autoimmune disease. Mov Disord 2008; 23 (10) 1370-1377
6 Whiteley AM, Swash M, Urich H. Progressive encephalomyelitis with rigidity. Brain 1976; 99 (1) 27-42
7 Pittock SJ, Yoshikawa H, Ahlskog JE , et al. Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction. Mayo Clin Proc 2006; 81 (9) 1207-1214
8 Matà S, Muscas GC, Naldi I , et al. Non-paraneoplastic limbic encephalitis associated with anti-glutamic acid decarboxylase antibodies. J Neuroimmunol 2008; 199 (1-2) 155-159
9 Malter MP, Helmstaedter C, Urbach H, Vincent A, Bien CG. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann Neurol 2010; 67 (4) 470-478
10 Graus F, Saiz A, Lai M , et al. Neuronal surface antigen antibodies in limbic encephalitis: clinical-immunologic associations. Neurology 2008; 71 (12) 930-936
11 McKeon A, Robinson MT, McEvoy KM , et al. Stiff-man syndrome and variants: clinical course, treatments, and outcomes. Arch Neurol 2012; 69 (2) 230-238
12 Liimatainen S, Peltola M, Sabater L , et al. Clinical significance of glutamic acid decarboxylase antibodies in patients with epilepsy. Epilepsia 2010; 51 (5) 760-767
13 Yoshimoto T, Doi M, Fukai N , et al. Type 1 diabetes mellitus and drug-resistant epilepsy: presence of high titer of anti-glutamic acid decarboxylase autoantibodies in serum and cerebrospinal fluid. Intern Med 2005; 44 (11) 1174-1177
14 Peltola J, Kulmala P, Isojärvi J , et al. Autoantibodies to glutamic acid decarboxylase in patients with therapy-resistant epilepsy. Neurology 2000; 55 (1) 46-50
15 Verrotti A, Greco R, Altobelli E, Latini G, Morgese G, Chiarelli F. Anticardiolipin, glutamic acid decarboxylase, and antinuclear antibodies in epileptic patients. Clin Exp Med 2003; 3 (1) 32-36
16 Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000; 342 (5) 314-319
17 Errichiello L, Perruolo G, Pascarella A , et al. Autoantibodies to glutamic acid decarboxylase (GAD) in focal and generalized epilepsy: a study on 233 patients. J Neuroimmunol 2009; 211 (1-2) 120-123
18 Zivotofsky AZ, Siman-Tov T, Gadoth N, Gordon CR. A rare saccade velocity profile in stiff-person syndrome with cerebellar degeneration. Brain Res 2006; 1093 (1) 135-140
19 Solimena M, Folli F, Aparisi R, Pozza G, De Camilli P. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 1990; 322 (22) 1555-1560
20 Butler MH, Solimena M, Dirkx Jr R, Hayday A, De Camilli P. Identification of a dominant epitope of glutamic acid decarboxylase (GAD-65) recognized by autoantibodies in stiff-man syndrome. J Exp Med 1993; 178 (6) 2097-2106
21 Ali F, Rowley M, Jayakrishnan B, Teuber S, Gershwin ME, Mackay IR. Stiff-person syndrome (SPS) and anti-GAD-related CNS degenerations: protean additions to the autoimmune central neuropathies. J Autoimmun 2011; 37 (2) 79-87
22 Walikonis JE, Lennon VA. Radioimmunoassay for glutamic acid decarboxylase (GAD65) autoantibodies as a diagnostic aid for stiff-man syndrome and a correlate of susceptibility to type 1 diabetes mellitus. Mayo Clin Proc 1998; 73 (12) 1161-1166
23 Christgau S, Aanstoot HJ, Schierbeck H , et al. Membrane anchoring of the autoantigen GAD65 to microvesicles in pancreatic beta-cells by palmitoylation in the NH2-terminal domain. J Cell Biol 1992; 118 (2) 309-320
24 Reetz A, Solimena M, Matteoli M, Folli F, Takei K, De Camilli P. GABA and pancreatic beta-cells: colocalization of glutamic acid decarboxylase (GAD) and GABA with synaptic-like microvesicles suggests their role in GABA storage and secretion. EMBO J 1991; 10 (5) 1275-1284
25 Hutchinson M, Waters P, McHugh J , et al. Progressive encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor antibody. Neurology 2008; 71 (16) 1291-1292
26 Mas N, Saiz A, Leite MI , et al. Antiglycine-receptor encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry 2011; 82 (12) 1399-1401
27 Raju R, Rakocevic G, Chen Z , et al. Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome. Brain 2006; 129 (Pt 12) 3270-3276
28 Ishida K, Mitoma H, Song SY , et al. Selective suppression of cerebellar GABAergic transmission by an autoantibody to glutamic acid decarboxylase. Ann Neurol 1999; 46 (2) 263-267
29 Mitoma H, Song SY, Ishida K, Yamakuni T, Kobayashi T, Mizusawa H. Presynaptic impairment of cerebellar inhibitory synapses by an autoantibody to glutamate decarboxylase. J Neurol Sci 2000; 175 (1) 40-44
30 Manto MU, Laute MA, Aguera M, Rogemond V, Pandolfo M, Honnorat J. Effects of anti-glutamic acid decarboxylase antibodies associated with neurological diseases. Ann Neurol 2007; 61 (6) 544-551
31 Rakocevic G, Raju R, Semino-Mora C, Dalakas MC. Stiff person syndrome with cerebellar disease and high-titer anti-GAD antibodies. Neurology 2006; 67 (6) 1068-1070
32 Dalakas MC. Advances in the pathogenesis and treatment of patients with stiff person syndrome. Curr Neurol Neurosci Rep 2008; 8 (1) 48-55
33 Murinson BB, Guarnaccia JB. Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease. Neurology 2008; 71 (24) 1955-1958
34 Holmøy T, Skorstad G, Røste LS, Scheie D, Alvik K. Stiff person syndrome associated with lower motor neuron disease and infiltration of cytotoxic T cells in the spinal cord. Clin Neurol Neurosurg 2009; 111 (8) 708-712
35 Witherick J, Highley JR, Hadjivassiliou M. Pathological findings in a case of stiff person syndrome with anti-GAD antibodies. Mov Disord 2011; 26 (11) 2138-2139
36 Ishida K, Mitoma H, Wada 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) 190-192
37 Dalakas MC. The role of IVIg in the treatment of patients with stiff person syndrome and other neurological diseases associated with anti-GAD antibodies. J Neurol 2005; 252 (Suppl. 01) I19-I25
38 Bonnan M, Cabre P, Olindo S, Signate A, Saint-Vil M, Smadja D. Steroid treatment in four cases of anti-GAD cerebellar ataxia [in French]. Rev Neurol (Paris) 2008; 164 (5) 427-433
39 Lauria G, Pareyson D, Pitzolu MG, Bazzigaluppi E. Excellent response to steroid treatment in anti-GAD cerebellar ataxia. Lancet Neurol 2003; 2 (10) 634-635
40 Nanri K, Okita M, Takeguchi M , et al. Intravenous immunoglobulin therapy for autoantibody-positive cerebellar ataxia. Intern Med 2009; 48 (10) 783-790
41 Vulliemoz S, Vanini G, Truffert A, Chizzolini C, Seeck M. Epilepsy and cerebellar ataxia associated with anti-glutamic acid decarboxylase antibodies. J Neurol Neurosurg Psychiatry 2007; 78 (2) 187-189