Clinical and neuroimaging phenotypes of autoimmune glial fibrillary acidic protein astrocytopathy: A systematic review and meta-analysis.

OBJECTIVE: This study was undertaken to provide a comprehensive review of neuroimaging characteristics and corresponding clinical phenotypes of autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A), a rare but severe neuroinflammatory disorder, to facilitate early diagnosis and appropriate treatment. METHODS: A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis)-conforming systematic review and meta-analysis was performed on all available data from January 2016 to June 2023. Clinical and neuroimaging phenotypes were extracted for both adult and paediatric forms. RESULTS: A total of 93 studies with 681 cases (55% males; median age = 46, range = 1-103 years) were included. Of these, 13 studies with a total of 535 cases were eligible for the meta-analysis. Clinically, GFAP-A was often preceded by a viral prodromal state (45% of cases) and manifested as meningitis, encephalitis, and/or myelitis. The most common symptoms were headache, fever, and movement disturbances. Coexisting autoantibodies (45%) and neoplasms (18%) were relatively frequent. Corticosteroid treatment resulted in partial/complete remission in a majority of cases (83%). Neuroimaging often revealed T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities (74%) as well as perivascular (45%) and/or leptomeningeal (30%) enhancement. Spinal cord abnormalities were also frequent (49%), most commonly manifesting as longitudinally extensive myelitis. There were 88 paediatric cases; they had less prominent neuroimaging findings with lower frequencies of both T2/FLAIR hyperintensities (38%) and contrast enhancement (19%). CONCLUSIONS: This systematic review and meta-analysis provide high-level evidence for clinical and imaging phenotypes of GFAP-A, which will benefit the identification and clinical workup of suspected cases. Differential diagnostic cues to distinguish GFAP-A from common clinical and imaging mimics are provided as well as suitable magnetic resonance imaging protocol recommendations.

Impact of COVID-19 vaccination or infection on disease activity in a radiologically isolated syndrome cohort: The VaxiRIS study.

BACKGROUND: Vaccination in patients with multiple sclerosis (MS) treated with immunosuppressive drugs is highly recommended. Regarding COVID-19 vaccination, no specific concern has been raised. OBJECTIVES: We aimed to evaluate if COVID-19 vaccination or infection increased the risk of disease activity, either radiological or clinical, with conversion to MS in a cohort of people with a radiologically isolated syndrome (RIS). METHODS: This multicentric observational study analyzed patients in the RIS Consortium cohort during the pandemic between January 2020 and December 2022. We compared the occurrence of disease activity in patients according to their vaccination status. The same analysis was conducted by comparing patients' history of COVID-19 infection. RESULTS: No difference was found concerning clinical conversion to MS in the vaccinated versus unvaccinated group (6.7% vs 8.5%, p > 0.9). The rate of disease activity was not statistically different (13.6% and 7.4%, respectively, p = 0.54). The clinical conversion rate to MS was not significantly different in patients with a documented COVID-19 infection versus non-infected patients. CONCLUSION: Our study suggests that COVID-19 infection or immunization in RIS individuals does not increase the risk of disease activity. Our results support that COVID-19 vaccination can be safely proposed and repeated for these subjects.

Typical linear radial periventricular enhancement in a patient with glial fibrillary acidic protein (GFAP) astrocytopathy.

OBJECTIVE: We describe an unusual case of corticosteroid-responsive autoimmune meningoencephalomyelitis with linear perivascular gadolinium enhancement but in the absence of anti- glial fibrillary acidic protein (GFAP) antibodies (ABs) in the cerebral spinal fluid (CSF). METHODS: The patient's clinical symptoms, brain magnetic resonance imaging (MRI) features, serum and CSF analysis and treatment were reviewed. RESULTS: A 47-year-old female experienced a subacute course with bilateral lower limbs weakness, unsteady walking, and dysuria. Brain MRI revealed typical radial perivascular gadolinium enhancement extending from the lateral ventricles to the white matter; MRI spine revealed lesions distributed in the entire spinal cord. Immunohistochemical staining of a brain biopsy revealed CD3+ T cells and CD20+ B cells cuffing around brain vessels, accompanied by CD68+ macrophages. CSF was negative for anti-GFAP ABs while serum was positive for anti-GFAP ABs (1:100). The patient responded well to corticosteroid. CONCLUSIONS: There are no uniform diagnostic criteria for autoimmune GFAP astrocytopathy. Our case suggested the importance of typical MRI findings in the diagnosis of this rare disease. Early treatments are very important to alleviate symptoms.

Age-dependent favorable visual recovery despite significant retinal atrophy in pediatric MOGAD: how much retina do you really need to see well?

