Neuro-Ophthalmologic Manifestations of Anti-GAD Antibody Syndrome
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. Neuro-ophthalmologic findings have also been reported in patients with AGA, including findings of retinopathy, ophthalmoplegia and diplopia, cerebellar ocular dysfunction, and nystagmus.
In one population study, the frequency of AGA positivity was 1.7%.  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%. 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%).
The etiology of AGA syndrome is not well understood, but thought to be related to an autoimmune or paraneoplastic pathophysiology. AGA are originally formed by B cells, which are able to cross the blood-brain barrier. 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. The fact that GAD65 is anchored to synaptic vesicles indicates it may play a role in the packaging and/or release of GABA.
There are two main mechanisms that have been proposed for how AGA disrupts GABAergic pathways. 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. In AGA neurologic syndromes such as SPS, this immunopathogenic mechanism produces skeletal muscle hyperactivity by targeting the inhibitory neurons that control alpha-motor neurons. 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. 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. 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.
Oscillopsia related to downbeat nystagmus has been reported in AGA positive stiff person syndrome (SPS). Another AGA positive patient presented with horizontal gaze-evoked and rebound nystagmus. Patients with AGA positive subacute cerebellar ataxia have presented with nystagmus, including cases of periodic alternating nystagmus (PAN), downbeat nystagmus (DBN) with slow vertical saccades, and bilateral horizontal rotary jerks with abolished vertical saccades.
Impaired Vestibulo-ocular Reflex (VOR)
A patient with increased titers of AGA was reported to have opsoclonus in addition to DBN. Laroumagne et al reported a patient with AGA positive small cell lung cancer and opsoclonus-myoclonus syndrome.
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.
Autoimmune retinopathy in an AGA positive patient with SPS has been reported, demonstrating that subacute progressive loss of vision is possible due to AGA attacking the inner and outer plexiform layers of the retina.
The presence of AGA in the right clinical setting can be helpful in the diagnosis of these specific conditions. AGA can be detected using blood or cerebrospinal fluid (CSF) testing.
Most AGA positive neurologic syndromes are treated medically. GABA agonists are used to replenish the lack of GABA, but only partially reduce symptoms. 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.
Patients have seen variable success in symptomatic relief with combinations of immunomodulation and muscle relaxants, but there is no cure.
Clinicians should be aware of the neuro-ophthalmic presentations for AGA including SPS, cerebellar eye signs and ataxia, nystagmus (especially downbeat), LADA, and ophthalmoplegia.
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