Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme for the synthesis of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Antibodies against glutamic acid decarboxylase (GAD) are associated with various neurologic conditions described in patients, including stiff person syndrome, cerebellar ataxia, refractory epilepsy, and limbic and extra limbic encephalitis. While there are few case reports and research on anti-GAD65 antibody-associated encephalitis in adults, such cases are extremely rare in pediatric cases.

For the first time, we report a case of anti-GAD65-positive autoimmune encephalitis associated with autoimmune polyendocrine syndrome (APS) type II. We reviewed previously published pediatric cases of anti-GAD65 autoimmune encephalitis to discuss their clinical features, laboratory tests, imaging findings, EEG patterns, and prognosis.

An 8-year-old, male child presented to the outpatient department after experiencing generalized convulsions for twenty days. The child was admitted for epilepsy and had received oral sodium valproate (500 mg/day) in another center, where investigations such as USG abdomen and MRI brain revealed no abnormalities, however, had abnormal EEG with diffuse mixed activity in the left anterior middle prefrontal temporal region. On the follow-up day, a repeat blood test showed a very low serum drug concentration of sodium valproate hence the dose was increased to 750 mg/day. Then, the child experienced adverse effects including increased sleep, thirst, and poor appetite, prompting the parents to discontinue the medication. A repeat MRI showed increased signals on FLAIR sequences in the right hippocampus hence admitted for further management. The child's past history included a diagnosis of hypothyroidism at the age of 4, and receiving levothyroxine 75 mcg once daily. His parents are healthy with no history of any similar neurological, autoimmune, or genetic diseases, but his uncle had a history of epilepsy. At presentation, he had uncontrolled blood glucose levels with elevated HbA1c levels. Additionally, the serum and CSF autoantibodies were positive against the anti-GAD65 antibody with the titer of 1:100 and 1:32 respectively. The patient was managed with a mixed type of insulin regimen and received first-line immunotherapy (intravenous immunoglobulin, IVIG) for five consecutive days, followed by oral prednisone and sodium valproate as an antiepileptic drug. Upon achieving a favorable clinical outcome, the patient was discharged with oral medications.

Among the 15 pediatric patients reported in this literature, nine presented with limbic encephalitis (LE), three with extralimbic encephalitis (ELE), and three with a combination of limbic and extralimbic encephalitis. Most of these cases exhibited T2-W FLAIR hyperintensities primarily localized to the temporal lobes in the early phase, progressing to hippocampal sclerosis/atrophy in the later phase on MRI. EEG commonly showed slow or spike waves on frontotemporal lobes with epileptic discharges. Prognostic factors varied among patients, with some experiencing persistent refractory seizures, type-1 diabetes mellitus (T1DM), persistent memory impairment, persistent disability requiring full assistance, and, in severe cases, death.

Our findings suggest that anti-GAD65 antibody-positive autoimmune encephalitis patients may concurrently present with other APS. Our unique case presented with multiple endocrine syndromes and represents the first reported occurrence in children. Early diagnosis and timely initiation of immunotherapy are crucial for improving clinical symptoms and reducing the likelihood of relapses or permanent disabilities. Therefore, emphasis should be placed on prompt diagnosis and appropriate treatment implementation to achieve better patient outcomes.

Since the discovery of the coronavirus disease 2019 outbreak, a vast majority of studies have been carried out that confirmed the worst outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with preexisting health conditions, including diabetes, obesity, hypertension, cancer, and cardiovascular diseases. Likewise, diabetes itself is one of the leading causes of global public health concerns that impose a heavy global burden on public health as well as socio-economic development. Both diabetes and SARS-CoV-2 infection have their independent ability to induce the pathogenesis and severity of multi-system organ failure, while the co-existence of these two culprits can accelerate the rate of disease progression and magnify the severity of the disease. However, the exact pathophysiology of multi-system organ failure in diabetic patients after SARS-CoV-2 infection is still obscure. This review summarized the organ-specific possible molecular mechanisms of SARS-CoV-2 and diabetes-induced pathophysiology of several diseases of multiple organs, including the lungs, heart, kidneys, brain, eyes, gastrointestinal system, and bones, and sub-sequent manifestation of multi-system organ failure.

A 16-year-old female patient presented with subacute onset of headaches, changes in acute mental status, expressive aphasia and auditory hallucinations. New oedema and enhancement of the temporal lobe were seen on brain MRI, with correlating subclinical seizures seen on electroencephalogram. Simultaneously, our patient was diagnosed with new-onset type 1 diabetes mellitus, with positive anti-glutamic acid decarboxylase (anti-GAD-65) antibodies in the serum. Cerebrospinal fluid studies remained negative, including anti-GAD-65 antibodies. Clinical remission was achieved with corticosteroids and intravenous immunoglobulins.

Diabetes mellitus (DM) is a well-known risk factor for cognitive dysfunction in aged populations. However, there are inconsistent reports about impaired fasting glucose or prediabetes as an independent risk factor for cognitive function. Glutamic acid decarboxylase 65 (GAD65) is the key enzyme responsible for γ-aminobutyric acid synthesis in the central nervous system. Antibodies against GAD65 (GAD65Abs) are not only detected in approximately 80% of early-onset type 1 DM, but also linked to several neurological disorders.

This study aims to investigate the association between GAD65Ab titer levels and cognitive performance. In addition, we assessed the effect of GAD65Ab on cognitive function in adults with normal fasting glucose, prediabetes and DM.

A total of 328 subjects aged 49.10 ± 5.72 years were enrolled from the Third Health and Nutrition Examination Survey dataset. Cognitive performance was assessed by three computerized neurobehavioral tests, including the serial digit learning test, simple reaction time test (SRTT) and symbol-digit substitution test (SDST).

Subjects with higher GAD65Ab titers had significantly poorer cognitive function in the SRTT and SDST (P < 0.05). Additionally, GAD65Ab was associated with cognitive decline in non-diabetic adults after adjusting for a number of relevant variables (P < 0.05 in both SRTT and SDST).

These results indicate that GAD65Ab may be a potential marker for cognitive impairment in non-diabetic adults.