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.

Recurrent Miller Fisher: A Case Report Along With a Literature and an EMG/NCS Review

MFS has been reported to recur in 10-12% of patients. There may be a genetic component related to HLA-DR2. Anti-GAD antibodies can be present in MFS along with anti-GQ1b. Common EMG/NCS associations consist of a predominantly axonal, sensory polyneuropathy and absent H reflexes. A 32-year-old female with a history of hypothyroidism presented to our institution twice with symptoms of diplopia, lower extremity weakness and distal paresthesias occurring a year apart. She had ophthalmoplegia, reduced reflexes, and ataxia on exam. CSF showed a borderline elevated protein of 47 and white blood cells <3. She was positive for anti-GQ1b both times. Her anti-GAD65 antibody was elevated during both admissions. EMG/NCS on her first admission revealed comparatively reduced sensory nerve action potentials (SNAPs) and a normal blink reflex. Her SNAPs improved on the second admission, however, the EMG was performed only 2 days after the onset of her symptoms, limiting some early findings that may have not matured electrophysiologically. She was treated with IVIG on both occasions with rapid recovery within 5 days. This case highlights the fact that MFS can be recurrent. It also provides further evidence that anti-GAD antibodies may be associated with MFS. Reported findings of the blink reflex in MFS are diverse and further data is needed to determine if certain findings are more predominant than others. Treatment typically consists of IVIG, though steroids may also be considered for recurrence. Prognosis is generally favorable, regardless of treatment.

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.

GAD65 antibody-associated neurologic disease presenting with hemiparkinsonism at onset

A 60-year old previously healthy left-handed man presented to clinic with 6 months of progressive slowness and stiffness on the left side. He described loss of dexterity in the left hand and feeling of “heaviness” in the left leg. On exam, he exhibited mild bradyphrenia and hypophonia, moderate left arm and leg bradykinesia and rigidity, and left leg hesitations and reduced left arm-swing upon walking (video 1). A month prior, he had undergone MRIs of the brain and cervical spine with and without gadolinium that were unremarkable. Initial serum testing including complete blood count, comprehensive metabolic panel, thyroid stimulating hormone, ceruloplasmin, and vitamin B12 levels were all unremarkable. The differential diagnosis at presentation included the spectrum of parkinsonian disorders with Parkinson's Disease being the most likely given his age group and the asymmetric parkinsonism. He was diagnosed with suspected Parkinson's Disease and levodopa therapy was initiated as the he felt his symptoms were functionally-limiting.

Anti-GAD65 antibody-associated hemiataxia

Autoimmune and paraneoplastic movement disorders are increasingly recognized as a result of improved methods in detecting antibodies directed against intracellular, membrane, and other antigens.1 High concentrations of anti-glutamic acid decarboxylase 65 (GAD65) antibodies are associated with several neurologic syndromes including stiff-person syndrome, epilepsy, limbic encephalitis, and cerebellar ataxia.2 Anti-GAD65-associated cerebellar ataxia is typically generalized with prominent gait disturbance and eye movement abnormalities.1 Limb ataxia is present in 60-70% of patients.3 Here we present 2 unusual cases of hemiataxia associated with high concentrations of anti-GAD65 antibodies.