GFAP is an intermediate astrocyte protein, located between the smaller microfilaments and larger microtubules, and is the primary component of intermediate filaments in astrocytes. It has important biological functions, including the maintenance of astrocytes’ morphological stability, involvement in the blood-brain barrier formation, and the regulation of synapse function. Autoimmune GFAP astrocytopathy is a recently defined autoimmune disease. Since GFAP antibodies have specific biomarkers [4,11−12], autoimmune GFAP astrocytopathy diagnosis primarily depends on GFAP antibody detection in the serum or SCF. So far, very few pediatric cases have been reported. In this study, we recruited 11 pediatric patients with GFAP antibodies in GSF and/or serum samples (titer ≥ 1:32) and all of them were only responds by corticosteroid treatment. We retrospectively revealed the characteristic clinical features of those pediatric patients.
The peak age of onset among our patients was 52 months, and most of them were preschool children. The youngest patient was 11 months, which was younger than any previous study [10, 15]. As far as we know, 11 months is the youngest age case to have been reported. The female and male ratio is 0.83, which is unlike the ratio found in adult patients. Like the previous studies, most patients have an acute or subacute onset. Clinical manifestations were encephalitis and meningoencephalitis, including fever ( 45.4%), headaches (27.3%), dizziness (18.2%), drowsiness (18.2%), and mental disorders (18.2%) [3, 9, 10, 13, 14, 15, 16, 17]. In our case, all of the patients who suffered from myelitis were showed longitudinally extensive transverse myelitis, like the previous study. Some clinical manifestations in adults were rarely seen in pediatric patients, such as consciousness disturbance, area postrema syndrome, prolonged gastrointestinal symptoms and so on,[7, 18, 19] were not seen in this study. Flanagan reported that 66% of the tumors were detected within 2 years of onset of symptoms, including ovarian teratoma, adenocarcinoma and glioma, yet we found that only three patients had a tumor, which is much lower than the frequency found in other reports.Therefore, patients should be monitored for underlying neoplasms within 2 years of GFAP disease onset.
CSF analysis from our patients with autoimmune GFAP astocytopathy showed that more than half had characterized inflammatory CSF. The high frequency of elevated CSF WBC count and slightly elevated protein levels and ADA levels is consistent with the literature . This high frequency of elevated CSF WBC count and protein level is not the only marker of this condition, but also occurs in infectious and neoplastic causes of meningoencephalitis. ADA plays an important role in the growth and differentiation of lymphocytes and macrophages, and some research suggest that the high ADA levels might be associated with immunological pathology during the early stage of autoimmune GFAP astrocytopathy. We found that some patients (72.7%) with a transiently mild decline of glucose level, while the lactic dehydrogenase (72.7%) were elevated, which were seldom reported in previous studies and uncommon in immune diseases. Hypoglycorrhachia is normally seen in the patients with tuberculous meningitis (TBM). It caused by release of glycolytic enzyme in the brain and glucose consumption by itself, but the reason for the hypoglycorrhachia in autoimmune GFAP astrocytopathy is unknown. As we know, this is the first time the changes of CSF lactic dehydrogenase in autoimmune GFAP astrocytopathy have been discussed. The lactic dehydrogenase is mainly related to the degree of cell necrosis and the damage of the cell membrane. Elevated lactic dehydrogenase was mainly found in local hypoxic necrosis, bacterial meningitis, cerebral infarction, lymphoma, brain trauma, hydrocephalus and so on. The reasons for the elevation of lactic dehydrogenase of this disease is uncertain, but we suggest that it maybe related to theimpaired brain cells and injured cell membranes found in autoimmune GFAP astrocytopathy.
From the brain MRI results, 90.0% of patients have abnormalities on T2-weighted and FLAIR sequences. Lesions can involve all of the nervous system, including the cortex, subcortical white matter, nerve nuclei of the deep brain (basal ganglia, hypothalamus, cerebellar dentate nuclei), brainstem, cerebellum, meninges, ventricle and callosum. In our case, the most common abnormalities were laminar patterns or line patterns hyperintense in bilateral thalamus, basal ganglia, periventricular white matter and juxtacortical white matter on T2-weighted imaging and FLAIR imaging. Those lesions, especially in the periventricular white matter and juxtacortical white matter, were just like the distribution along the Virchow-Robin space, which were different from the adult abnormalities [2–5, 10, 12]. The Virchow-Robin space is surrounding the walls of vessels as they course from the subarachnoid space through the brain parenchyma, and it does not communicate directly with the subarachnoid space. The Vichow-Robin space can provide the changes for the extraneous antigen into the brain, and the interstitial fluids partly participate in the immunomodulatory effect. Also, it can be one way in which the disease spreads . The autoimmune GFAP astrocytopathy revealed marked inflammatory responses around the perivascular region and small blood vessels [2, 5, 13, 20, 21], emanating from GFAP-enriched peri-lateral ventricular regions, frequently seen in the basal ganglia, hypothalamus, and the white matter (subcortical or/and around the ventricle). We speculated that in our case, the five patients showed bilateral hyperintense in the thalamus, basal ganglia, periventricular white matter and juxtacortical white matter, were related to the accumulation of inflammatory cells, antigens and antibodies in the perivascular space and the Vichow-Robin space. It should be noted that previous studies have proposed that bilateral thalamus abnormal hyperintense signal was the characteristic manifestation of autoimmune GFAP astrocytopathy,and some studies can see similar signal changes in the bilateral basal ganglia, thalamus and white matter [2–5, 10, 12].The characteristic pattern of brain linear perivascular radial gadolinium enhancement in the white matter, perpendicular to the ventricle, were only seen in two patients in our study, which is also consistent in the pattern of inflammation around the small vessels . However, in our cases, it is markedly lower than in adults’ patients. Although previous studies have pointed out that brain linear perivascular radial gadolinium enhancement is a characteristic manifestation of the disease, Jonathan Wickel also pointed out that radial perivascular emphasis is not necessarily associated with GFAP antibodies .
Four patients showed abnormal enhancement of leptomeninges, which rarely occurs in autoimmune encephalitis. GFAP, an intermediate astrocyte protein between the smaller microfilaments and larger microtubules, is the primary component of intermediate filaments in astrocytes. It has important biological functions, including the maintenance of astrocytes’ morphological stability, involvement in blood-brain barrier formation, and the regulation of synapse function. Perhaps that enhancement was caused by gadolinium leaking from the damaged blood-brain barrier, but the reason is unknown. The previously study indicated that the radial enhanced patterns were relative to the gadolinium leakage from compromised vascular walls [2, 23]. This raises some questions: Why are the radial enhancing patterns rare in pediatric patients? Is it that pediatric patients of this disease are seldom injured in the small vascular walls? Previous studies have shown that all of them were normal on DWI, but our findings were different. The reason for this is also uncertain. Myelitis is relative rare compared adult patients [10,24−28]. In our cases, all of two myelitis pediatric patients showed longitudinally extensive myelitic abnormalities, and a slight enhancement.