Working Diagnosis:
Auto-immune encephalitis with anti-GAD65 antibody

Treatment:
The patient was treated with three anti-epileptic medications, plasmapheresis, intravenous immunoglobulin (IVIG), and intravenous steroids with transition to oral prednisone at discharge. She was started on iron and Vitamin B12 supplementation with a goal of Vitamin B12 level above 400. At discharge, she had cessation of focal status epilepticus and she was scheduled for close follow up with neurology for repeat MRI and antibody titers in 3 weeks.

Outcome:
This patient returned to college where she passed her final exams with honors and was able to resume regular physical activity. Neurology has weaned her prednisone and antiepileptic medications but she continues to receive regular IVIG infusions. The repeat MRI demonstrated stable findings without signs of pathologic signaling or volume loss of the temporal region. Her antibody titers remain positive for Anti-GAD65 Antibody. Her sister with Type 1 Diabetes Mellitus was also later identified as a carrier of Anti-GAD65 Antibody.

Author's Comments:
Autoimmune encephalitis (AIE) is an immune mediated inflammatory condition of the brain with many etiologies. The most common are herpes simplex virus, varicella zoster, and enterovirus. AIE primarily affects women more than men, usually in their teens to 50s. Symptoms evolve over weeks to months and include refractory seizures, neuropsychiatric disorders, and cognitive dysfunction. Diagnosis requires neuroimaging, EEG, lumbar puncture, and serology testing for biomarkers. If suspicious for AIE, testing for herpes simplex virus, varicella-zoster, and enterovirus is recommended as these are the most common causative agents, but if symptoms worsen, experts recommend obtaining NMDA-receptor Antibody testing and a malignancy evaluation. When one suspects AIE, early treatment with intravenous steroids, intravenous immunoglobulin (IVIG), and plasmapheresis to remove the Anti-GAD65 Antibodies improves outcomes. In an athlete with recurrent concussions, post-traumatic amnesia is a common finding. However, in the setting of acute and worsening memory changes, one must expand the differential to include more rare causes such as AIE.

Editor's Comments:
Anti-GAD65 antibodies are associated with multiple autoimmune conditions including stiff person syndrome, cerebellar ataxia, Type 1 Diabetes Mellitus, thyroiditis, and pernicious anemia. Encephalitis secondary to anti-GAD65 antibodies will almost always present with seizures, often refractory to treatment. Glutamic acid decarboxylase 65 is an enzyme in the central nervous system that is pivotal in producing GABA, the major inhibitory neurotransmitter. While much is unknown, the T-cell mediated immune response is thought to play an important role in development of autoimmune encephalitis secondary to anti-GAD65 antibodies.
Autoimmune Encephalitis (AIE) due to anti-GAD65 antibody is exceptionally rare, however, it is associated with high morbidity including severe, permanent neurologic impairment, coma, and even death. Recognition must be fast because delays in definitive care with IVIG, high dose steroids, and even plasmapheresis increases the risk of permanent disability. It is notable that this athlete was able to return to high level academic and athletic performance because even with prompt identification and treatment, most patients see only modest improvement and many will continue to have seizures and some type of cognitive impairment. Multiple studies have shown that only 18-20% of patients with AIE due to anti-GAD65 antibodies are seizure-free after treatment and as many as 70% of them continue to have some form of cognitive disturbance.

This case underscores the importance of keeping a wide differential and paying attention to the full clinical picture. It could be easy to evaluate this athlete with a history of recurrent concussion and attribute her mental status changes to previous head injuries. However, the rapid deterioration is what makes this case stand out and thanks to the high level of suspicion of her care team, she has been able to return to full activity and academic performance.

References:
Abbound H, Titulaer MJ. Autoimmune (including paraneoplastic encephalitis: Management. UpToDate. Updated March 11, 2025. Accessed April 22, 2025. https://www.uptodate.com/contents/autoimmune-including-paraneoplastic-encephalitis-management?topicRef=15759&source=see_link#H516436976.
Dalmau J, Rosenfeld M. Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis. UpToDate. Updated March 28, 2025. Accessed April 22, 2025. https://www.uptodate.com/contents/autoimmune-including-paraneoplastic-encephalitis-clinical-features-and-diagnosis#references.
Diagnosis and Management of Autoimmune Encephalitis. Cleveland Clinic. Accessed April 22, 2025. https://my.clevelandclinic.org/departments/neurological/depts/multiple-sclerosis/ms-approaches/diagnosis-and-management-of-autoimmune-encephalitis.
Dubey D, et al. Autoimmune encephalopathy epidemiology and a comparison to infectious encephalitis. Annals of Neurology. 2018;83:166. doi: 10.1002/ana.25131
Gole S, Anand A. Autoimmune Encephalitis. StatPearls. Updated January 2, 2023. Accessed April 22, 2025. https://www.ncbi.nlm.nih.gov/books/NBK578203/.
Venkatesan A, Geocadin RG. Diagnosis and management of acute encephalitis. Neurol Clin Practice. 2014; 4(3): 206-215. doi: 10.1212/CPJ.0000000000000036.

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