Autoimmune polyendocrine syndromes (APS) is rare clinical conditions caused by immune tolerance disruption, leading to impaired function of multiple endocrine glands and ultimately causing functional damage. APS can be classified into three main types: APS-1, APS-2, and X-linked immunodysregulation, polyendocrinopathy, and enteropathy (IPEX) (1). APS-1 is an autosomal recessive disorder caused by mutations in the autoimmune regulator gene (AIRE). APS-2 is a complex genetic disease involving multiple genes, with genetic susceptibility associated with human leukocyte antigen (HLA), major histocompatibility complex-related gene A, lymphotyrosine phosphatase, and cytotoxic T cell-associated antigen 4 gene polymorphisms. IPEX is an X-linked recessive disorder caused by mutations in the JM2 gene, located in the centromere region of the X chromosome (Xq11.3-q13.3), later known as forkhead box protein 3 (FOXP3). IPEX affects only males, often presenting with refractory diarrhea, diabetes, eczema, hemolytic anemia, thyroiditis, and severe infections within a few months of birth (2, 3).

Glutamic acid decarboxylase (GAD) is an intracellular enzyme expressed in neurons and insulin-secreting pancreatic β cells. Its physiological function is the decarboxylation of glutamate to gamma-aminobutyric acid (GABA) (4, 5). Previous studies have shown that GAD65 is associated with various diseases, including stiff person syndrome (SPS) (6–8).

SPS was first reported by Woltman and Moersch in 1956, who described 14 patients with this rare neuroimmune disease characterized by progressive axial muscle stiffness and painful muscle spasms (9). The pathophysiology of SPS is not completely understood but is believed to involve anti-glutamic acid decarboxylase (anti-GAD) antibodies. High serum anti-GAD65 antibody titers (>1:10,000 by ELISA) are found in up to 80% of patients (10, 11). Treatment typically involves GABAergic drugs such as benzodiazepines, corticosteroids, plasmapheresis, and intravenous immune globulin (12).

The incidence of SPS is extremely low. According to a survey by Hadavi et al., the incidence in the general population of the United Kingdom is about 1 in 1,000,000, with females affected approximately twice as often as males (13). The incidence rate in Asia and other regions has not been reported.

APS with anti-GAD65 antibody-associated SPS are clinically rare, and almost no reports of their coexistence have been found in PubMed. Here, we present a case of APS-2 with anti-GAD65 antibody-associated SPS and review relevant literature to enhance clinical awareness of this condition.

A 22-year-old man was admitted to the hospital due to recurrent episodes of consciousness loss for 10 years, which occurred twice in the past week. Ten years ago, the patient was discovered by family members lying in bed and panting heavily while sleeping. At that time, he couldn’t breathe properly and was frothing at the mouth. After 2-3 minutes, the symptoms resolved on their own. The patient was diagnosed with epilepsy at a local hospital and treated accordingly, though specific details are unknown. One month later, he experienced another loss of consciousness, accompanied by involuntary limb convulsions, upward eyeball movements, and frothing at the mouth, which improved after 3-4 minutes. These episodes recurred multiple times, leading to a diagnosis of epilepsy at another hospital. He was prescribed lamotrigine (100mg in the morning), clonazepam (4mg in the evening), and topiramate (100mg in the morning and evening). The seizures varied, predominantly presenting as minor and absent seizures, with fewer major seizures and decreasing intervals between episodes (from once a month to once every half month), including two seizures in the past week. For further diagnosis and treatment, he sought medical attention at our department, planning to address epilepsy on March 20, 2024.

During the disease course, the patient has experienced consciousness disorders, involuntary limb shaking, frothing at the mouth, trunk stiffness leading to a hunchback ( Figure 1A ), and lower back and abdominal pain. Emotional tension often triggers involuntary abdominal muscle contractions ( Supplementary Video 1 ), which disappear during sleep. His diet, sleep, and urination remain normal, though he frequently experiences diarrhea.

APS-2 is a disease that involves multiple systems and is influenced by genetic and environmental factors. Its course of disease progression varies greatly, with diverse manifestations, and its severity is influenced by multiple factors (14). Currently, there is no effective cure for APS-2, and treatment mainly relies on hormone replacement and symptomatic supportive treatment (15).

