Isolated optic neuritis with positive glial fibrillary acidic protein antibody.

BACKGROUND AND OBJECTIVES: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy (GFAP-A) has been reported as a spectrum of autoimmune, inflammatory central nervous system disorders. Linear perivascular radial gadolinium enhancement patterns on brain magnetic resonance imaging (MRI) are a hallmark of these disorders. GFAP-A is associated with cerebrospinal fluid (CSF) GFAP antibody (GFAP-Ab), while the association with serum GFAP-Ab is less clear. This study aimed to observe the clinical characteristic and MRI changes of GFAP-Ab-positive optic neuritis (ON). METHODS: We performed a retrospective, observational case study at the department of neurology, Beijing Tongren Hospital, from December 2020 to December 2021. The serum of 43 patients and CSF samples of 38 patients with ON were tested for GFAP-Ab by cell-based indirect immune-fluorescence test. RESULTS: Four patients (9.3%) were detected GFAP-Ab positive, and in three out of the four patients, GFAP-Abs were detected only in serum. All of them demonstrated unilateral optic neuritis. Three patients (1, 2, and 4) experienced severe visual loss (best corrected visual acuity ≤ 0.1). Two patients (2 and 4) had experienced more than one episode of ON at the time of sampling. MRI showed optic nerve hyperintensity on T2 FLAIR images in all GFAP-Ab positive patients, and orbital section involvement was the most common. During follow-up (mean 4.5 ± 1 months), only Patient 1 had a recurrent ON, and no patient developed new other neurological events or systemic symptoms. CONCLUSION: GFAP-Ab is rare in patients with ON and may manifest as isolated, relapsing ON. This supports the notion that the GFAP-A spectrum should comprise isolated ON.

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OBJECTIVES: To study the clinical features of children with autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A). METHODS: A retrospective analysis was performed on the medical data of 34 children with GFAP-A who attended the Department of Neurology, Children's Hospital of Chongqing Medical University, from January 2020 to February 2022. The medical data included clinical manifestations, cerebrospinal fluid features, imaging examination results, treatment, and prognosis. RESULTS: The median age of onset was 8.4 (range 1.9-14.9) years for the 34 children with GFAP-A. The main clinical manifestations included headache (50%, 17/34), fever (47%, 16/34), visual impairment (47%, 16/34), and disturbance of consciousness (44%, 15/34). Abnormal cerebrospinal fluid results were observed in 19 children (56%, 19/34), among whom 8 children had positive autoantibody. The children with overlap syndrome had significantly higher recurrence rate and rate of use of immunosuppressant than those without overlap syndrome (P<0.05). About 77% (24/31) of the children had good response to immunotherapy, and only 1 child had poor prognosis. CONCLUSIONS: Children with GFAP-A often have non-specific clinical symptoms and show good response to immunotherapy. Children with overlap syndrome have a high recurrence rate, and early application of immunosuppressants may help to prevent recurrence and alleviate symptoms.

CLIPPERS and its mimics: evaluation of new criteria for the diagnosis of CLIPPERS.

OBJECTIVE: To evaluate the accuracy of the recently proposed diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). METHODS: We enrolled 42 patients with hindbrain punctate and/or linear enhancements (<3 mm in diameter) and tested the CLIPPERS criteria. RESULTS: After a median follow-up of 50 months (IQR 25-82), 13 out of 42 patients were CLIPPERS-mimics: systemic and central nervous system lymphomas (n=7), primary central nervous system angiitis (n=4) and autoimmune gliopathies (n=2). The sensitivity and specificity of the CLIPPERS criteria were 93% and 69%, respectively. Nodular enhancement ( ≥ 3 mm in diameter), considered as a red flag in CLIPPERS criteria, was present in 4 out of 13 CLIPPERS-mimics but also in 2 out of 29 patients with CLIPPERS, explaining the lack of sensitivity. Four out of 13 CLIPPERS-mimics who initially met the CLIPPERS criteria displayed red flags at the second attack with a median time of 5.5 months (min 3, max 18), explaining the lack of specificity. One of these four patients had antimyelin oligodendrocyte glycoprotein antibodies, and the three remaining patients relapsed despite a daily dose of prednisone/prednisolone ≥ 30 mg and a biopsy targeting atypical enhancing lesions revealed a lymphoma. CONCLUSIONS: Our study highlights that (1) nodular enhancement should be considered more as an unusual finding than a red flag excluding the diagnosis of CLIPPERS; (2) red flags may occur up to 18 months after disease onset; (3) as opposed to CLIPPERS-mimics, no relapse occurs when the daily dose of prednisone/prednisolone is ≥ 30 mg; and (4) brain biopsy should target an atypical enhancing lesion when non-invasive investigations remain inconclusive.

