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Clinical characteristics of patients with cerebellar ataxia associated with anti-GAD antibodies

Características clínicas de pacientes com ataxia cerebelar associada a anticorpos anti-GAD

ABSTRACT

The enzyme glutamic acid decarboxylase (GAD), present in GABAergic neurons and in pancreatic beta cells, catalyzes the conversion of gamma-aminobutyric acid (GABA). The cerebellum is highly susceptible to immune-mediated mechanisms, with the potentially treatable autoimmune cerebellar ataxia associated with the GAD antibody (CA-GAD-ab) being a rare, albeit increasingly detected condition. Few cases of CA-GAD-ab have been described.

Methods

This retrospective and descriptive study evaluated the clinical characteristics and outcomes of patients with CA-GAD-ab.

Result

Three patients with cerebellar ataxia, high GAD-ab titers and autoimmune endocrine disease were identified. Patients 1 and 2 had classic stiff person syndrome and insidious-onset cerebellar ataxia, while Patient 3 had pure cerebellar ataxia with subacute onset. Patients received intravenous immunoglobulin therapy with no response in Patients 1 and 3 and partial recovery in Patient 2.

Conclusion

CA-GAD-ab is rare and its clinical presentation may hamper diagnosis. Clinicians should be able to recognize this potentially treatable autoimmune cerebellar ataxia.

autoimmunity; cerebellar ataxia; diabetes mellitus

RESUMO

A enzima ácido glutâmico descarboxilase (GAD), presente nos neurônios GABAérgicos e células beta do pâncreas, catalisa a conversão do ácido gama-aminobutírico (GABA). O cerebelo é altamente susceptível a mecanismos imunomediados, sendo a ataxia cerebelar associada ao anticorpo anti-GAD (CA-GAD) uma doença potencialmente tratável. Embora rara, sua frequência é crescente, com poucos casos descritos.

Métodos

Estudo retrospectivo e descritivo avaliando características clínicas e desfechos da CA-GAD.

Resultados

Três pacientes com CA-GAD, altos títulos de anti-GAD e doença endócrina autoimune foram identificados. Os pacientes 1 e 2 tinham síndrome da pessoa rígida em forma clássica e apresentação insidiosa da ataxia cerebelar, enquanto o paciente 3 tinha ataxia cerebelar pura e apresentação subaguda. Os pacientes 1 e 3 não melhoraram com imunoglobulina intravenosa e o paciente 2 teve recuperação parcial.

Conclusão

A CA-GAD é rara e pode ter apresentação clínica desafiadora. Os médicos devem ser capazes de reconhecer essa forma potencialmente tratável de ataxia cerebelar autoimune.

autoimunidade; ataxia cerebelar; diabetes mellitus

The spectrum of neurological syndromes associated with anti-glutamic acid decarboxylase antibodies (GAD-ab) is not well established and seems broader than previously believed11. Saiz A, Blanco Y, Sabater L, González F, Bataller L, Casamitjana R et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain. 2008;131(10):2553-63. https://doi.org/10.1093/brain/awn183
https://doi.org/10.1093/brain/awn183...
. The main neurological syndromes related to GAD-ab include stiff person syndrome (SPS), cerebellar ataxia, limbic encephalitis and epilepsy11. Saiz A, Blanco Y, Sabater L, González F, Bataller L, Casamitjana R et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain. 2008;131(10):2553-63. https://doi.org/10.1093/brain/awn183
https://doi.org/10.1093/brain/awn183...
,22. 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):544-51. https://doi.org/10.1002/ana.21123
https://doi.org/10.1002/ana.21123...
,33. Vianello M, Tavolato B, Giometto B. Glutamic acid decarboxylase autoantibodies and neurological disorders. Neurol Sci. 2002;23(4):145-51. https://doi.org/10.1007/s100720200055
https://doi.org/10.1007/s100720200055...
. Glutamic acid decarboxylase is a cytoplasmic rate-limiting enzyme that catalyzes the conversion of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter present in the central nervous system (CNS). It is found primarily in GABAergic neurons and in beta cells in the islets of Langerhans in the pancreas22. 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):544-51. https://doi.org/10.1002/ana.21123
https://doi.org/10.1002/ana.21123...
,44. Fenalti G, Buckle AM. Structural biology of the GAD autoantigen. Autoimmun Rev. 2010;9(3):148-52. https://doi.org/10.1016/j.autrev.2009.05.003
https://doi.org/10.1016/j.autrev.2009.05...
. Glutamic acid decarboxylase is produced in two different isoforms with molecular weights of 65 and 67 kilodaltons (GAD65 and GAD67) encoded by two distinct genes; the main target for GAD-ab in neurological diseases is GAD6511. Saiz A, Blanco Y, Sabater L, González F, Bataller L, Casamitjana R et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain. 2008;131(10):2553-63. https://doi.org/10.1093/brain/awn183
https://doi.org/10.1093/brain/awn183...
,22. 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):544-51. https://doi.org/10.1002/ana.21123
https://doi.org/10.1002/ana.21123...
,33. Vianello M, Tavolato B, Giometto B. Glutamic acid decarboxylase autoantibodies and neurological disorders. Neurol Sci. 2002;23(4):145-51. https://doi.org/10.1007/s100720200055
https://doi.org/10.1007/s100720200055...
,44. Fenalti G, Buckle AM. Structural biology of the GAD autoantigen. Autoimmun Rev. 2010;9(3):148-52. https://doi.org/10.1016/j.autrev.2009.05.003
https://doi.org/10.1016/j.autrev.2009.05...
.