GAD65 is one of the two subtypes of GAD, encoded by the GAD2 gene on chromosome 10 (10p12.1). It is primarily expressed at the post-natal stage and is responsible for the rapid synthesis of GABA required for synaptic transmission (16, 17). GAD65 is mainly located in the pre-synaptic end of nerve terminals, where it exists in its inactive form, unbound to the pyridoxal phosphate (PLP) cofactor. It can quickly switch from the inactive to the active form, allowing the rapid synthesis of GABA when needed (18, 19). GAD65 antibodies can cause various neurological syndromes, including borderline encephalitis, SPS, refractory epilepsy, and cerebellar ataxia (20, 21). Additionally, anti-GAD65-positive patients can exhibit myasthenia gravis, thyroiditis, pernicious anemia, vitiligo, type 1 diabetes, and other diseases (22–26).

This patient, a young male, presented with epilepsy symptoms and had comorbid conditions, including type 1 diabetes, vitiligo, and autoimmune thyroid disease, indicating the presence of autoimmune and endocrine system diseases. APS can be diagnosed when a patient exhibits dysfunction in two or more endocrine glands (27). APS-2 is the most common type, typically occurring in adults with a male-to-female ratio of 1:3 (28–30). The diagnosis of APS-2 requires the presence of two out of the following three autoimmune diseases: Addison’s disease, AITD, and type 1 diabetes (31). AITD combined with type 1 diabetes is the most common combination, accounting for about 60% of cases. This patient presented with type 1 diabetes and autoimmune thyroid disease, meeting the criteria for APS-2. Whole exome gene testing did not reveal any SNVs or CNVs highly correlated with APS and with sufficient evidence of pathogenicity. As a result, the patient was eventually recognized as having the APS-2 (AITD, type 1 diabetes) subtype of APS. Upon admission, the CSF anti-GAD65 antibody test was positive, and there were no significant abnormalities in tumor markers. The patient exhibited a stiff trunk, involuntary abdominal muscle contractions triggered by emotional tension, and symptoms that disappeared during sleep. Electromyography (EMG) showed sustained normal action potentials in trunk muscles at rest and increased motor units after passive exercise. These findings are consistent with the new diagnostic criteria for SPS proposed by Nicholas H et al. (32) in 2023, which emphasize the importance of antibodies in disease diagnosis. The diagnostic criteria for SPS are as follows: 1. Symptoms meeting one of the following criteria: a. Stiffness involving central trunk muscles and/or limb muscles; b. Episodic spasms induced by sound, sensation, or emotion involving mid-axial trunk muscles and/or limb muscles. 2. Signs meeting one of the following criteria: a. Increased muscle tone (trunk or extremities); b. Synchronized stiffness of paraspinal and rectus abdominis muscles; c. Lumbar lordosis deformity. 3. Serology meeting one of the following criteria: a. High titer anti-GAD65 antibody in serum or positive anti-GAD antibody in CSF; b. Positive serum and/or CSF anti-GlyR antibody; c. Positive serum and/or CSF anti-amphiphysin antibodies; 4. Electrophysiology meeting one of the following criteria: a. Needle pole electromyography indicating improper relaxation of paraspinal muscles; b. Surface EMG recording overreaction to sound or external sensations; c. Co-contraction of agonist-antagonist muscles detected by EMG. 5. Exclusion of other diagnoses. The patient met all the diagnostic criteria for SPS. Thus, the comprehensive diagnosis was anti-GAD65 antibody-associated SPS and APS-2 (AITD, type 1 diabetes). However, after intravenous injection of 10 mg diazepam, the effect was slow, and the sustained action potential in the resting state did not completely disappear after 5 minutes. This might be due to decreased sensitivity to diazepam from the long-term use of the antiepileptic drug clonazepam.

