Stiff Person Syndrome and Encephalitis with GAD Antibodies with Severe Anterograde Amnesia in an Adolescent: A Case Study and Literature Review

Antiglutamic acid decarboxylase (GAD65) encephalitis is rare and few pediatric cases have been reported, with variable clinical presentations. A 14-year-old female adolescent was managed in our department. She had been treated for several months for drug-resistant temporal lobe epilepsy and gradually presented major anterograde amnesia with confusion. Upon her arrival at the University Hospital Centre, she showed a classical form of stiff person syndrome. The brain magnetic resonance imaging showed bitemporal hyperintensities and hypertrophy of the amygdala. The blood and cerebrospinal fluid were positive for GAD65 antibodies. At 2 years of immunosuppressive treatment and rehabilitation, the course showed partial improvement of the memory and neuropsychiatric impairment, and epilepsy that continued to be active. GAD65 antibodies are associated with various neurological syndromes, and this presentation combining limbic encephalitis and stiff person syndrome is the first pediatric form published to date; there are also few cases described in adults.

Clinical Heterogeneity in Acute Symptomatic Seizures due to Autoimmune Encephalitis Related to GAD65 Antibodies

<b><i>Introduction:</i></b> This study aimed to explore the diversity and clinical features of acute symptomatic seizures due to autoimmune encephalitis related to anti-glutamate decarboxylase (GAD) 65 antibodies. <b><i>Methods:</i></b> Clinical data of a series of 6 patients positive for anti-GAD65 antibodies were retrospectively analyzed. <b><i>Results:</i></b> Five of the patients were male and 1 was a female, with a median age of 44.1 years (range 18–70 years). Seizure forms were varied in 6 patients when they were admitted to the hospital: 3 cases of seizures only and 3 accompanied by other symptoms, such as mental disorder, cognitive impairment, cerebellar ataxia, and ocular movement disorder. Three patients (50%) had coexisting systemic autoimmune diseases, including diabetes mellitus, vitiligo, and hyperthyroidism. Five patients (83%) had abnormal brain MRI findings. They were all treated by immunotherapy, 5 of 6 patients improved significantly but relapsed after withdrawing methylprednisolone, and 1 patient got deteriorated. None of them were diagnosed with tumors. <b><i>Conclusions:</i></b> Clinical features of acute symptomatic seizures related to GAD65 antibodies are diverse, and early and continuous immunotherapy is necessary for patients.

Case Report: Autoimmune Encephalitis Associated With Anti-glutamic Acid Decarboxylase Antibodies: A Pediatric Case Series

Background: 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 extralimbic encephalitis. There have been some case reports and investigations regarding anti-GAD65 antibody-associated encephalitis in adult populations, but pediatric cases are rare. We retrospectively analyzed the clinical data of three anti-GAD65 antibody-positive patients to explore the diversity and clinical features of anti-GAD65 antibody-associated pediatric autoimmune encephalitis.Methods: The clinical data of a series of three patients positive for anti-GAD65 antibody were retrospectively analyzed. GAD65 antibodies were determined in serum and CSF using a cell-based assay.Results: All three patients were female, and the onset ages were 4 years and 9 months, 6 years, and 16 years old. Their clinical phenotypes included autoimmune limbic encephalitis, extralimbic encephalitis, and encephalitis combining limbic and extralimbic encephalitis. The clinical symptoms included seizures, memory deficits, drowsiness, dysautonomia, and headache. All patients had abnormal carinal MRI and EEG. All patients received immunotherapy and had transiently good responsiveness, but one patient then experienced relapse. In follow-up, one patient with extralimbic encephalitis recovered completely, while two patients with limbic involvement had poor outcomes with refractory focal epilepsy.Conclusion: In addition to limbic encephalitis, extralimbic encephalitis is also an important phenotype in patients who are positive for anti-GAD65 antibodies. Early diagnosis and immunotherapy can improve the symptoms. However, patients with limbic encephalitis often have refractory epilepsy in the chronic phase and have a poor long-term outcome.

Clinical spectrum of high-titre GAD65 antibodies

ObjectiveTo determine clinical manifestations, immunotherapy responsiveness and outcomes of glutamic acid decarboxylase-65 (GAD65) neurological autoimmunity.MethodsWe identified 323 Mayo Clinic patients with high-titre (>20 nmol/L in serum) GAD65 antibodies out of 380 514 submitted anti-GAD65 samples (2003–2018). Patients classified as having GAD65 neurological autoimmunity after chart review were analysed to determine disease manifestations, immunotherapy responsiveness and predictors of poor outcome (modified Rankin score >2).ResultsOn review, 108 patients were classified as not having GAD65 neurological autoimmunity and 3 patients had no more likely alternative diagnoses but atypical presentations (hyperkinetic movement disorders). Of remaining 212 patients with GAD65 neurological autoimmunity, median age at symptom onset was 46 years (range: 5–83 years); 163/212 (77%) were female. Stiff-person spectrum disorders (SPSD) (N=71), cerebellar ataxia (N=55), epilepsy (N=35) and limbic encephalitis (N=7) could occur either in isolation or as part of an overlap syndrome (N=44), and were designated core manifestations. Cognitive impairment (N=38), myelopathy (N=23) and brainstem dysfunction (N=22) were only reported as co-occurring phenomena, and were designated secondary manifestations. Sustained response to immunotherapy ranged from 5/20 (25%) in epilepsy to 32/44 (73%) in SPSD (p=0.002). Complete immunotherapy response occurred in 2/142 (1%). Cerebellar ataxia and serum GAD65 antibody titre >500 nmol/L predicted poor outcome.InterpretationHigh-titre GAD65 antibodies were suggestive of, but not pathognomonic for GAD65 neurological autoimmunity, which has discrete core and secondary manifestations. SPSD was most likely to respond to immunotherapy, while epilepsy was least immunotherapy responsive. Complete immunotherapy response was rare. Serum GAD65 antibody titre >500 nmol/L and cerebellar ataxia predicted poor outcome.

