Autoimmune neurological diseases associated with anti-GAD65 antibodies are rare, rendering them intractable, untraceable, difficult to diagnose, and with poor prognosis. Although a few studies have reported the MRI findings for autoimmune epilepsy related to anti-GAD65 antibody, studies focusing on the serial MRI manifestations and their clinical relationship remains unexplored. Herein, we described the serial MRI manifestations and the outcomes of immunotherapy of anti-GAD65 autoimmune neurological syndromes with an intent to assist physicians in recognizing such uncommon diseases and highlighting the significance of early immunotherapy.
All patients in the present cohorts have undergone baseline MRI examinations. In addition to parenchymal atrophy, the common imaging findings showed MTL aberrant signal or cortical/subcortical parenchymal T2 hyperintensity. Moreover, these results were consistent with previously published reports [5]. Hence, a generalized classification was employed in the current work for the baseline images into cortical/subcortical parenchymal type and MTL type, both of which had parenchymal atrophy. The MTL lesions mainly showed aberrant signals in the hippocampus, parahippocampal gyrus, and amygdaloid nucleus. Furthermore, in most cases, bilateral MTL was involved, and unilateral lesions were also observed occasionally. Interestingly, the patients with cortical/subcortical parenchymal T2 hyperintensity presented with acute newly-onset of neurological symptoms such as epileptic seizures, mental disorders, visual or olfactory hallucination, and cognition impairments, whereas those with MTL swelling and T2 hyperintensity displayed chronic epilepsy or progressive cognitive impairment. In general, the clinical manifestations in patients with cortical/subcortical lesions were often emergency and critical. The newly-onset seizures were characterized by brief and frequent focal seizure onsets, which may occur dozens of times in a day, each lasting only a few seconds.
According to a previous study, SPS cases revealed no distinct manifestations upon MRI examination. The MRI scans of the brain and spinal cord appeared to be normal, hence posing difficulty in predicting early disease progression [3]. Surprisingly in the current cohort, the MRI scans of SPS patients revealed hyperintense T2FLAIR signals in the bilateral hippocampus and para-hippocampal gyrus as well as diffuse atrophy in bilateral cerebral hemispheres, albeit no significant cerebral impairment was observed. These results provided evidence suggesting a continuum of diverse neurological phenotypes of anti-GAD antibodies by previously reported studies [6].
All of the patients received the first-line immunotherapy either with intravenous immunoglobulin(IVIG) or intravenous methylprednisolone (IVMP) or both. Moreover, the clinical responses from the immunotherapy were found to be quite similar to the observations from previously reported studies [9]. Among MTL cases, the overall non-epilepsy symptoms and newly-onset seizures had a superior immunotherapeutic response in comparison with chronic TLE symptoms. In the current cohort, one of the three patients with cortical/subcortical lesions developed into status epilepsy and died of circulatory failure. Another patient was comatose but showed recovery after receiving immunotherapy. Post immunotherapy, one patient was diagnosed seizure-free. This varied response to the treatment can be attributed to the delay in early diagnosis. In the current work, it was noted that 4 patients with chronic MTLE (Mesial Temporal Lobe Epilepsy) were diagnosed late. The delay in diagnosis spanned from as late as 2 years to more than 10 years. The permissible delayed diagnosis time in patients with good curative effect ranged from 1 week to 1 month, which highlighted the significance of early diagnosis and early initiation of immunotherapy for the prognosis of the GAD65-related neurological symptoms.
Additionally, serial MRI investigations were carried out for 8 of 15 patients. Patients showing cortical/subcortical changes in MRI had a dramatic response to immunotherapy. In the current cohort, MRI scans revealed an increase in the size of lesions within the first two weeks in two patients with cortical/subcortical type and later showed marked recovery after receiving immunotherapy. Interestingly, one case displayed visual hallucinations 5 months after receiving immunotherapy. The MRI scans revealed new lesions in the occipital lobe, although the EEG showed no significant epileptic discharge. The location of aberrant MRI signals in cortical patients was consistent with epileptic symptomatology. It can be hypothesized that the aberrant signals of MRI can be a manifestation of brain injury caused by a GAD65-antibody-mediated immune response. However, a previous study reported that a GAD65-positive patient with aberrant MRI signals was associated with brain edema developed due to frequent non-convulsive seizures [10]. MRI re-examination of patients with MTL showed progressive brain atrophy and intense MRI signals. At present, the pathogenesis and pathophysiology of GAD65-related encephalitis remain unclear. The clinical manifestations of cortical/subcortical parenchymal type and MTL type show marked differences in MRI investigations and treatment response. These distinct alterations in MRI examinations are thought to be associated with two distinct pathogenesis. The mechanism of GAD65-related autoimmune epilepsy with hippocampal injury has been studied recently. These studies corroborate the effect of hippocampal injury in GAD65-related autoimmune epilepsy with the pathogenic effect of CD8 + T-cells, as well as contrast activity of CD4 + T-cells in autoimmune encephalitis [11]. Therefore, research on immune system response in patients with cortical lesions has promising potential for the development of future therapeutic interventions.
A duly note must be taken of certain limitations of the current work. The present retrospective work had a relatively low sample size due to the rare occurrence of GAD-related neurological symptoms. Furthermore, a lack of quantitative imaging analysis of brain atrophy due to phenotypical variations. Moreover, the cohort showed varying degrees of cognitive impairment. Therefore, a thorough and detailed investigation must be continued through research on the changes in brain function and morphology.