Glutamic acid decarboxylase (GAD) is an enzyme that converts glutamate, the major excitatory neurotransmitter in the central nervous system, into gamma-aminobutyric acid (GABA). Autoantibodies against this enzyme (anti-GAD antibodies) are involved in many clinical syndromes, including cerebellar ataxia, stiff person syndrome (SPS), and insulin-dependent diabetes mellitus. These diseases are collectively referred to as GAD antibody spectrum disorders (GAD-SD)3).
There are two isoforms of GAD: GAD67 and GAD65. GAD67 is distributed throughout the cytoplasm, whereas GAD65 attaches to the membrane of synaptic vesicles and localizes to nerve terminals. GAD65 is encoded by the GAD2 gene (chromosome 10p12.1) and is responsible for the rapid synthesis of GABA required for synaptic transmission2).
The positivity rate of anti-GAD antibodies is 1.7% in the general population and 3.7–4.7% in newly diagnosed type 2 diabetes patients (ADOPT study). High titers of anti-GAD antibodies are found in approximately 80% of type 1 diabetes patients and about 60% of SPS patients3). The prevalence of SPS is estimated at 1–2 per million people2).
The following neuro-ophthalmological findings have been reported in anti-GAD antibody-positive patients:
GAD is also expressed in pancreatic beta cells. Approximately 80% of patients with type 1 diabetes are positive for anti-GAD antibodies, and 30–60% of patients with GAD-SD have comorbid type 1 diabetes3). However, among patients with type 1 diabetes, only about 1 in 10,000 develop SPS, making it rare.
The neuro-ophthalmic symptoms of anti-GAD antibody syndrome are diverse.
SPS-related systemic symptoms include trunk and limb muscle rigidity, painful muscle spasms, and gait disturbance4).
Nystagmus
Downbeat nystagmus (DBN): Reported in SPS patients along with oscillopsia. It is the most representative type of nystagmus.
Gaze-evoked nystagmus and rebound nystagmus: Nystagmus induced by horizontal gaze.
Periodic alternating nystagmus (PAN): Reported in patients with subacute cerebellar ataxia.
Bilateral horizontal rotatory jerk nystagmus: Accompanied by loss of vertical saccades.
Ophthalmoplegia and retinopathy
Bilateral ophthalmoplegia: In a case with mixed thymoma, horizontal and upward eye movements were almost completely lost.
Vestibulo-ocular reflex (VOR) impairment: Bilateral horizontal VOR impairment or prolonged VOR.
Autoimmune retinopathy: Degeneration of the inner and outer plexiform layers has been reported in SPS patients.
Opsoclonus: Multidirectional saccadic eye movements in addition to downbeat nystagmus.
The etiology of anti-GAD antibody syndrome is not fully understood, but it is thought to be related to autoimmune or paraneoplastic conditions.
SPS has the following three subtypes 4).
In a report of 20 SPS patients, 75% had other autoimmune diseases (hypothyroidism in 11, IDDM in 7, myasthenia gravis in 2, Sjögren’s syndrome in 2, etc.) 5).
Furthermore, 95% (19/20) had serological evidence of gluten sensitivity, and 30% had confirmed celiac disease 5).
The diagnosis of anti-GAD antibody syndrome is made by combining clinical symptoms, predisposing risk factors, and laboratory test results.
The new diagnostic criteria proposed by Nicholas H et al. in 2023 consist of the following five items2).
| Item | Description |
|---|---|
| Clinical symptoms | Stiffness of the trunk and limbs, or spasms triggered by sound, sensation, or emotion |
| Clinical signs | Increased muscle tone, synchronous rigidity of paraspinal and rectus abdominis muscles, lumbar hyperlordosis |
| Serum findings | High-titer anti-GAD65 antibodies (serum/CSF), or anti-GlyR/anti-amphiphysin antibodies |
Electrophysiological findings (EMG showing incomplete relaxation of paraspinal muscles, exaggerated response to sound stimuli, co-contraction of antagonist muscles) and exclusion diagnosis are added for comprehensive evaluation.
Diseases presenting with eye movement disorders and diplopia that require differentiation include myasthenia gravis, Wernicke encephalopathy, progressive supranuclear palsy, and multiple sclerosis.
Treatment for anti-GAD antibody syndrome combines symptomatic therapy and immunomodulatory therapy. There is no curative treatment.
Symptomatic Therapy
Benzodiazepines: Enhance GABAergic pathways and form the basis of symptomatic treatment for SPS2).