The cerebellum is an encephalic region highly susceptible to immune-mediated mechanisms. Cerebellar ataxia associated with anti-GAD-ab (CA-GAD-ab) is a rare and potentially treatable form of immune-mediated cerebellar ataxia, the detection of which is increasing55. Honnorat J, Saiz A, Giometto B, Vincent A, Brieva L, Andres C et al. Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol. 2001;58(2):225-30. https://doi.org/10.1001/archneur.58.2.225
https://doi.org/10.1001/archneur.58.2.22...
,66. 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):213-232. https://doi.org/10.1007/s12311-015-0664-x
https://doi.org/10.1007/s12311-015-0664-...
,77. Mitoma H, Hadjivassiliou M, Honnorat J. Guidelines for treatment of immune-mediated cerebellar ataxias. Cerebellum Ataxias. 2015;2(1):14. https://doi.org/10.1186/s40673-015-0034-y
https://doi.org/10.1186/s40673-015-0034-...
. The exact pathogenic role of GAD-ab in the cerebellar ataxias has yet to be fully understood; however, experimental data have suggested a direct excitotoxic effect of GAD-ab on Purkinje cells88. Vianello M, Tavolato B, Armani M, Giometto B. Cerebellar ataxia associated with anti-glutamic acid decarboxylase autoantibodies. Cerebellum. 2003;2(1):77-9. https://doi.org/10.1080/14734220309432
https://doi.org/10.1080/14734220309432...
. The presence of GAD-ab serves to confirm a possible autoimmune pathogenesis in the syndrome of cerebellar ataxia55. Honnorat J, Saiz A, Giometto B, Vincent A, Brieva L, Andres C et al. Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol. 2001;58(2):225-30. https://doi.org/10.1001/archneur.58.2.225
https://doi.org/10.1001/archneur.58.2.22...
,66. 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):213-232. https://doi.org/10.1007/s12311-015-0664-x
https://doi.org/10.1007/s12311-015-0664-...
,88. Vianello M, Tavolato B, Armani M, Giometto B. Cerebellar ataxia associated with anti-glutamic acid decarboxylase autoantibodies. Cerebellum. 2003;2(1):77-9. https://doi.org/10.1080/14734220309432
https://doi.org/10.1080/14734220309432...
.

The objective of the current investigation was to evaluate a series of patients with cerebellar ataxia associated to anti-GAD-ab, comparing their clinical characteristics and outcomes. There are few descriptions of CA-GAD-ab in the literature; therefore, this information is useful to clinicians dealing with cases of immune-mediated cerebellar ataxias.

METHODS

This is a retrospective and descriptive study conducted by reviewing the clinical characteristics and outcomes of consecutive patients with CA-GAD-ab evaluated in the Neurology and Nutrology departments of the Clementino Fraga Filho Hospital of the Federal University of Rio de Janeiro between February 2013 and December 2015. Three CA-GAD-ab patients were selected retrospectively. Full consent was obtained from the all patients.

All CA-GAD-ab patients were submitted to a complete neurological evaluation; cerebrospinal fluid examination; a laboratory work-up that included measurement of onconeural antibodies, autoimmune encephalitis antibodies and serum levels of GAD-ab; genetic evaluation; and brain magnetic resonance imaging (MRI) scans. Brain MRI was performed in a 1.5T scanner Avanto (Siemens Medical Systems, Erlangen, Germany).

Diabetes was defined according to the criteria established by the American Diabetes Association99. Association AD. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014;37 Suppl 1:S81-90. https://doi.org/10.2337/dc14-S08
https://doi.org/10.2337/dc14-S08...
. Classic SPS was diagnosed in accordance with the Dalakas criteria1010. Dalakas MC. Stiff person syndrome: advances in pathogenesis and therapeutic interventions. Curr Treat Options Neurol. 2009;11(2):102-10. https://doi.org/10.1007/s11940-009-0013-9
https://doi.org/10.1007/s11940-009-0013-...
, with SPS variants being defined according to Barker et al1111. Barker RA, Revesz T, Thom M, Marsden CD, Brown P. Review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry. 1998;65(5):633-40. https://doi.org/10.1136/jnnp.65.5.633
https://doi.org/10.1136/jnnp.65.5.633...
. Serum GAD-ab (GAD65-ab isoform) was measured with direct radiobinding assay, with the cut-off value for positivity being ≥ 1.0 Ui/ml. High titers of GAD-ab were defined as > 100Ui/ml.