Interaction Between GAD65 Antibodies and Dietary Fish Intake or Plasma Phospholipid n-3 Polyunsaturated Fatty Acids on Incident Adult-Onset Diabetes: The EPIC-InterAct Study

<b><i>Objective:</i></b> Islet autoimmunity is associated with diabetes incidence. We investigated whether there was an interaction between dietary fish intake or plasma phospholipid polyunsaturated omega-3 fatty acid (n-3 PUFA) concentration with GAD65 antibody positivity on the risk of developing adult onset diabetes. <p><b><i>Research Design and Methods:</i></b> We used prospective data on 11,247 incident cases of adult onset diabetes and 14,288 non-cases from the EPIC-InterAct case-cohort study, conducted in eight European countries. Baseline plasma samples were analyzed for GAD65 antibodies and phospholipid n-3 PUFAs. Adjusted hazard ratios (HRs) for incident diabetes in relation to GAD65 antibody status and tertiles of plasma phospholipid n-3 PUFA or fish intake were estimated using Prentice-weighted Cox regression. Additive (proportion attributable to interaction; AP) and multiplicative interaction between GAD65 antibody positivity (≥65 U/ml) and low fish/n-3 PUFA were assessed.</p> <p><b><i>Results:</i></b> The hazard of diabetes in antibody positive individuals with low intake of total and fatty fish, respectively, was significantly elevated (HR 2.52, 95% CI 1.76-3.63; 2.48, 1.79-3.45) compared to people who were GAD65 antibody negative and had high fish intake, with evidence of additive (AP 0.44, 95% CI 0.16-0.72; 0.48, 0.24-0.72) and multiplicative (p=0.0465; 0.0103) interaction. Individuals with high GAD65 antibody levels (≥167.5 U/ml) and low total plasma phospholipid n-3 PUFA had more than 4-fold higher hazard of diabetes (HR 4.26, 2.70-6.72), AP 0.46 (0.12-0.80), compared to antibody negative individuals with high n-3 PUFA. </p> <b><i>Conclusions:</i></b> High fish intake or relative plasma phospholipid n-3 PUFA concentrations may partially counteract the increased diabetes risk conferred by GAD65 antibody positivity.

Interaction Between GAD65 Antibodies and Dietary Fish Intake or Plasma Phospholipid n-3 Polyunsaturated Fatty Acids on Incident Adult-Onset Diabetes: The EPIC-InterAct Study

<b><i>Objective:</i></b> Islet autoimmunity is associated with diabetes incidence. We investigated whether there was an interaction between dietary fish intake or plasma phospholipid polyunsaturated omega-3 fatty acid (n-3 PUFA) concentration with GAD65 antibody positivity on the risk of developing adult onset diabetes. <p><b><i>Research Design and Methods:</i></b> We used prospective data on 11,247 incident cases of adult onset diabetes and 14,288 non-cases from the EPIC-InterAct case-cohort study, conducted in eight European countries. Baseline plasma samples were analyzed for GAD65 antibodies and phospholipid n-3 PUFAs. Adjusted hazard ratios (HRs) for incident diabetes in relation to GAD65 antibody status and tertiles of plasma phospholipid n-3 PUFA or fish intake were estimated using Prentice-weighted Cox regression. Additive (proportion attributable to interaction; AP) and multiplicative interaction between GAD65 antibody positivity (≥65 U/ml) and low fish/n-3 PUFA were assessed.</p> <p><b><i>Results:</i></b> The hazard of diabetes in antibody positive individuals with low intake of total and fatty fish, respectively, was significantly elevated (HR 2.52, 95% CI 1.76-3.63; 2.48, 1.79-3.45) compared to people who were GAD65 antibody negative and had high fish intake, with evidence of additive (AP 0.44, 95% CI 0.16-0.72; 0.48, 0.24-0.72) and multiplicative (p=0.0465; 0.0103) interaction. Individuals with high GAD65 antibody levels (≥167.5 U/ml) and low total plasma phospholipid n-3 PUFA had more than 4-fold higher hazard of diabetes (HR 4.26, 2.70-6.72), AP 0.46 (0.12-0.80), compared to antibody negative individuals with high n-3 PUFA. </p> <b><i>Conclusions:</i></b> High fish intake or relative plasma phospholipid n-3 PUFA concentrations may partially counteract the increased diabetes risk conferred by GAD65 antibody positivity.