Neuro-Ophthalmologic Manifestations of Anti-GAD Antibody Syndrome

From EyeWiki

Disease Entity

Glutamic acid decarboxylase (GAD) is an enzyme responsible for the conversion of glutamic acid to gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the nervous system. Antibodies against this enzyme (GAD) are known as anti-GAD antibodies (AGA) and have been implicated in numerous clinical syndromes, including cerebellar ataxia, stiff person syndrome, and insulin-dependent diabetes mellitus.[1] Neuro-ophthalmologic findings have also been reported in patients with AGA, including findings of retinopathy, ophthalmoplegia and diplopia, cerebellar ocular dysfunction, and nystagmus.[2][3][4]


In one population study, the frequency of AGA positivity was 1.7%. [5] In A Diabetes Outcome Prevention Trial (ADOPT) of recently diagnosed type II diabetics in Europe and North America found a prevalence of AGA ranging from 3.7-4.7%.[6] Other studies have found an even higher prevalence of high AGA levels in patients with type I diabetes (80%) or stiff-person syndrome (SPS, 60%).[7]


The etiology of AGA syndrome is not well understood, but thought to be related to an autoimmune or paraneoplastic pathophysiology.[2] AGA are originally formed by B cells, which are able to cross the blood-brain barrier.[8] There are two GAD isoforms that play a role in the synthesis of GABA: GAD67 and GAD65. GAD67 is an enzyme found throughout the cytosol of cells, while GAD65 is post-translationally modified to become attached to the membrane of synaptic vesicles and therefore localized to the nerve terminal.[9] The fact that GAD65 is anchored to synaptic vesicles indicates it may play a role in the packaging and/or release of GABA.[10]

Infectious etiologies and malignancy may play a role in development of AGA syndrome. Herpes simplex virus, teratomas, small cell lung cancer, thymomas, and use of immune checkpoint inhibitors have also been identified as possible triggers of autoimmune encephalitides associated with AGA[11]. In cases of HSV-associated AGA syndrome, response has been noted with immunotherapy rather than antiviral treatment, suggesting production of autoantibodies rather than viral activity are the direct trigger for AGA syndrome[12]. The implication is that anti-GAD antibodies may persist even after antiviral or antitumor treatment.

Clinicians should note that cases of AGA syndrome with viral etiology such as HSV may also present with psychiatric symptoms due to temporal lobe or limbic encephalitis. Psychiatric findings in addition to horizontal ophthalmoplegia and/or vertical nystagmus should raise suspicion for AGA syndrome.


There are two main mechanisms that have been proposed for how AGA disrupts GABAergic pathways.[8] One such proposal is that AGA attacks the GAD enzyme, thus inhibiting the formation of GABA in the CNS. This is supported by the in-vitro activity of AGA IgG against GAD.[13] In AGA neurologic syndromes such as SPS, this immunopathogenic mechanism produces skeletal muscle hyperactivity by targeting the inhibitory neurons that control alpha-motor neurons.[2] In cases of cerebellar ataxia, the predominance of GABAergic neurons in the cerebellum (Purkinje’s cells, Golgi’s cells, etc) may explain the pathogenesis of cerebellar atrophy seen in AGA positive patients.[4] The second possible mechanism involves interference in the release of GABA by inhibiting the exocytosis of synaptic vesicles. A low level of this inhibitory neurotransmitter in neuronal synapses causes patients to subsequently develop motor and cognitive symptoms as a result of hyperexcitability of the CNS. At the cellular level, a study of GAD65 deficient mice found that while low-frequency stimulation of inhibitory interneurons remained intact, sustained stimulation revealed a defect in GABA release.[10] This suggests that a lack of GAD65 impairs mobilization of vesicles and/or replenishment of vesicles at the synaptic release sites during times of high neurotransmitter turnover.

Ocular Manifestations


Oscillopsia related to downbeat nystagmus has been reported in AGA positive stiff person syndrome (SPS).[2] Another AGA positive patient presented with horizontal gaze-evoked and rebound nystagmus.[2] Patients with AGA positive subacute cerebellar ataxia have presented with nystagmus, including cases of periodic alternating nystagmus (PAN),[1] downbeat nystagmus (DBN) with slow vertical saccades,[1] and bilateral horizontal rotary jerks with abolished vertical saccades.[4]

Impaired Vestibulo-ocular Reflex (VOR)

One AGA positive patient with diplopia demonstrated an impaired horizontal VOR bilaterally.[2] Another case of AGA positive cerebellar ataxia demonstrated a prolonged VOR.[1]

Opsoclonus-Myoclonus Syndrome

A patient with increased titers of AGA was reported to have opsoclonus in addition to DBN.[14] Laroumagne et al reported a patient with AGA positive small cell lung cancer and opsoclonus-myoclonus syndrome.[15]


Many patients with AGA present with episodic or persistent horizontal diplopia. A patient positive for AGA and a mixed-type thymoma was found to have almost complete bilateral ophthalmoplegia for horizontal and upward ocular movements.[2]