RESULTS

The three patients (two men and one woman) identified with CA-GAD-ab were between 43 and 57 years of age (mean: 49.3 years). The characteristics of the patients are shown in Table 1. Onset was either subacute or insidious. All patients had global cerebellar ataxia, although in Patient 2 the condition was predominantly axial. In Patients 1 and 2, classical SPS was associated with cerebellar ataxia, while Patient 3 had pure cerebellar ataxia. None of the patients had SPS variants, epilepsy or limbic encephalitis. Multidirectional nystagmus of CNS origin, and cerebellar dysarthria, were present in the patients. There were no findings of downbeat nystagmus, opsoclonus-myoclonus, ocular flutter, periodic alternating nystagmus or palatal myoclonus. None of the patients had a family history of cerebellar ataxia.

All three patients met the criteria for endocrine disease: latent autoimmune diabetes of adults in Patients 1 and 2 and autoimmune polyglandular syndrome type 2 in Patient 3. Two patients had a family history of endocrine disease. All the patients had high titers of GAD-ab (Patient 1: 102Ui/ml, Patient 2: 200 Ui/ml, Patient 3: 200Ui/ml). Onconeural antibodies and autoimmune encephalitis antibodies, genetic evaluation, screenings for endocrine or organ specific autoimmunity were all normal (Table). Cerebrospinal fluid examination revealed the presence of anti-GAD in Patient 1, while Patient 2 tested normal, and oligoclonal bands were found in Patient 3. Brain MRI scans revealed cerebellar atrophy only in Patient 3 (Figure).

Table
Epidemiological and clinical characteristics of the analyzed patients.

Figure
Patient 3. Sagittal T1-weighted image showing cerebellar atrophy. A) Initial brain MRI showing normal cerebellum; B) Brain MRI two years later showing prominent cerebellar atrophy.

Following intravenous immunoglobulin therapy (IVIG, 0.4 g/kg/day for 5 days, followed by two cycles of single monthly doses 1g/kg), there was no improvement in Patients 1 and 3, and Patient 2 had a partial recovery.

DISCUSSION

Cerebellar ataxia associated with anti-GAD-ab is a rare disorder characterized by cerebellar ataxia concomitant in the presence of GAD-ab. The precise mechanism behind this condition remains unknown55. Honnorat J, Saiz A, Giometto B, Vincent A, Brieva L, Andres C et al. Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol. 2001;58(2):225-30. https://doi.org/10.1001/archneur.58.2.225
https://doi.org/10.1001/archneur.58.2.22...
,66. 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):213-232. https://doi.org/10.1007/s12311-015-0664-x
https://doi.org/10.1007/s12311-015-0664-...
,88. Vianello M, Tavolato B, Armani M, Giometto B. Cerebellar ataxia associated with anti-glutamic acid decarboxylase autoantibodies. Cerebellum. 2003;2(1):77-9. https://doi.org/10.1080/14734220309432
https://doi.org/10.1080/14734220309432...
,1212. Manto MU, Hampe CS, Rogemond V, Honnorat J. Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia. Orphanet J Rare Dis. 2011;6(1):3. https://doi.org/10.1186/1750-1172-6-3
https://doi.org/10.1186/1750-1172-6-3...
. The disease affects mostly women in their sixth decade of life55. Honnorat J, Saiz A, Giometto B, Vincent A, Brieva L, Andres C et al. Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol. 2001;58(2):225-30. https://doi.org/10.1001/archneur.58.2.225
https://doi.org/10.1001/archneur.58.2.22...
,66. 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):213-232. https://doi.org/10.1007/s12311-015-0664-x
https://doi.org/10.1007/s12311-015-0664-...
,88. Vianello M, Tavolato B, Armani M, Giometto B. Cerebellar ataxia associated with anti-glutamic acid decarboxylase autoantibodies. Cerebellum. 2003;2(1):77-9. https://doi.org/10.1080/14734220309432
https://doi.org/10.1080/14734220309432...
,1212. Manto MU, Hampe CS, Rogemond V, Honnorat J. Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia. Orphanet J Rare Dis. 2011;6(1):3. https://doi.org/10.1186/1750-1172-6-3
https://doi.org/10.1186/1750-1172-6-3...
. The present study evaluated three patients in their fifth and sixth decades of life, with two of these patients being male. As shown in this study, CA-GAD-ab may be either of insidious or subacute onset, with the disease tending to progress slowly over time55. Honnorat J, Saiz A, Giometto B, Vincent A, Brieva L, Andres C et al. Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol. 2001;58(2):225-30. https://doi.org/10.1001/archneur.58.2.225
https://doi.org/10.1001/archneur.58.2.22...
,66. 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):213-232. https://doi.org/10.1007/s12311-015-0664-x
https://doi.org/10.1007/s12311-015-0664-...
. All the patients reported here had global cerebellar ataxia; however, in Patient 2 the cerebellar ataxia was predominantly axial. Gait ataxia appears to be a severe and common problem in this condition11. Saiz A, Blanco Y, Sabater L, González F, Bataller L, Casamitjana R et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain. 2008;131(10):2553-63. https://doi.org/10.1093/brain/awn183
https://doi.org/10.1093/brain/awn183...
,55. Honnorat J, Saiz A, Giometto B, Vincent A, Brieva L, Andres C et al. Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol. 2001;58(2):225-30. https://doi.org/10.1001/archneur.58.2.225
https://doi.org/10.1001/archneur.58.2.22...
,66. 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):213-232. https://doi.org/10.1007/s12311-015-0664-x
https://doi.org/10.1007/s12311-015-0664-...
,1313. Pedroso JL, Braga-Neto P, Dutra LA, Barsottini OG. Cerebellar ataxia associated to anti-glutamic acid decarboxylase autoantibody (anti-GAD): partial improvement with intravenous immunoglobulin therapy. Arq Neuropsiquiatr. 2011;69(6):993. https://doi.org/10.1590/S0004-282X2011000700030
https://doi.org/10.1590/S0004-282X201100...
.

