Encephalopathy and adrenal insufficiency secondary to anti-glutamic acid decarboxylase antibodies

Dear Editor:

Although autoimmune encephalopathies are frequently described,¹ encephalopathies associated with autoimmune polyglandular syndromes with antibodies targeting glutamic acid decarboxylase (anti-GAD) are much rarer.² We present a case of encephalopathy associated with anti-GAD antibodies and adrenal insufficiency manifesting with akinetic mutism and non-convulsive status epilepticus.

Our patient was an 82-year-old woman with history of hypothyroidism. She was admitted due to a one-month history of unsteady gait, hyporexia, and weight loss. The week before admission, she presented disorientation and bradypsychia. Laboratory analysis detected hyponatraemia (118 mEq/L). Despite slow correction of sodium levels (123 mEq/L at 24 hours), she presented hallucinations, confusion, and finally severe akinetic mutism within hours. She also presented oropharyngeal candidiasis.

Contrast brain MRI and head CT scans showed no relevant alterations. A CSF analysis yielded no abnormal results. Subsequent follow-up blood analyses revealed no significant improvement in sodium levels, with concentrations ranging from 125 to 128 mEq/L despite restriction of water intake and administration of hypertonic saline. Osmolality was low in the serum (255 mOsm/kg) and normal in urine (550 mOsm/kg). Chest, abdomen, and pelvis CT and PET/CT scans revealed no abnormalities. EEG revealed non-convulsive status epilepticus. We started treatment with lacosamide and subsequently intravenous valproate, which improved EEG activity; akinetic mutism persisted, however. Suspecting autoimmune encephalopathy, we requested an immunological study including tests for antibodies associated with the disease, and started empirical treatment with intravenous methylprednisolone 1 g/day for 5 days. The patient showed a partial improvement, with fluctuation of the symptoms, and we subsequently started treatment with intravenous immunoglobulins dosed at 0.4 g/kg/day for 5 days, achieving significant improvements in her clinical status. Adrenal insufficiency, hypoglycaemia, and hyponatraemia improved after administration of hydrocortisone. The immunological study revealed high anti-GAD antibody titres (119; normal range, <10); vitamin B₁₂ deficiency (192 ng/L) and presence of anti–gastric parietal cell antibodies (titre of 1/80) were also detected. Gastroscopy revealed atrophic gastritis. Treatment led to clinical, electrophysiological, and EEG improvements; the patient continued to present disorientation and slightly decreased speech fluency. We administered 2 additional cycles of intravenous immunoglobulins; the patient has presented no further relapses after 6 months of follow-up.

Glutamic acid decarboxylase is expressed in the pancreatic islets and the central nervous system.³ One of its functions is to convert glutamate into gamma-aminobutyric acid (GABA). The neurotransmitter GABA has an inhibitory function in the central nervous system. Anti-GAD antibodies act mainly on the GAD65 isoform, which is directly involved in neurotransmission, inhibiting the conversion of glutamate into GABA.⁴ Anti-GAD antibodies have been associated with cerebellar ataxia, limbic encephalitis, stiff person syndrome, movement disorders, autoimmune epilepsy, and oculomotor alterations.^5–9 From an endocrinology viewpoint, anti-GAD antibodies have been associated with type 1 diabetes mellitus and autoimmune polyglandular syndromes. The exact mechanism by which a single antibody is involved in such a wide range of syndromes remains a mystery.⁴

Our patient presented autoimmune encephalitis, non-convulsive status epilepticus, and endocrine disorders compatible with a polyglandular syndrome: she presented oropharyngeal candidiasis and adrenal insufficiency, 2 of the diagnostic criteria for autoimmune polyglandular syndrome type 1, as well as mild pernicious anaemia.⁹ Although anti-GAD antibodies are most clearly associated with type 1 diabetes mellitus, our patient’s episodes of hypoglycaemia were attributed to adrenal insufficiency. Presence of anti-GAD antibodies has been reported in 41% of patients with autoimmune polyglandular syndrome type 1,¹⁰ and in only 12%-18% of patients with type 1 diabetes mellitus, but is not included as a diagnostic criterion of the syndrome.¹¹ In our case, mycosis may also have been caused by the systemic disorder our patient presented during the month before admission. In this scenario, presence of adrenal insufficiency and pernicious anaemia should be considered symptoms of autoimmune polyglandular syndrome type 4, which includes other autoimmune endocrine disorders not meeting diagnostic criteria for other autoimmune polyglandular syndromes; the literature also includes cases of autoimmune polyglandular syndrome type 4 associated with anti-GAD antibodies.⁹

Early diagnosis and treatment of autoimmune encephalitis is essential. According to the criteria established by Graus et al.,¹² diagnosis may be established in the absence of pathological brain MRI or CSF analysis findings if the patient presents compatible symptoms and epileptic seizures not explained by history of epilepsy, and once other causes have been ruled out. Diagnosis may be confirmed by slow or epileptiform EEG activity in both temporal lobes and presence of antineuronal antibodies.¹²

Presence of anti-GAD antibodies is sometimes the result of paraneoplastic processes.^13,14 In our patient, a thorough examination ruled out presence of tumours. Given the strong suspicion of autoimmune encephalopathy (with compatible clinical and electrophysiological signs) and having ruled out other causes, we started empirical treatment; diagnosis was subsequently confirmed by presence of high anti-GAD antibody titres.

Glucocorticoids and immunoglobulins constitute the treatment of choice for neurological disorders associated with anti-GAD antibodies³; in cases of high index of suspicion, administration should start before laboratory results are returned.

In conclusion, co-presence of heterogeneous neurological and endocrine symptoms may point to autoimmune disorders associated with anti-GAD antibodies. Early diagnosis and treatment with immune therapy greatly determine prognosis.

Funding

The authors have received no funding for this study.