The discrimination between autoimmune glial fibrillary acidic protein astrocytopathy and tuberculous meningitis.

OBJECTIVE: The differential diagnosis between autoimmune glial fibrillary acidic protein astrocytopathy (AGFAPA) mimicking tuberculous meningitis and tuberculous meningitis (TBM) remains challenging in clinical practice. This study aims to identify the clinical, laboratory parameters, and clinical score systems that may be helpful in differentiating AGFAPA from TBM. METHOD: Overall 22 AGFAPA patients who were initially misdiagnosed as TBM (AGFAPA-TBM) and 30 confirmed TBM patients were included. The clinical, laboratory, imaging parameters, Thwaites systems, and Lancet consensus scoring systems (LCSS) of all patients were reviewed. Logistic regression was employed to establish a diagnostic formula to differentiate AGFAPA-TBM from TBM. The receiver operating characteristic (ROC) curve was applied to determine the best diagnostic critical point of the formula. RESULTS: Urinary retention was more frequent in AGFAPA-TBM patients (72.7% vs 33.3%, p = 0.012). A significantly lower ratio of T-SPOT. TB was noted in AGFAPA-TBM patients (9.1% vs 82.1%, p < 0.001). We found the LCSS was able to differentiate AGFAPA-TBM from TBM (AUC value 0.918, 95% CI=0.897-0.924). Furthermore, we set up a new scoring system with three variables: urinary retention, T-SPOT. TB, and cerebral imaging criteria in LCSS. The proposed diagnostic score ranges from -8 to 2, and a score of ≥ 0 was suggestive of AGFAPA-TBM (AUC value 0.938, 95% CI=0.878-0.951). CONCLUSIONS: This study is the first to evaluate the Thwaites system and LCSS in AGFAPA-TBM and TBM. We provide an alternative diagnostic formula to differentiate AGFAPA-TBM from TBM and suggest testing for GFAP antibodies to avoid misdiagnosis when this scoring system meets AGFAPA-TBM.

Overlapping Epstein-Barr virus encephalitis and autoimmune glial fibrillary acidic protein astrocytopathy.

We describe three cases of overlapping Epstein-Barr virus (EBV) Encephalitis and Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy (GFAP-A). The three cases all presented with initial symptoms of fever, headache, coma, and posture tremor of the upper limbs, then followed by limb weakness and dysuria. All of the three cases were on ventilators. Case 1 and 2 improved dramatically after intravenous methylprednisoloneand immunoglobulin treatment. However, case 3 presented dyspneic, and died from gastrointestinal hemorrhage. The GFAP-A triggered by EBV intracranial infection could initially masquerade as EBV encephalitis only, and the detection of GFAP antibody is essential for differentiation.

Autoimmune glial fibrillary acidic protein astrocytopathy coexistent with reversible splenial lesion syndrome: A case report and literature review.

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a rare autoimmune disorder. Reversible splenial lesion syndrome (RESLES) is a transient clinical-imaging syndrome characterized by specific magnetic resonance imaging (MRI) pattern. A 58-year-old man was admitted with a fever, headache, and confusion for 1 week. Brain MRI showed abnormal leptomeningeal enhancement in the brainstem and high signal intensity on diffusion-weighted MRI of the corpus callosum. Anti-GFAP antibody was positive in the serum and cerebrospinal fluid analysis. This patient significantly improved and had no relapse after glucocorticoid and immune suppressant therapy. A repeated brain MRI revealed the lesion in the corpus callosum and abnormal leptomeningeal enhancement in the brainstem disappeared. Linear perivascular radial enhancement is the characteristic pattern of autoimmune GFAP astrocytopathy which is rarely coexistent with RESLES.

Epstein-Barr virus: To be a trigger of autoimmune glial fibrillary acidic protein astrocytopathy?

