GAD antibody-associated limbic encephalitis in a young woman with APECED

Abstract

The autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome is a genetic disorder caused by a mutation in the autoimmune regulator (AIRE) gene. Immune deficiency, hypoparathyroidism and Addison’s disease due to autoimmune dysfunction are the major clinical signs of APECED. We report on a 21-year-old female APECED patient with two inactivating mutations in the AIRE gene. She presented with sudden onset of periodic nausea. Adrenal insufficiency was diagnosed by means of the ACTH stimulation test. Despite initiation of hormone replacement therapy with hydrocortisone and fludrocortisone, nausea persisted and the patient developed cognitive deficits and a loss of interest which led to the diagnosis of depression. She was admitted to the psychiatric department for further diagnostic assessment. An EEG showed a focal epileptic pattern. Glutamic acid decarboxylase (GAD) antibodies, which had been negative eight years earlier, were now elevated in serum and in the cerebrospinal fluid. Oligoclonal bands were positive indicating an inflammatory process with intrathecal antibody production in the central nervous system (CNS). The periodic nausea was identified as dialeptic seizures, which clinically presented as gastrointestinal aura followed by episodes of reduced consciousness that occurred about 3–4 times per day. GAD antibody-associated limbic encephalitis (LE) was diagnosed. Besides antiepileptic therapy, an immunosuppressive treatment with corticosteroids was initiated followed by azathioprine. The presence of nausea and vomiting in endocrine patients with autoimmune disorders is indicative of adrenal insufficiency. However, our case report shows that episodic nausea may be a symptom of epileptic seizures due to GAD antibodies-associated LE in patients with APECED.Learning points:Episodic nausea cannot only be a sign of Addison’s disease, but can also be caused by epileptic seizures with gastrointestinal aura due to limbic encephalitis.GAD antibodies are not only found in diabetes mellitus type 1, but they are also associated with autoimmune limbic encephalitis and can appear over time.Limbic encephalitis can be another manifestation of autoimmune disease in patients with APECED/APS-1 that presents over the time course of the disease.

Cefepime‐induced encephalopathy: Neural mass modeling of triphasic wave‐like generalized periodic discharges with a high negative component (Tri‐HNC)

“…To explore other possible applications of neural mass modeling, we simulated the EEG of other disorders related to the dysfunction of GABAergic interneurons. We were able to generate a 0.5–1 Hz Tri‐HNC similar to that seen in some patients with glutamic acid decarboxylase antibody‐associated encephalitis, who showed 0.3–0.5 Hz Tri‐HNC (Fig. c).…”

Autoimmune encephalitis with psychiatric features in adults: historical evolution and prospective challenge

“…Stiff person autoimmune serum autoantibodies suffice, but for others, like autoimmune encephalitis, intrathecal GAD65 is required to confirm autoimmunity (Graus et al 2020 ). GAD65-positive encephalitis was diagnosed in a woman with depressive syndrome, cognitive impairment, and autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome diagnosed after detecting CSF antibodies (Kopczak et al 2017 ) and confirming their relevance to autoimmunity. Mood dysfunction and cognitive impairment are frequent symptoms in GAD65-positive encephalitis (Hansen et al 2016 ; Hansen et al 2018 ).…”

Genetic predisposition to autoimmune encephalitis and paraneoplastic neurological syndromes

“…Whereas APS type 1 (also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, APECED) is a rare monogenic disease caused by AIRE (autoimmune regulator gene, a transcription factor expressed in the thymic medulla) mutations, APS type 2 is a polygenic disorder associated with the HLA haplotypes DR3/4-DQ2/8 and non-HLA loci such as tyrosine-protein phosphatase nonreceptor type 22 (PTPN22, a negative regulator of T cell receptor signaling) and cytotoxic T lymphocyte protein 4 (CTLA4, an immune checkpoint that downregulates T cells) [44,45]. Interestingly, a single case of APS type 1 with co-occurring anti-GAD65 limbic encephalitis has been published [46], and two uncommon AIRE variants were reported in another patient from a different study [47]. Similarly, T1DM-related variants of CTLA4 and PTPN22 were detected in the same case series of patients with neurological syndromes and GAD65 autoantibodies [47].…”