Although APS is called an autoimmune polyendocrine syndrome, non-endocrine organs are often affected, such as hair loss, vitiligo, and celiac disease (27). These findings are consistent with the patient’s symptoms, which included hair loss, vitiligo, and chronic diarrhea. Additionally, the patient’s low testosterone level could be attributed to testicular dysfunction caused by APS (2). The patient was admitted to the hospital due to epilepsy, and conventional antiepileptic treatment was ineffective. It is believed that the refractory epilepsy was caused by positive anti-GAD65 antibodies (33). The patient’s chronic hypokalemia is likely due to prolonged use of steroid drugs, which increase potassium ion excretion in the distal renal tubules and collecting ducts (34). It is also noteworthy that this patient had eosinophilia. While eosinophilia is more common in IPEX, its specific pathogenesis remains unclear, and it has not been previously described in APS-2.

There is currently no unified treatment plan for diseases related to positive anti-GAD65 antibodies. SPS is a progressive disease that, if not treated promptly, can lead to severe disability and even death (35). Misdiagnosis is common due to insufficient understanding by clinicians, often being mistaken for dystonia, somatic conversion disorders, motor neuron diseases, and other conditions, resulting in delayed diagnosis and treatment (36). The treatment of SPS is multifaceted, typically requiring a combination of medication (symptomatic treatment and immunotherapy) and non-pharmacological interventions. Benzodiazepine drugs, which enhance γ-GABAergic neural pathways, can improve muscle stiffness and spasms, making them the cornerstone of symptomatic treatment for SPS. Other similar drugs, such as baclofen, tizanidine, and botulinum toxin, can also be used for symptomatic treatment of SPS. Non-pharmacological interventions, including selective physical therapy (such as stretching and gait training), hyperthermia, and spinal pressure manipulation, are also effective measures for SPS treatment (37).

If symptomatic treatment and non-pharmacological interventions are ineffective, immunotherapy should be considered. Immunotherapy generally involves immunosuppressants, plasma exchange, or immunoglobulins (38). However, the optimal timing and drug selection for its intervention are not yet clear. IVIG is the most widely used and proven effective measure (38–40), with high-dose IVIG providing a stronger therapeutic response than low-dose regimens (41). Considering that the patient was already taking prednisone acetate 10mg and clonazepam 4mg, and taking into account our team’s experience with the medication and relevant studies (42–44), it was decided to treat the patient with IVIG 0.4 mg/kg for 7 days. For individuals who cannot tolerate IVIG, rituximab may be an effective alternative (45). Other immunotherapy methods, such as plasma exchange (46) and autologous hematopoietic stem cell transplantation (47), may also help improve SPS symptoms. In addition, a recent study on stiff-person syndrome with comorbid myasthenia gravis found that efgartigimod may be a candidate for the treatment of SPS and other autoantibody-mediated neurological disorders, and the research evidence provides another possibility for treating patients with anti-GAD-related disorders (48).

In this case, the patient continued to experience lower back and abdominal pain, involuntary abdominal muscle contractions, and limb stiffness despite treatment with clonazepam and steroid drugs. These symptoms significantly improved following IVIG shock therapy. This suggests that treatment with IVIG may contribute to improved outcomes in cases of APS-2 combined with anti-GAD65 antibody-related SPS. Additionally, this report is the first to note that APS-2 patients can exhibit eosinophilia, expanding the known clinical phenotype of APS-2.

However, certain limitations exist in the case data. This report highlights eosinophilia as a new phenotype of APS-2 but does not establish a direct link between this phenotype and the anti-GAD65 antibody. Future research will explore the relationship between eosinophilia and anti-GAD65 antibodies. Additionally, the patient was discharged from the hospital within a short period of time after receiving 1 time IVIG treatment, after which only remote follow-up and observation were performed, and the clinical information obtained may have been biased. At a later stage, the patient may be hospitalized for observation and, if necessary, repeat immunomodulatory treatment, according to the patient’s wishes. This will allow a more comprehensive assessment of the response and long-term prognosis of the patient after multiple IVIG treatments.

In conclusion, both APS and SPS are rare clinical conditions, and their comorbidity is even rarer. Symptoms vary, the condition is often insidious, and misdiagnosis or missed diagnosis is common. Treatment regimens are complex. This article presents a rare case of APS-2 with a novel clinical phenotype combined with anti-GAD65 antibody-associated SPS. After additional treatment with IVIG, the patient’s recovery was still satisfactory, and relevant literature is reviewed, which is beneficial for improving the understanding of the disease by clinical doctors.