BACKGROUND: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a novel autoimmune disease of central nervous system (CNS). It is unclear whether Epstein-Barr virus (EBV) is related to autoimmune GFAP astrocytopathy. OBJECTIVE: To describe the clinical, laboratory, and imaging characteristics of patients with autoimmune GFAP astrocytopathy. METHODS: The clinical, laboratory, and imaging findings of patients are presented. The levels of GFAP in CSF were detected by ELISA. T and B cell subsets in CSF were detected by flow cytometry. GFAP-IgG in serum and cerebrospinal fluid (CSF) were tested by cell-based assay (CBA) and tissue-based assay (TBA). RESULTS: All three patients had fever, cognitive dysfunction, limb weakness, and positive GFAP-IgG with EBV infection in CSF. Enteric glia cells may involve in this disease. Typical imaging findings include the gadolinium enhancement of linear perivascular radial perpendicular to the ventricle, meningeal enhancement (especially in midbrain interpeduncal fossa), longitudinally extensive lesions involving spindle cords, and more T2/Flair-hyperintense lesions in the periventricular white matter at late stage. The patients had poor response to antiviral treatment and strong response to steroid pulse therapy. CONCLUSION: EBV could induce CNS autoimmune response in autoimmune GFAP astrocytopathy. The detection of GFAP-IgG and EBV may facilitate the early diagnosis in these patients.

Case report: Excessive daytime sleepiness as a presenting manifestation of autoimmune glial fibrillary acidic protein astrocytopathy.

Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is a recently discovered autoimmune inflammatory disease of the central nervous system. It presents with a variety of clinical symptoms, including fever, seizures, psychiatric symptoms, limber weakness, and sensory symptoms. However, the symptoms of sleep disorders have not been sufficiently addressed. Here, we report a case of GFAP-A in which the patient complained of excessive daytime sleepiness and an excessive need for sleep. Our patient was a 58-year-old male who experienced excessive daytime sleepiness for 50 days following SARS-CoV-2 infection. He was diagnosed with coronavirus disease 2019 on June 1st. On the 7th of June, he experienced excessive daytime sleepiness, nausea, reduced food intake, lower limb weakness, and dysuria. Subsequently, his sleepiness significantly deteriorated on July 21st. Five months prior, the patient underwent laparoscopic partial right nephrectomy for clear-cell renal cell carcinoma. Brain MRI revealed abnormal hyperintense lesions in the pontine brain and around the mesencephalic aqueduct on T2 and T2-fluid attenuated inversion recovery (T2-FLAIR) sequences However, these lesions did not exhibit any pathological enhancement. Spinal cord MRI revealed lesions in the C6-C7 and T2-T3 segments on the T2 sequence. His Epworth Sleepiness Scale (ESS) score was 16 (reference range, <10), and 24-hour polysomnography supported the diagnosis of rapid-eye-movement sleep disorder and severe sleep apnea-hypopnea syndrome. Glial fibrillary acidic protein IgG antibodies were detected in the cerebrospinal fluid (1:32, cell-based assay) but not in the serum. The level of hypocretin in the cerebrospinal fluid was 29.92 pg/mL (reference range ≥110 pg/mL), suggesting narcolepsy type 1. After treatment with corticosteroids for approximately 1 month, the patient showed considerable clinical and radiological improvement, as well as an increase in hypocretin levels. Although repeated polysomnography and multiple sleep latency tests suggested narcolepsy, his ESS score decreased to 8. Our findings broaden the range of clinical manifestations associated with GFAP-A, thereby enhancing diagnostic and therapeutic strategies for this disease. Additionally, our results indicate a potential common autoimmune mechanism involving GFAP-A and orexin system dysregulation, warranting further investigation.

Autoimmune glial fibrillary acidic protein astrocytopathy masquerading as tuberculosis of the central nervous system: a case series.

We describe the case history of three patients with meningoencephalitis who were initially treated for presumed tuberculous meningoencephalitis before being diagnosed with autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. We highlight the overlapping clinical features between autoimmune GFAP astrocytopathy and tuberculous meningoencephalitis and the challenges in early diagnosis, as both entities respond to an initial course of steroids accompanying antituberculous medications. Early evaluation of GFAP-immunoglobulin G in the cerebrospinal fluid of patients who present with aseptic meningoencephalitis could reveal autoimmune GFAP astrocytopathy, which responds favorably to immunotherapy.

A case of autoimmune glial fibrillary acidic protein astrocytopathy presenting with magnetic resonance imaging mimics of multiple sclerosis.

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is an inflammatory disorder of the central nervous system. On magnetic resonance imaging, the neuroradiological signature is a linear radial enhancement pattern of cerebral white matter (MRI). Dawson's fingers, on the other hand, and ovoid lesions with open-ring enhancement have long been recognized as distinct features of multiple sclerosis (MS). We herein report a case of autoimmune GFAP astrocytopathy presenting with these MRI findings specific to MS. Autoimmune GFAP astrocytopathy could mimic the MRI features of MS and should be included in the differential diagnosis of MS.

MRI findings of autoimmune glial fibrillary acidic protein astrocytopathy involving infratentorial: Case report.

Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is a new type of autoimmune astrocytopathy first defined in 2016. Lack of clinical understanding, often misdiagnosed as optic neuromyelitis or multiple sclerosis. We report the clinical and MRI findings of an elderly patient with autoimmune glial fibrillary acidic protein astrocytopathy. With intractable vomiting as the first symptom, the brainstem showed typical vascular enhancement. GFAP-A lacks specificity in clinical and MRI scans. When enhancement reveals paraventricular "vascular-like enhancement" or central spinal cord tubular enhancement, it is important to consider the possibility of this disease.

MRI features and evolution of autoimmune glial fibrillary acidic protein astrocytopathy: A retrospective cross-sectional and longitudinal study.

BACKGROUND: Autoimmune glial fibrillary acidic protein astrocytopathy (AGA) is a relatively novel disease. The early diagnosis of this inflammatory central nervous system (CNS) disorder remains challenging. OBJECTIVES: We aimed to explore the imaging manifestations and evolution of AGA to facilitate its successful diagnosis and monitoring. METHODS: From January 2016 to January 2021, a total of 15 consecutive patients, who were hospitalised in our institution and confirmed AGA clinically, were enrolled in this IRB-approved retrospective study. All clinical features and MRI manifestations were analysed cross-sectionally and longitudinally. Distribution, morphology, enhancement pattern and evolution of AGA lesions were assessed visually and evaluated semi-quantitatively by calculating the burden of disease (BOD) and the signal intensity ratio (SIR). Chi-square, Mann-Whitney U and Kolmogorov-Smirnov Z tests were performed for lesion patterns' statistical comparison. RESULTS: Fever, limb weakness, headache and cognitive impairment were the most common symptoms in AGA. 14 patients were initially misdiagnosed as infection (n = 9), demyelination (n = 4) or infarction (n = 1). The median time interval from onset to confirmed AGA diagnosis was 46 days. Both BOD and SIR progressed in the natural course and were relieved after immunotherapy on MRI. Meningeal enhancement, one of the most common MRI findings in patients with AGA (100%), relieved faster than intraparenchymal enhancement (p <0.001) and peri­ventricular radial linear (PVRL) enhancement (p <0.001) after the initiation of immunotherapy. Non-enhanced lesions had lower BOD (p <0.001) and were relieved slower (p <0.001) than enhanced ones. CONCLUSIONS: MRI provides valuable neuroradiological indicators for the diagnosis and follow-up of AGA. The CNS enhancement patterns (meningeal / PVRL) facilitate the early diagnosis and treatment response monitoring of AGA, while lesion manifestation in the spinal cord contributes to the follow-up. The evolution inconsistency of AGA lesions in different regions may be attributed to the discrepancy within glial fibrillary acidic protein subtypes.

Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy in Children: A Retrospective Analysis of 35 Cases.

Objective: To analyze the clinical manifestations, imaging, electroencephalography, treatment, and prognosis of 35 cases of autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) in children. Methods: Children hospitalized in the Department of Neurology, Hunan Children's Hospital, China, between January 2015 and June 2021, owing to autoimmune diseases of the central nervous system were subjected to a cell-based assay (CBA). The assay identified 40 children positive for GFAP-immunoglobulin (Ig)G antibodies in the serum and/or the cerebrospinal fluid. Based on clinical manifestations and imaging characteristics, five children who were only positive for GFAP-IgG antibodies in serum were excluded, and the remaining 35 children were diagnosed with autoimmune GFAP-A. The clinical data derived from the 35 children were retrospectively analyzed. Results: A total of 35 children, including 23 males and 12 females with a mean age of 6.3 ± 0.6 years, manifested clinical symptoms of fever (62.9%), headache (42.9%), convulsions (42.9%), abnormal mental behavior (51.4%), disorders of consciousness (54.3%), visual disturbance (22.9%), ataxia (11.4%), paralysis (40%), and autonomic dysfunction (25.7%). One child exhibited only the clinical symptom of peripheral facial nerve palsy. Eleven out of 35 children were also positive for other antibodies. In addition to the common overlapping autoimmune syndromes, one case of autoimmune GFAP-A also manifested as Bickerstaff's brainstem encephalitis. Linear periventricular enhancement upon MRI was significantly less frequent in children (8.5%) than in adults. In pediatric patients, MRI contrast enhancement was principally seen in the meninges and brain lobes. Although repeated relapse (17.1%) and sequelae symptoms (20%) occurred in some cases, most children showed a favorable prognosis. Spearman's rank correlation showed that the antibody titer was not significantly associated with the severity of the initial disease conditions. Conclusions: The disease diagnosis in children seropositive for GFAP antibodies only should receive a comprehensive diagnosis based on their clinical symptoms, imaging, electroencephalographic characteristics, and treatment responses. Some patients with relapses should receive repeated gamma globulin and corticosteroid therapy or the addition of immunosuppressants to their therapeutic regimen, and slow-dose tapering of corticosteroids and extended treatment are recommended for patients with overlapping autoimmune syndromes.