Autoimmune retinopathy in an AGA positive patient with SPS has been reported, demonstrating that subacute progressive loss of vision is possible due to AGA precipitating degeneration of the inner and outer plexiform layers of the retina.[3]


A diagnosis of AGA syndrome should be made in the context of clinical presentation, predisposing risk factors, and laboratory work. AGA can be detected using serology or cerebrospinal fluid (CSF) testing.[8]


Most AGA positive neurologic syndromes are treated medically. GABA agonists are used to replenish the lack of GABA, but only partially reduce symptoms.[2] Additional symptomatic treatment includes high doses of baclofen and diazepam to reduce hyperexcitability, as well as immunomodulation with IVIG and plasmapheresis to target the AGA pathogenic antibody response.[8]


Patients have seen variable success in symptomatic relief with combinations of immunomodulation and muscle relaxants, but there is no cure.[2]


Clinicians should be aware of the neuro-ophthalmic presentations for AGA including SPS, cerebellar eye signs and ataxia, nystagmus (especially downbeat), LADA, and ophthalmoplegia.


  1. 1.0 1.1 1.2 1.3 Tilikete C, Vighetto A, Trouillas P, Honnorat J. Potential role of anti-GAD antibodies in abnormal eye movements. Ann N Y Acad Sci. 2005;1039:446-454. doi:10.1196/annals.1325.042
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Eggenberger ER, Lee AG, Thomas M, Lai EC. Neuro-Ophthalmologic Findings in Patients with the Anti-GAD Antibody Syndrome. Neuro-Ophthalmol. 2006;30(1):1-6. doi:10.1080/01658100600599410
  3. 3.0 3.1 Steffen H, Menger N, Richter W, et al. Immune-mediated retinopathy in a patient with stiff-man syndrome. Graefes Arch Clin Exp Ophthalmol Albrecht Von Graefes Arch Klin Exp Ophthalmol. 1999;237(3):212-219. doi:10.1007/s004170050221
  4. 4.0 4.1 4.2 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):462-468. doi:10.1001/archneur.1995.00540290050017
  5. Sørgjerd EP, Thorsby PM, Torjesen PA, Skorpen F, Kvaløy K, Grill V. Presence of anti-GAD in a non-diabetic population of adults; time dynamics and clinical influence: results from the HUNT study. BMJ Open Diabetes Res Care. 2015;3(1). doi:10.1136/bmjdrc-2014-000076
  6. Zinman B, Kahn SE, Haffner SM, et al. Phenotypic characteristics of GAD antibody-positive recently diagnosed patients with type 2 diabetes in North America and Europe. Diabetes. 2004;53(12):3193-3200. doi:10.2337/diabetes.53.12.3193
  7. Solimena M, De Camilli P. Autoimmunity to glutamic acid decarboxylase (GAD) in Stiff-Man syndrome and insulin-dependent diabetes mellitus. Trends Neurosci. 1991;14(10):452-457. doi:10.1016/0166-2236(91)90044-u
  8. 8.0 8.1 8.2 8.3 Tohid H. Anti-glutamic acid decarboxylase antibody positive neurological syndromes. Neurosciences. 2016;21(3):215-222. doi:10.17712/nsj.2016.3.20150596
  9. Ellis TM, Atkinson MA. The clinical significance of an autoimmune response against glutamic acid decarboxylase. Nat Med. 1996;2(2):148-153. doi:10.1038/nm0296-148
  10. 10.0 10.1 Tian N, Petersen C, Kash S, Baekkeskov S, Copenhagen D, Nicoll R. The role of the synthetic enzyme GAD65 in the control of neuronal gamma-aminobutyric acid release. Proc Natl Acad Sci U S A. 1999;96(22):12911-12916. doi:10.1073/pnas.96.22.12911
  11. Alexopoulos H, Dalakas MC. The immunobiology of autoimmune encephalitides. J Autoimmun. 2019;104:102339. doi:10.1016/j.jaut.2019.102339
  12. Tsiortou P, Alexopoulos H, Dalakas MC. GAD antibody-spectrum disorders: progress in clinical phenotypes, immunopathogenesis and therapeutic interventions. Ther Adv Neurol Disord. 2021;14:17562864211003486. doi:10.1177/17562864211003486
  13. Dinkel K, Meinck HM, Jury KM, Karges W, Richter W. Inhibition of gamma-aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff-man syndrome. Ann Neurol. 1998;44(2):194-201. doi:10.1002/ana.410440209
  14. Shaikh AG, Wilmot G. Opsoclonus in a patient with increased titers of anti-GAD antibody provides proof for the conductance-based model of saccadic oscillations. J Neurol Sci. 2016;362:169-173. doi:10.1016/j.jns.2016.01.038
  15. Laroumagne S, Elharrar X, Coiffard B, et al. “Dancing Eye Syndrome” Secondary to Opsoclonus-Myoclonus Syndrome in Small-Cell Lung Cancer. Case Rep Med. 2014;2014. doi:10.1155/2014/545490
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