Anti-GAD65 antibody-associated autoimmune encephalitis followed by Clostridium difficile colitis: A case report

Abstract

BACKGROUND

Anti-GAD65 antibody-associated autoimmune encephalitis is a rare immune-mediated disorder often presenting with refractory seizures. Diagnosis is established by antibody detection after exclusion of alternative causes. Immunosuppressive therapy is the main treatment but may increase susceptibility to opportunistic infections.

CASE SUMMARY

We present the first reported case of anti-GAD65 antibody-associated autoimmune encephalitis complicated by Clostridium difficile (C. difficile) colitis in a previously healthy 21-year-old woman. The patient initially presented with fever, seizures, and encephalopathy. Extensive workup for infectious and paraneoplastic encephalitis was negative. Elevated anti-GAD65 antibodies in both serum and cerebrospinal fluid are consistent with the suspected diagnosis. She received immunotherapy with intravenous methylprednisolone, immunoglobulin, and plasma exchange. During hospitalization, the patient developed C. difficile colitis, confirmed by sigmoidoscopy, and was treated with oral vancomycin. The onset of colitis coincided with immunosuppressive therapy, highlighting the vulnerability to opportunistic infections. Neurological recovery was gradual but incomplete at one-year follow-up.

CONCLUSION

Clinicians should maintain suspicion for gastrointestinal infections such as C. difficile in patients receiving immunosuppression for autoimmune encephalitis.

Key Words: Clostridioides difficile; Anti-GAD65 antibody; Autoimmune encephalitis; Colitis; Magnetic resonance imaging; Case report

Core Tip: We report the first case of anti-GAD65 autoimmune encephalitis in a 21-year-old woman, complicated by Clostridium difficile colitis during immunosuppressive therapy. Neurological recovery was incomplete at 1 year. Clinicians should watch for such infections to improve outcomes.

INTRODUCTION

Autoimmune encephalitis is a type of encephalitis mediated by autoimmune mechanisms, involving immune response against central nervous system (CNS) antigens[1]. Distinct subtypes of autoimmune encephalitis are classified based on the specific autoantibodies involved, each associated with different clinical manifestations and prognosis.

GAD65 is a 65-kDa enzyme responsible for catalyzing the conversion of glutamic acid to gamma aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the CNS[2]. The presence of serum anti-GAD65 antibodies has recently emerged as a biomarker for CNS autoimmune disorders, as well as polyendocrine autoimmunity, most commonly in association with type 1 diabetes mellitus[3,4]. Anti-GAD65 antibody-associated autoimmune encephalitis is usually characterized by acute or subacute seizures, psychiatric symptoms and cognitive dysfunction. Patients may exhibit isolated symptoms or a combination of clinical features[5-7].

Clostridium difficile (C. difficile) is a gram-positive, spore-forming, anaerobic bacterium and is primarily responsible for antibiotic-associated colitis[8]. Although traditionally considered a primary healthcare-associated infection, its incidence in community settings has been rising. C. difficile infection (CDI) ranges from asymptomatic colonization to severe conditions such as pseudomembranous colitis and toxic megacolon with septic shock, which can lead to fatal outcomes[9]. Disruption of the normal gut microbiota, often due to antibiotic use, is a key risk factor for CDI[10]. C. difficile produces toxins A and B, which lead to intestinal inflammation, epithelial damage, and systemic immune activation[11]. Emerging evidence suggests that CDI may not be confined to gastrointestinal pathology alone; it may also contribute to broader immune dysregulation[12,13]. This has prompted growing interest in the possible role of CDI in precipitating or modulating autoimmune and neuroinflammatory disorders, including autoimmune encephalitis.

In this case report, we present a 21-year-old woman with anti-GAD65 antibody encephalitis presenting with multiple seizures, who subsequently developed C. difficile colitis.

CASE PRESENTATION

Chief complaints

A previously healthy 21-year-old woman presented to the Emergent Department with acute onset of fever, confusion, and multiple seizures.

History of present illness

The patient arrived disoriented, with deficits in recognition of familiar individuals, including her mother.