Uncommon inflammatory/immune-related myelopathies.

The differential diagnosis for immune-mediated myelopathies is broad. Although clinical manifestations overlap, certain presentations are suggestive of a particular myelopathy etiology. Spine MRI lesion characteristics including the length and location, and the pattern of gadolinium enhancement, help narrow the differential diagnosis and exclude an extrinsic compressive cause. The discovery of specific antibodies that serve as biomarkers of myelitis such as aquaporin-4-IgG and myelin-oligodendrocyte -glycoprotein-IgG (MOG-IgG), has improved our understanding of myelitis pathophysiology and facilitated diagnosis. In this review we will focus on the pathophysiology, clinical presentation, imaging findings and treatment and outcomes of uncommon immune-mediated myelopathies.

Autoimmune Brainstem Encephalitis: An Illustrative Case and a Review of the Literature.

Autoimmune brainstem encephalitis (BSE) is a rare neurological condition with a wide range of underlying etiologies. It can be subdivided into two broad groups: a primary inflammatory disease of the central nervous system (CNS) or a brainstem disorder secondary to systemic diseases where the CNS is only one of many affected organs. Symptoms range from mild to life-threatening manifestations. Most cases respond well to immunotherapy. Therefore, broad and in-depth knowledge of the various inflammatory disorders that target the brainstem is essential for guiding the diagnostic approach and assisting in early initiation of appropriate therapy. We herein report on a case of BSE and provide an overview of the various causes of autoimmune BSE with an emphasis on the clinical manifestations and diagnostic approach.

Autoimmune glial fibrillary acidic protein astrocytopathy mimics infectious meningitis: Two case reports.

BACKGROUND: Autoimmune glial fibrillary acidic protein astrocytopathy (A-GFAP-A) has been recently characterized as a novel autoimmune central nervous system (CNS) disorder with GFAP antibody as the biomarker. However, nonspecific symptoms of A-GFAP-A contribute to misdiagnosis. CASE PRESENTATION: The patients presented with initial symptoms of fever, headache, and nuchal rigidity. Case 1 exhibited mild signs of irritability, active tendon reflexes, and dysuria; case 2 had transient loss of consciousness. Cerebrospinal fluid (CSF) revealed lymphocytosis, elevated protein level, and decreased glucose level. Magnetic resonance imaging (MRI) revealed radial gadolinium enhancement perpendicular to the lateral ventricle. Viral meningitis or tubercular meningitis was suspected. However, their inflammatory and pathogenic indicators showed no abnormal changes, and empirical antibiotic and antiviral drugs did not result in remarkable recovery. Subsequently, cases were detected with a strongly positive expression of GFAP antibody in CSF and the symptoms improved dramatically after high-dose methylprednisolone pulse treatment. CONCLUSION: A-GFAP-A with meningitis-like symptoms could initially masquerade as intracranial infection, and prompt detection of GFAP antibody is essential for differentiation.

A Case Report of Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy Diagnosed After Long Term Diagnosis of Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids.

Cases of autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy who were initially diagnosed with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) were rarely reported. Herein, we reported a 31-year-old woman who presented with 7 years of recurrent headache. Her clinical history, symptoms, brain MRI enhancement features, and response to treatment during each attack were reviewed. Her brain MRI 7 years ago demonstrated characteristic pepper-like enhancement of pontine and cerebellum and her symptoms resolved completely after taking a high-dose of steroids. She was suspected with the diagnosis of CLIPPERS, and she experienced five relapses once the oral steroid was tapered below 20 mg/day. During her last relapse, she experienced fever and psychosis, and GFAPα-antibodies were detected in her serum and cerebrospinal fluid by antigen-transfected HEK293 cell-based assay (indirect immunofluorescence assay). She obtained relief again after steroid therapy, and her diagnosis converted to autoimmune GFAP astrocytopathy. Autoimmune GFAP astrocytopathy may mimic CLIPPERS, both clinically and radiologically. Long-term follow-up is essential for necessary diagnosis revision at each new attack in patients with a diagnosis of CLIPPERS.