Few reports have been published on patients with CA-GAD-ab presenting with neuro-ophthalmic abnormalities1414. Ances BM, Dalmau JO, Tsai J, Hasbani MJ, Galetta SL. Downbeating nystagmus and muscle spasms in a patient with glutamic-acid decarboxylase antibodies. Am J Ophthalmol. 2005;140(1):142-4. https://doi.org/10.1016/j.ajo.2004.12.052
https://doi.org/10.1016/j.ajo.2004.12.05...
,1515. Antonini G, Nemni R, Giubilei F, Gragnani F, Ceschin V, Morino S et al. Autoantibodies to glutamic acid decarboxylase in downbeat nystagmus. J Neurol Neurosurg Psychiatry. 2003;74(7):998-9. https://doi.org/10.1136/jnnp.74.7.998
https://doi.org/10.1136/jnnp.74.7.998...
,1616. 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
https://doi.org/10.1001/archneur.62.8.13...
,1717. Dubbioso R, Marcelli V, Manganelli F, Iodice R, Esposito M, Santoro L. Anti-GAD antibody ocular flutter: expanding the spectrum of autoimmune ocular motor disorders. J Neurol. 2013;260(10):2675-7. https://doi.org/10.1007/s00415-013-7110-0
https://doi.org/10.1007/s00415-013-7110-...
,1818. Tilikete C, Vighetto A, Trouillas P, Honnorat J. Potential role of anti-GAD antibodies in abnormal eye movements. Ann N Y Acad Sci. 2005;1039(1):446-54. https://doi.org/10.1196/annals.1325.042
https://doi.org/10.1196/annals.1325.042...
,1919. Vale TC, Pedroso JL, Alquéres RA, Dutra LA, Barsottini OG. Spontaneous downbeat nystagmus as a clue for the diagnosis of ataxia associated with anti-GAD antibodies. J Neurol Sci. 2015;359(1-2):21-3. https://doi.org/10.1016/j.jns.2015.10.024
https://doi.org/10.1016/j.jns.2015.10.02...
. The three patients evaluated here had typical multidirectional nystagmus of CNS origin, although the spectrum of ocular manifestations in patients with CA-GAD-ab may be broader1313. Pedroso JL, Braga-Neto P, Dutra LA, Barsottini OG. Cerebellar ataxia associated to anti-glutamic acid decarboxylase autoantibody (anti-GAD): partial improvement with intravenous immunoglobulin therapy. Arq Neuropsiquiatr. 2011;69(6):993. https://doi.org/10.1590/S0004-282X2011000700030
https://doi.org/10.1590/S0004-282X201100...
,1414. Ances BM, Dalmau JO, Tsai J, Hasbani MJ, Galetta SL. Downbeating nystagmus and muscle spasms in a patient with glutamic-acid decarboxylase antibodies. Am J Ophthalmol. 2005;140(1):142-4. https://doi.org/10.1016/j.ajo.2004.12.052
https://doi.org/10.1016/j.ajo.2004.12.05...
,1515. Antonini G, Nemni R, Giubilei F, Gragnani F, Ceschin V, Morino S et al. Autoantibodies to glutamic acid decarboxylase in downbeat nystagmus. J Neurol Neurosurg Psychiatry. 2003;74(7):998-9. https://doi.org/10.1136/jnnp.74.7.998
https://doi.org/10.1136/jnnp.74.7.998...
,1616. 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
https://doi.org/10.1001/archneur.62.8.13...
,1717. Dubbioso R, Marcelli V, Manganelli F, Iodice R, Esposito M, Santoro L. Anti-GAD antibody ocular flutter: expanding the spectrum of autoimmune ocular motor disorders. J Neurol. 2013;260(10):2675-7. https://doi.org/10.1007/s00415-013-7110-0
https://doi.org/10.1007/s00415-013-7110-...
. Recent studies have shown that spontaneous downbeat nystagmus can represent an important clue for a diagnosis of CA-GAD-ab1818. Tilikete C, Vighetto A, Trouillas P, Honnorat J. Potential role of anti-GAD antibodies in abnormal eye movements. Ann N Y Acad Sci. 2005;1039(1):446-54. https://doi.org/10.1196/annals.1325.042
https://doi.org/10.1196/annals.1325.042...
. It is probably related to abnormal GABAergic transmission at the cerebellum and its connections1414. Ances BM, Dalmau JO, Tsai J, Hasbani MJ, Galetta SL. Downbeating nystagmus and muscle spasms in a patient with glutamic-acid decarboxylase antibodies. Am J Ophthalmol. 2005;140(1):142-4. https://doi.org/10.1016/j.ajo.2004.12.052
https://doi.org/10.1016/j.ajo.2004.12.05...
,1717. Dubbioso R, Marcelli V, Manganelli F, Iodice R, Esposito M, Santoro L. Anti-GAD antibody ocular flutter: expanding the spectrum of autoimmune ocular motor disorders. J Neurol. 2013;260(10):2675-7. https://doi.org/10.1007/s00415-013-7110-0
https://doi.org/10.1007/s00415-013-7110-...
,1818. Tilikete C, Vighetto A, Trouillas P, Honnorat J. Potential role of anti-GAD antibodies in abnormal eye movements. Ann N Y Acad Sci. 2005;1039(1):446-54. https://doi.org/10.1196/annals.1325.042
https://doi.org/10.1196/annals.1325.042...
.