History of past illness

The patient had no past illness.

Personal and family history

The patient had no personal or family history of illness.

Physical examination

The patient appeared confused and disoriented, with deficits in recognition of familiar individuals.

Laboratory examinations

Lumbar puncture revealed cerebrospinal fluid (CSF) with white blood cell count of 33/μL, protein 70 mg/dL, and glucose 98 mg/dL. Polymerase chain reaction of herpes simplex virus and oligoclonal bands were negative. The meningitis/encephalitis panel and microbial cultures showed no evidence of infection. Urine drug screen was unremarkable.

Serum anti-GAD65 antibodies were measured using enzyme-linked immunosorbent assay. Serum analysis revealed elevated anti-GAD65 antibody level of 123.9 IU/mL (normal value less than 5 IU/mL). CSF analysis also revealed a positive tilter of anti-GAD65 antibody using the same assay. Screening for other autoimmune encephalitis-related antibodies (including anti- NMDA, LGI-1, CASPR2, AMPA1, AMPA2, GlyR1, GABA-A, GABA-B, GFAP, MOG, AQP4, IgLON5, mGluR1, mGluR5, Ganglionic AchR, amphiphysin, Hu, SOX1) was also negative. No evidence of systemic autoimmune or paraneoplastic disorders was identified based on clinical assessment and imaging studies.

Imaging examinations

An urgent brain computed tomography (CT) was performed and showed no acute abnormalities. Brain magnetic resonance imaging (MRI) revealed extensive hyperintensities on fluid attenuated inversion recovery in the cortical and subcortical regions, most prominent in the bilateral temporal, frontal lobes, caudate, putamen, hypothalamus and medial dorsal thalamus, to a lesser extent parietal occipital cortex, superior cerebellum and dorsal pontine. There is no evidence of diffusion restriction or hemorrhage. However, subtle leptomeningeal enhancement is present. The initial MRI brain images when the patient was enrolled is illustrated in Figure 1.

Figure 1 The initial brain magnetic resonance images when the patient was enrolled. A and B: Axial fluid attenuated inversion recovery imaging; C: Axial diffusion weighted imaging; D: Axial apparent diffusion coefficient imaging; E: Sagittal fluid attenuated inversion recovery imaging; F: Axial susceptibility weighted imaging; G: Axial T₁-weighted imaging, pre-contrast; H: Gadolinium-enhanced axial T₁-weighted imaging.

CT of the chest, abdomen, and pelvis, as well as pelvic ultrasound, demonstrated no evidence of mass or malignancy.

FINAL DIAGNOSIS

Anti-GAD65 antibody-associated autoimmune encephalitis and C. difficile colitis.

TREATMENT

On day 4, her condition deteriorated rapidly, complicated by diffuse cerebral edema and signs of transtentorial herniation. High-dose intravenous methylprednisolone (IVMP) was given. She underwent emergency bilateral decompressive craniectomy and placement of an external ventricular drain. Intravenous immunoglobulin (IVIG) was administered for autoimmune encephalitis after 5 days of IVMP. The patient’s clinical status remained poor with minimal radiographic improvement.

In week 2, a flexible sigmoidoscopy revealed pseudomembranous colitis, for which the patient received oral vancomycin. Toxicologic screening, prompted by the discovery of vape pens near the patient, was negative for contaminants or substances of concern. However, the patient's hospital course was complicated by persistent, unprovoked seizures. Electroencephalography predominantly showed 14- to 20-Hz beta activity. Episodes of neuro-storming, characterized by full-body tremors and tachycardia, were managed with baclofen and propranolol. Plasma exchange was performed every other day for a total of 7 sessions with gradual neurological improvement observed over the course of treatment.

OUTCOME AND FOLLOW-UP

Repeat MRI in week 4 demonstrated stable to mildly improved findings. Given the evolving picture of autoimmune encephalitis, rituximab was also initiated as part of immunotherapy. The patient was discharged in stable condition and transferred to a local hospital for ongoing rehabilitation and supportive care. At that time, the patients demonstrated slow but consistent neurological recovery.

