Serum glutamate decarboxylase antibodies and neurological disorders: when to suspect their association?

OBJECTIVES: To explore different neurological manifestations with suspicion of being associated to serum glutamate decarboxylase antibodies (GAD-Abs) in order to better characterize anti-GAD neurological syndromes. METHODS: Observational retrospective study including all patients for whom GAD65-Abs titers in serum were requested by the Neurology Department at La Paz University Hospital between 2015 and 2019. GAD-Abs were measured by ELISA. Demographic data, neurological symptoms, comorbidity with diabetes mellitus (DM) or with another autoimmune disease, and GAD-Abs titers were studied. Stiff-person syndrome, ataxia, encephalitis, and epilepsy were considered typical anti-GAD neurological syndromes and were compared to other atypical manifestations. RESULTS: A total of 173 patients (51.7% men, mean age 51.62) were included. A progressive increase in requests of serum GAD-Abs has occurred over the last 5 years, especially in patients with atypical neurological manifestations. GAD-Abs were found in the serum of 22 patients (12.7%); of those, 15 (68.18%) suffered a typical anti-GAD syndrome. Presence of DM or another organ-specific autoimmune disease was predictive of GAD-AB seropositivity (p < 0.001). 6.6% of requested patients with an atypical syndrome had GAD-Abs, but serum levels were significantly lower than those found in patients with a typical syndrome (706.67 vs 1430.23 UI/mL; Mann-Whitney U, p = 0.034), and were finally diagnosed with another neurological disease. CONCLUSION: Serum GAD-Abs were infrequently found in patients with clinical phenotypes other than those classically described as anti-GAD disorders, and with very low titers. In typical anti-GAD syndromes, there is a high comorbidity with DM and with other autoimmune diseases, and high serum GAD-Abs levels are usually present.

Functional assessment of the visual pathway with multifocal visual evoked potentials, and their relationship with disability in patients with multiple sclerosis.

OBJECTIVE: To objectively evaluate the visual function, and the relationship between disability and optic nerve dysfunction, in patients with multiple sclerosis (MS) and optic neuritis (ON), using multifocal visual evoked potentials (mfVEP). METHODS: This observational, cross-sectional study assessed 28 consecutive patients with clinically definite MS, according to the McDonald criteria, and 19 age-matched healthy subjects. Disability was recorded using the Expanded Disability Status Scale (EDSS) score. The patients' mfVEP were compared to their clinical, psychophysical (Humphrey perimetry) and structural (optic coherence tomography (OCT)) diagnostic test data. RESULTS: We observed a significant agreement between mfVEP amplitude and Humphrey perimetry/OCT in MS-ON eyes, and between mfVEP amplitude and OCT in MS but non-ON eyes. We found significant differences in EDSS score between patients with abnormal and normal mfVEP amplitudes. Abnormal mfVEP amplitude defects (from interocular and monocular probability analysis) were found in 67.9% and 73.7% of the MS-ON and MS-non-ON group eyes, respectively. Delayed mfVEP latencies (interocular and monocular probability analysis) were seen in 70.3% and 73.7% of the MS-ON and MS-non-ON groups, respectively. CONCLUSIONS: We found a significant relationship between mfVEP amplitude and disease severity, as measured by EDSS score, that suggested there is a role for mfVEP amplitude as a functional biomarker of axonal loss in MS.

Neurological manifestations of immune origin after COVID-19 vaccination: retrospective case study.

Objectives: To know the frequency and characteristics of neurological manifestations of probable immune origin occurring after exposure to COVID-19 vaccination. In addition, to pre-study the usefulness of the Spanish pharmacovigilance system and lymphocyte transformation test in establishing causality. Methods: Retrospective case study, including patients admitted to the Neurology department from January 2021 to May 2022 with a probable neuroimmune disorder. Demographic, clinical and COVID-19 vaccination antecedent data were collected from medical records. Results: From a total of 108 patients, 30 were excluded due to a different etiological diagnosis after follow-up. Thirty-six patients (46.2%) had received the COVID-19 vaccine in the previous 3 months (21.8% during the previous month). BioNTech-Pfizer vaccine was the most frequent in this group (63.9%). 69/108 were female and mean age 51.2 years (SD 22.59), with no significant difference with not recently-vaccinated (U-Mann Whitney, p = 0.256). The neurological syndromes found were (vaccinated/total): polyradiculoneuropathy (8/16), encephalitis (5/11), multiple sclerosis relapse (5/16), optic neuritis (1/4), myelitis (3/6), cranial neuropathy (6/10), aseptic meningitis (1/3) and others (7/11). Acute immunosuppressive treatment was administered in 61.1% of cases and 47.2% presented complete clinical improvement, without significant differences with non-vaccinated patients (chi-square, p = 0.570). Eleven vaccinated patients were studied in the pharmacovigilance office for possible adverse drug reaction. Causality according to the Spanish pharmacovigilance system (SPVS) algorithm was "Related" to COVID-19 vaccine (score ≥ 4) in 11 cases with positive in vitro study (lymphocyte transformation test) to polyethylene glycol-2000 and polysorbate-80 in 4 cases. Conclusion: Neuroimmune disorders appearing after administration of COVID-19 vaccine do not seem to present important differentiating clinical and/or evolutive features. Delayed hypersensitivity to vaccine excipients could be one of the pathophysiological mechanisms, and lymphocyte transformation test is a useful tool to identify it.

Putamina involvement in Wernicke encephalopathy induced by Janus Kinase 2 inhibitor.

OBJECTIVE: The aim of the study was to report a case of Wernicke encephalopathy (WE) due to fedratinib (Janus Kinase 2 inhibitor) treatment with atypical neuroimaging findings. METHODS: We present a detailed report of the case and literature review. RESULTS: A 68-year-old woman under treatment with fedratinib (investigational JAK2 inhibitor) developed memory impairment, diplopia, and ataxia compatible with WE. Brain magnetic resonance imaging showed extensive lesions involving medial thalami, periaqueductal gray, caudate nuclei, and putamina. Thiamine supplementation provided clinical recovery and radiological improvement of the lesions described. Basal ganglia lesions have been previously described in children with this disease, but this is rarely found in adults. Clinical trials including fedratinib have been recently discontinued, and its involvement in pathogenesis of WE may be related to thiamine-transporter inhibition. CONCLUSIONS: Our case represents an example of drug-related WE, with a rare radiological pattern. Precocious diagnosis and treatment are essential to prevent irreversible brain injury.