Patients 1 and 2 have a more complex phenotype: classic SPS and cerebellar ataxia. Stiff person syndrome is a rare disorder characterized by muscle rigidity and episodic axial muscle spasms1010. Dalakas MC. Stiff person syndrome: advances in pathogenesis and therapeutic interventions. Curr Treat Options Neurol. 2009;11(2):102-10. https://doi.org/10.1007/s11940-009-0013-9
https://doi.org/10.1007/s11940-009-0013-...
,2020. Lorish TR, Thorsteinsson G, Howard FM Jr. Stiff-man syndrome updated. Mayo Clin Proc. 1989;64(6):629-36. https://doi.org/10.1016/S0025-6196(12)65339-7
https://doi.org/10.1016/S0025-6196...
. Continuous contraction of opposing muscles is caused by involuntary motor unit firing at rest and represents a clinical and electrophysiological hallmark of the disease1010. Dalakas MC. Stiff person syndrome: advances in pathogenesis and therapeutic interventions. Curr Treat Options Neurol. 2009;11(2):102-10. https://doi.org/10.1007/s11940-009-0013-9
https://doi.org/10.1007/s11940-009-0013-...
,2020. Lorish TR, Thorsteinsson G, Howard FM Jr. Stiff-man syndrome updated. Mayo Clin Proc. 1989;64(6):629-36. https://doi.org/10.1016/S0025-6196(12)65339-7
https://doi.org/10.1016/S0025-6196...
. It is also related to the autoimmune pathogenesis of the disease, and, although the antibody spectrum associated with SPS has broadened, GAD-ab and anti-amphiphysin remain those most typically associated with SPS1010. Dalakas MC. Stiff person syndrome: advances in pathogenesis and therapeutic interventions. Curr Treat Options Neurol. 2009;11(2):102-10. https://doi.org/10.1007/s11940-009-0013-9
https://doi.org/10.1007/s11940-009-0013-...
,1111. Barker RA, Revesz T, Thom M, Marsden CD, Brown P. Review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry. 1998;65(5):633-40. https://doi.org/10.1136/jnnp.65.5.633
https://doi.org/10.1136/jnnp.65.5.633...
,2020. Lorish TR, Thorsteinsson G, Howard FM Jr. Stiff-man syndrome updated. Mayo Clin Proc. 1989;64(6):629-36. https://doi.org/10.1016/S0025-6196(12)65339-7
https://doi.org/10.1016/S0025-6196...
,2121. Balint B, Bhatia KP. Stiff person syndrome and other immune-mediated movement disorders: new insights. Curr Opin Neurol. 2016;29(4):496-506. https://doi.org/10.1097/WCO.0000000000000351
https://doi.org/10.1097/WCO.000000000000...
. The association between SPS and CA-GAD-ab is even more unusual and creates additional challenges to diagnosis and treatment2020. Lorish TR, Thorsteinsson G, Howard FM Jr. Stiff-man syndrome updated. Mayo Clin Proc. 1989;64(6):629-36. https://doi.org/10.1016/S0025-6196(12)65339-7
https://doi.org/10.1016/S0025-6196...
,2121. Balint B, Bhatia KP. Stiff person syndrome and other immune-mediated movement disorders: new insights. Curr Opin Neurol. 2016;29(4):496-506. https://doi.org/10.1097/WCO.0000000000000351
https://doi.org/10.1097/WCO.000000000000...
,2222. Fernandes M, Munhoz RP, Carrilho PE, Arruda WO, Lorenzoni PJ, Scola RH et al. Neurological disorders associated with glutamic acid decarboxylase antibodies: a Brazilian series. Arq Neuropsiquiatr. 2012;70(9):657-61. https://doi.org/0.1590/S0004-282X2012000900002
https://doi.org/0.1590/S0004-282X2012000...
,2323. Betterle C, Lazzarotto F, Presotto F. Autoimmune polyglandular syndrome Type 2: the tip of an iceberg? Clin Exp Immunol. 2004;137(2):225-33. https://doi.org/10.1111/j.1365-2249.2004.02561.x
https://doi.org/10.1111/j.1365-2249.2004...
,2424. 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):1068-70. https://doi.org/10.1212/01.wnl.0000237558.83349.d0
https://doi.org/10.1212/01.wnl.000023755...
,2525. Ariño H, Gresa-Arribas N, Blanco Y, Martínez-Hernández 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
https://doi.org/10.1001/jamaneurol.2014....
,2626. Gordon CR, Zivotofsky AZ, Siman-Tov T, Gadoth N, Dalakas MC. Stiff person syndrome with cerebellar disease and high-titer anti-GAD antibodies. Neurology. 2007;68(14):1161. https://doi.org/10.1212/01.wnl.0000261162.61360.a2
https://doi.org/10.1212/01.wnl.000026116...
. This overlap emphasizes a possible common mechanism, which is probably related to the widespread distribution of GAD throughout the CNS11. Saiz A, Blanco Y, Sabater L, González F, Bataller L, Casamitjana R et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain. 2008;131(10):2553-63. https://doi.org/10.1093/brain/awn183
https://doi.org/10.1093/brain/awn183...
,22. 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):544-51. https://doi.org/10.1002/ana.21123
https://doi.org/10.1002/ana.21123...
,44. Fenalti G, Buckle AM. Structural biology of the GAD autoantigen. Autoimmun Rev. 2010;9(3):148-52. https://doi.org/10.1016/j.autrev.2009.05.003
https://doi.org/10.1016/j.autrev.2009.05...
,66. 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):213-232. https://doi.org/10.1007/s12311-015-0664-x
https://doi.org/10.1007/s12311-015-0664-...
.