The patient was readmitted to our hospital in week 9 for planned bilateral cranioplasty. Subsequent imaging revealed hydrocephalus, for which a right occipital ventriculoperitoneal shunt was placed. Postoperatively, she developed a right-sided subdural hygroma and underwent burr hole evacuation in week 10.

Over the course of the one-year follow-up, the patient’s neurological status demonstrated significant improvement, although the long-term cognitive and functional prognosis remains guarded. Timeline of symptoms and management of this patient is illustrated in Figure 2.

Figure 2 Timeline of symptoms and management of the patient. CSF: Cerebrospinal fluid; IVIG: Intravenous immunoglobulin; IVMP: Intravenous methylprednisolone.

DISCUSSION

To the best of our knowledge, no previous case of anti-GAD65 autoimmune encephalitis complicated by C. difficile colitis has been clearly documented in the literature. Anti-GAD65 antibody-associated autoimmune encephalitis is a well-recognized subtype of autoimmune encephalitis, typically presenting with seizures, cognitive impairment, and behavioral changes[14]. The diagnosis in this patient was based on her clinical presentation, characteristic neuroimaging, negative infectious and paraneoplastic work up and detection of high-titer GAD65 antibodies in both serum and CSF, fulfilling the Graus criteria for autoimmune encephalitis[15].

The development of CDI in the subacute phase prompted consideration of the broader interaction between gut dysbiosis, systemic immune activation, and CNS autoimmunity; however, no direct relationship can be inferred from this case. While CDI is primarily considered a gastrointestinal disorder triggered by antibiotic-associated microbiota disruption, it also induces a robust inflammatory response through the release of toxins A and B[16]. These toxins can lead to epithelial damage, cytokine release, and systemic immune dysregulation[17]. Such systemic inflammation could theoretically aggravate or modulate ongoing neuroinflammation in autoimmune encephalitis[18]. In this case, CDI most likely developed as a complication of immunosuppressive therapy.

Recent studies suggest that the gut-brain-immune interaction plays a significant role in neurological diseases[19,20]. Disruption of gut homeostasis may influence CNS autoimmunity through multiple pathways, including molecular mimicry, immune cell trafficking, and cytokine-mediated signaling[21]. Though a direct causal link between CDI and autoimmune encephalitis has not been established, this case highlights a potential association worth further investigation.

Additionally, the immunosuppressive therapy used to treat autoimmune encephalitis, including high-dose IVMP, IVIG, and plasma exchange, likely increased the patient’s susceptibility to secondary infections such as CDI[22]. This reinforces the need for careful monitoring for opportunistic infections during immunotherapy in patients with autoimmune neurologic conditions.

Autoimmune encephalitis and CDI may have occurred coincidentally in this patient, and the available evidence does not support a direct immunopathological link. Further research is needed to investigate whether gastrointestinal infections such as CDI can influence the trajectory or severity of autoimmune encephalitis. In this case, serial measurements of anti-GAD65 antibody titers were not performed during follow-up, which limits our ability to assess dynamic changes in antibody levels in relation to clinical course.

Clinicians should remain vigilant for secondary infections in patients with autoimmune encephalitis, especially during or after immunosuppressive treatment. A thorough evaluation for gastrointestinal symptoms and early intervention may reduce complications and improve outcomes in these complex cases.

CONCLUSION

We report a rare case of anti-GAD65 antibody-associated autoimmune encephalitis in a young woman, followed by C. difficile colitis. The patient presented with seizures and encephalopathy, requiring immunotherapy and surgical intervention. Autoimmune Encephalitis may be complicated by infections such as CDI, especially under immunosuppressive treatment. This case highlights the potential link between gut inflammation and neuroimmune dysregulation. Neurologists should be alert to gastrointestinal symptoms and infection risks in autoimmune encephalitis patients, as early detection and treatment of complications are critical for improving outcomes.

ACKNOWLEDGEMENTS

We acknowledge the patient and her family for generously consenting to the publication of this case report.