Baclofen: A GABA_B agonist. May be highly effective for vertical nystagmus and periodic alternating nystagmus. Prescription example: Gabalon tablets (5 mg) 3–6 tablets/day, divided into 1–3 doses.
Dantrolene and Tizanidine: Used as muscle relaxants in combination therapy5).
Gabapentin: Expected to provide additional symptom relief5).
Prism glasses: Used to reduce oscillopsia caused by gaze-dependent nystagmus.
Immunomodulatory Therapy
IVIG: Most widely used and proven effective 2). High dose 0.4 g/kg × 7 days reported effective 2).
Plasmapheresis: Aimed at removing pathogenic anti-GAD antibodies.
Steroid pulse therapy: Methylprednisolone 500 mg/day × 6 days 3).
Rituximab: Considered as an alternative for IVIG-intolerant cases 2).
Mycophenolate mofetil: Used for long-term management as an oral immunosuppressant5).
Yang et al. (2025) reported that a patient with anti-GAD65 antibody-related SPS complicated by APS-2 received additional IVIG (0.4 g/kg × 7 days), with abdominal muscle spasms disappearing on day 3 and marked improvement in truncal rigidity on day 72). No symptom recurrence was observed at the 1-month follow-up.
In contrast, Hadjivassiliou et al. (2021) reported limited long-term efficacy of IVIG in 20 SPS cases (used in 9 cases, long-term efficacy in only 1 case). Oral immunosuppressants (mycophenolate mofetil) were reported to be more effective5).
Baclofen (GABA_B agonist) may be highly effective for vertical nystagmus, periodic alternating nystagmus, and superimposed saccadic intrusions. A prescription example is Gabalon tablets (5 mg) 3–6 tablets/day. Prism glasses may also be tried to reduce oscillopsia.
Two main theories have been proposed for the mechanism by which anti-GAD antibodies inhibit GABAergic pathways.
One theory is that anti-GAD antibodies attack the GAD enzyme, inhibiting GABA synthesis in the central nervous system (CNS). The activity of anti-GAD IgG in vitro supports this mechanism.
The theory is that anti-GAD antibodies interfere with GABA release from synaptic vesicles. Studies in GAD65-deficient mice showed that GABA release is maintained under low-frequency stimulation, but defects in GABA release become apparent under sustained stimulation. This suggests that the lack of GAD65 impairs the mobilization and replenishment of synaptic vesicles during periods of high neurotransmitter turnover.
Anti-GAD antibodies recognize different epitopes in type 1 diabetes and SPS3).
This difference in recognition patterns is considered one of the reasons why the same anti-GAD antibody presents different clinical features.
All cerebellar outputs are inhibitory. Cerebellar damage due to immunological mechanisms disrupts this inhibitory output regulation, leading to a hyperexcitable state in the CNS 5). In immune-mediated cerebellar ataxia, this hyperexcitability is more pronounced than in hereditary or degenerative forms, manifesting clinically as stiffness and spasms in SPS and cortical myoclonus.
The cerebellum is rich in GABAergic neurons (Purkinje cells, Golgi cells). Impairment of GABA production and release by anti-GAD antibodies selectively affects these cells, causing cerebellar atrophy and oculomotor dysfunction.
Hadjivassiliou et al. (2021) found serological evidence of gluten sensitivity in 19 of 20 SPS patients (95%), and confirmed celiac disease in 6 patients. A gluten-free diet (GFD) improved symptoms in 12/19 patients, and 7 patients were able to achieve long-term management with GFD alone 5). It has been suggested that gluten sensitivity may drive the immune response in anti-GAD-related diseases.
Sano et al. (2025) reported a case of GAD-SD and type 1 diabetes after allogeneic hematopoietic stem cell transplantation. Abnormal immune reconstitution after transplantation may have triggered an autoimmune response. To date, 6 cases of GAD-SD after HCT have been reported, with onset ranging from 10 months to 4 years3).
Sibilla et al. (2025) reported the first case of insulinoma complicating anti-GAD antibody-positive SPS (type 1). Neurological symptoms improved partially and transiently after tumor resection4).
Efgartigimod (FcRn inhibitor) has been reported to be effective in patients with SPS and myasthenia gravis, and is attracting attention as a new treatment candidate for anti-GAD-related diseases2). Autologous hematopoietic stem cell transplantation has also been reported as an option for refractory cases5).