A personal or familial history of other autoimmune diseases such as autoimmune diabetes mellitus, Addison’s disease, hemolytic anemia or thyroiditis is commonly found in CA-GAD-ab66. 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):213-232. https://doi.org/10.1007/s12311-015-0664-x
https://doi.org/10.1007/s12311-015-0664-...
,2222. Fernandes M, Munhoz RP, Carrilho PE, Arruda WO, Lorenzoni PJ, Scola RH et al. Neurological disorders associated with glutamic acid decarboxylase antibodies: a Brazilian series. Arq Neuropsiquiatr. 2012;70(9):657-61. https://doi.org/0.1590/S0004-282X2012000900002
https://doi.org/0.1590/S0004-282X2012000...
. All the patients reported here had an endocrine disorder: two had latent autoimmune diabetes of adults and one had autoimmune polyglandular syndrome type 2, also known as Schmidt syndrome, which is the most common of the immunoendocrinopathy syndromes characterized by the obligatory occurrence of autoimmune Addison’s disease in combination with thyroid autoimmune disorders and/or autoimmune diabetes mellitus (type 1 diabetes mellitus or latent autoimmune diabetes of adults)2323. Betterle C, Lazzarotto F, Presotto F. Autoimmune polyglandular syndrome Type 2: the tip of an iceberg? Clin Exp Immunol. 2004;137(2):225-33. https://doi.org/10.1111/j.1365-2249.2004.02561.x
https://doi.org/10.1111/j.1365-2249.2004...
. It should be emphasized, however, that even if there is no association with endocrinopathy, all patients with new onset of unexplained cerebellar ataxia should be investigated for treatable conditions66. 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):213-232. https://doi.org/10.1007/s12311-015-0664-x
https://doi.org/10.1007/s12311-015-0664-...
such as CA-GAD-ab.

Cerebrospinal fluid analysis may be normal or may show oligoclonal bands, mild pleocytosis and intrathecal synthesis of GAD-abs11. Saiz A, Blanco Y, Sabater L, González F, Bataller L, Casamitjana R et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain. 2008;131(10):2553-63. https://doi.org/10.1093/brain/awn183
https://doi.org/10.1093/brain/awn183...
,22. 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):544-51. https://doi.org/10.1002/ana.21123
https://doi.org/10.1002/ana.21123...
,33. Vianello M, Tavolato B, Giometto B. Glutamic acid decarboxylase autoantibodies and neurological disorders. Neurol Sci. 2002;23(4):145-51. https://doi.org/10.1007/s100720200055
https://doi.org/10.1007/s100720200055...
. Brain MRI may also be normal or may reveal cerebellar atrophy11. Saiz A, Blanco Y, Sabater L, González F, Bataller L, Casamitjana R et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain. 2008;131(10):2553-63. https://doi.org/10.1093/brain/awn183
https://doi.org/10.1093/brain/awn183...
,22. 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):544-51. https://doi.org/10.1002/ana.21123
https://doi.org/10.1002/ana.21123...
,33. Vianello M, Tavolato B, Giometto B. Glutamic acid decarboxylase autoantibodies and neurological disorders. Neurol Sci. 2002;23(4):145-51. https://doi.org/10.1007/s100720200055
https://doi.org/10.1007/s100720200055...
,55. Honnorat J, Saiz A, Giometto B, Vincent A, Brieva L, Andres C et al. Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol. 2001;58(2):225-30. https://doi.org/10.1001/archneur.58.2.225
https://doi.org/10.1001/archneur.58.2.22...
. For unknown reason, cerebellar atrophy is generally seen in patients with CA-GAD-ab without SPS55. Honnorat J, Saiz A, Giometto B, Vincent A, Brieva L, Andres C et al. Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol. 2001;58(2):225-30. https://doi.org/10.1001/archneur.58.2.225
https://doi.org/10.1001/archneur.58.2.22...
,66. 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):213-232. https://doi.org/10.1007/s12311-015-0664-x
https://doi.org/10.1007/s12311-015-0664-...
,2424. 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):1068-70. https://doi.org/10.1212/01.wnl.0000237558.83349.d0
https://doi.org/10.1212/01.wnl.000023755...
, and the patients in the present study are no exception.

The majority of cases of CA-GAD-ab reported in the literature involved high levels of GAD-ab11. Saiz A, Blanco Y, Sabater L, González F, Bataller L, Casamitjana R et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain. 2008;131(10):2553-63. https://doi.org/10.1093/brain/awn183
https://doi.org/10.1093/brain/awn183...
,66. 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):213-232. https://doi.org/10.1007/s12311-015-0664-x
https://doi.org/10.1007/s12311-015-0664-...
,2525. Ariño H, Gresa-Arribas N, Blanco Y, Martínez-Hernández 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
https://doi.org/10.1001/jamaneurol.2014....
,2626. Gordon CR, Zivotofsky AZ, Siman-Tov T, Gadoth N, Dalakas MC. Stiff person syndrome with cerebellar disease and high-titer anti-GAD antibodies. Neurology. 2007;68(14):1161. https://doi.org/10.1212/01.wnl.0000261162.61360.a2
https://doi.org/10.1212/01.wnl.000026116...
but, even if the titers are low, the condition may be associated with an autoimmune mechanism1313. Pedroso JL, Braga-Neto P, Dutra LA, Barsottini OG. Cerebellar ataxia associated to anti-glutamic acid decarboxylase autoantibody (anti-GAD): partial improvement with intravenous immunoglobulin therapy. Arq Neuropsiquiatr. 2011;69(6):993. https://doi.org/10.1590/S0004-282X2011000700030
https://doi.org/10.1590/S0004-282X201100...
,2727. 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
https://doi.org/10.1007/s12311-012-0411-...
. A diagnosis of CA-GAD-ab is supported by the positivity for GAD-ab. The patients in this study had high titers, reinforcing the immune-mediated mechanism11. Saiz A, Blanco Y, Sabater L, González F, Bataller L, Casamitjana R et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain. 2008;131(10):2553-63. https://doi.org/10.1093/brain/awn183
https://doi.org/10.1093/brain/awn183...
,66. 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):213-232. https://doi.org/10.1007/s12311-015-0664-x
https://doi.org/10.1007/s12311-015-0664-...
.

Despite the absence of randomized controlled studies, immunotherapy regimens such as glucocorticoid, intravenous immunoglobulin, plasma exchange, and immunosuppressive agents in varying combinations are the mainstay of the treatment77. Mitoma H, Hadjivassiliou M, Honnorat J. Guidelines for treatment of immune-mediated cerebellar ataxias. Cerebellum Ataxias. 2015;2(1):14. https://doi.org/10.1186/s40673-015-0034-y
https://doi.org/10.1186/s40673-015-0034-...
,1313. Pedroso JL, Braga-Neto P, Dutra LA, Barsottini OG. Cerebellar ataxia associated to anti-glutamic acid decarboxylase autoantibody (anti-GAD): partial improvement with intravenous immunoglobulin therapy. Arq Neuropsiquiatr. 2011;69(6):993. https://doi.org/10.1590/S0004-282X2011000700030
https://doi.org/10.1590/S0004-282X201100...
,2525. Ariño H, Gresa-Arribas N, Blanco Y, Martínez-Hernández 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
https://doi.org/10.1001/jamaneurol.2014....
,2828. Nanri K, Okita M, Takeguchi M, Taguchi T, Ishiko T, Saito H et al. Intravenous immunoglobulin therapy for autoantibody-positive cerebellar ataxia. Intern Med.. 2009;48(10):783-90. https://doi.org/10.2169/internalmedicine.48.1802
https://doi.org/10.2169/internalmedicine...
,2929. Dogan VB. An anti-GAD autoantibody-associated cerebellar syndrome case: a curable cause of ataxia. Neurol Sci. 2015;36(10):1929-31. https://doi.org/10.1007/s10072-015-2280-4
https://doi.org/10.1007/s10072-015-2280-...
,3030. 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
https://doi.org/10.1136/jnnp.2006.091116...
. The response to treatment is variable, with complete remission being rare. However, there are a few reports that show favorable response1313. Pedroso JL, Braga-Neto P, Dutra LA, Barsottini OG. Cerebellar ataxia associated to anti-glutamic acid decarboxylase autoantibody (anti-GAD): partial improvement with intravenous immunoglobulin therapy. Arq Neuropsiquiatr. 2011;69(6):993. https://doi.org/10.1590/S0004-282X2011000700030
https://doi.org/10.1590/S0004-282X201100...
,3030. 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
https://doi.org/10.1136/jnnp.2006.091116...
. No correlation has been found between serum GAD-ab titers and the severity of the disease, its phenotype or response to treatment55. Honnorat J, Saiz A, Giometto B, Vincent A, Brieva L, Andres C et al. Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol. 2001;58(2):225-30. https://doi.org/10.1001/archneur.58.2.225
https://doi.org/10.1001/archneur.58.2.22...
,77. Mitoma H, Hadjivassiliou M, Honnorat J. Guidelines for treatment of immune-mediated cerebellar ataxias. Cerebellum Ataxias. 2015;2(1):14. https://doi.org/10.1186/s40673-015-0034-y
https://doi.org/10.1186/s40673-015-0034-...
,2525. Ariño H, Gresa-Arribas N, Blanco Y, Martínez-Hernández 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
https://doi.org/10.1001/jamaneurol.2014....
. The patients evaluated here underwent intravenous immunoglobulin therapy; however, partial recovery was achieved in Patient 2 alone, with Patients 1 and 3 showing no response to the treatment.

Recently, an increasing number of neurological disorders have been associated with GAD-ab11. Saiz A, Blanco Y, Sabater L, González F, Bataller L, Casamitjana R et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain. 2008;131(10):2553-63. https://doi.org/10.1093/brain/awn183
https://doi.org/10.1093/brain/awn183...
. Of the three patients with CA-GAD-ab described here, one had pure CA-GAD-ab, while the two remaining patients had a more complex phenotype, CA-GAG-ab plus SPS. The reason behind the susceptibility of the cerebellum to this form of immune-mediated disease is not fully understood, but is probably related to the distribution of GAD in Purkinje cells and a direct excitotoxic effect of GAD-ab66. 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):213-232. https://doi.org/10.1007/s12311-015-0664-x
https://doi.org/10.1007/s12311-015-0664-...
. Some autopsy studies have revealed a selective loss of Purkinje cells3030. 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
https://doi.org/10.1136/jnnp.2006.091116...
. The potential pathogenic role of GAD-ab in neurological disorders remains to be clarified; however, plausible hypotheses include the inhibition of GABA synthesis and interference with exocytosis2525. Ariño H, Gresa-Arribas N, Blanco Y, Martínez-Hernández 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
https://doi.org/10.1001/jamaneurol.2014....
. Further studies are required to understand the exact mechanisms of cerebellar ataxia in patients with GAD-Ab.

The full spectrum of CA-GAD-ab is vast and its clinical presentation can be challenging. Therefore, clinicians should be able to recognize this potentially treatable autoimmune condition when faced with any of the aforementioned neurological disorders.

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  • Support: Rio de Janeiro State Foundation for the Support of Research (FAPERJ – Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro).

Publication Dates

  • Publication in this collection
    Mar 2017

History

  • Received
    17 Aug 2016
  • Reviewed
    05 Nov 2016
  • Accepted
    05 Dec 2016
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