BACKGROUND: To investigate age-related severity, patterns of retinal structural damage, and functional visual recovery in pediatric and adult cohorts of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) optic neuritis (ON). METHODS: All MOGAD patients from the 5 participating centers were included. Patients with initial manifestation <18 years were included in the pediatric (MOGADped) cohort and patients with ≥18 years in the adult (MOGADadult) cohort. For patients with MOGAD ON, examinations at least ≥6 months after ON onset were included in the analyses. Using spectral domain optical coherence tomography (SD-OCT), we acquired peripapillary retinal nerve fiber layer thickness (pRNFL) and volumes of combined ganglion cell and inner plexiform layer (GCIPL). High- and 2.5% low-contrast visual acuity (HCVA, LCVA) and visual-evoked potentials (VEP) were obtained. RESULTS: Twenty MOGADped (10.3±3.7 years, 30 MOGAD ON eyes) and 39 MOGADadult (34.9±11.6 years, 42 MOGAD ON eyes) patients were included. The average number of ON episodes per ON eye was similar in both groups (1.8±1.3 and 2.0±1.7). In both pediatric and adult MOGAD, ON led to pronounced neuroaxonal retinal atrophy (pRNFL: 63.1±18.7 and 64.3±22.9 µm; GCIPL: 0.42±0.09 and 0.44±0.13 mm3, respectively) and moderate delay of the VEP latencies (117.9±10.7 and 118.0±14.5 ms). In contrast, visual acuity was substantially better in children (HCVA: 51.4±9.3 vs. 35.0±20.6 raw letters, p=0.001; LCVA: 22.8±14.6 vs. 13.5±16.4, p=0.028). Complete visual recovery (HCVA-logMAR 0.0) occurred in 73.3% of MOGADped and 31% MOGADadults ON eyes, while 3.3% and 31% demonstrated moderate to severe (logMAR > 0.5) visual impairment. Independent of retinal atrophy, age at ON onset significantly correlated with visual outcome. CONCLUSION: Pediatric MOGAD ON showed better visual recovery than adult MOGAD ON despite profound and almost identical neuroaxonal retinal atrophy. Age-related cortical neuroplasticity may account for the substantial discrepancy between structural changes and functional outcomes.

Severe diarrhea in a 10-year-old girl with Aicardi-Goutières syndrome due to IFIH1 gene mutation.

Interferon-induced with helicase C domain 1 (IFIH1) is a cytosolic sensor of dsRNA that induces an anti-viral Type I interferon (IFN) state. A gain-of-function mutation in IFIH1 can cause increased Type I IFN activity and is clinically associated with Aicardi-Goutières syndrome (AGS). AGS is a multisystem disease, characterized as an early-onset progressive encephalopathy with basal ganglia calcification and systemic lupus erythematosus-like features. Gastrointestinal manifestation is rare in AGS patients. We described a 10-year-old female patient with a heterozygous IFIH1 gene mutation who presented with gastrointestinal colitis, cystitis and very severe diarrhea as initial major manifestations of AGS. Proteinuria with high titer of antinuclear antibody and anti-double-stranded DNA was found in this patient. She also had growth retardation and a history of seizures (about two episodes each year) but without attacks until 7 years old. Serum cytokines detected by flow cytometry indicated extremely high level of interleukin 6 (1970.1 pg/ml) and IFN-α (204.1 pg/ml). A contrast-enhanced CT scan of the whole abdomen and an intestinal hydro-MRI indicated that the walls of her stomach, small bowel, colon, and bladder were in various degrees of edema and thickened states. Whole exome sequencing analysis indicated that she harbors an IFIH1 heterozygous mutation (c.2336G > A (p.R779H)) in both blood and intestinal samples. Abundant inflammatory cells infiltration into the intestinal epithelium was observed by immunohistochemical staining. Positive staining of caspase 4 and caspase 5 suggested that the signaling pathway of pyroptosis was involved in the mechanism of intestinal inflammation in AGS. Diarrhea was significantly improved after steroids and intravenous immunoglobulin treatments. Gastrointestinal colitis and cystitis can be rare manifestations of AGS with IFIH1 mutation. Caspase and its related inflammasome pathway may involve in the pathogenesis of AGS.

MOGAD: How It Differs From and Resembles Other Neuroinflammatory Disorders.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a distinct CNS inflammatory disease with symptoms and imaging findings that overlap other neuroinflammatory disorders. We highlight the imaging characteristics of MOGAD and contrast them with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). Intracranial features that suggest MOGAD include childhood acute disseminated encephalomyelitis pattern with diffuse signal abnormality in the cortical gray matter, subcortical white matter, deep white matter, and deep gray matter on T2-weighted and FLAIR images; few bilateral T2-hyperintense fluffy and poorly demarcated lesions; pontine or thalamic involvement (or both); and cerebellar peduncle lesions in children. Intraorbitally, one sees edematous, enlarged, tortuous optic nerve or nerves; bilateral long-segment T2 hyperintensity of anterior segments of the optic nerve; sparing of the optic chiasm and retrochiasmatic pathways; and perioptic nerve sheath and surrounding orbital fat enhancement. Spinal involvement is seen as longitudinally extensive transverse myelitis with a sagittal T2-hyperintense intramedullary spinal line, the axial "H" spinal cord sign (central cord gray matter T2 hyperintensity), and conus medullaris involvement. Early accurate diagnosis of MOGAD is important because prognosis and treatment differ from those for NMOSD and MS.

Opsoclonus-myoclonus in Aicardi-Goutières syndrome.

Aicardi-Goutières syndrome (AGS) is a rare genetic neuroinflammatory disorder caused by abnormal upregulation of type 1 interferon signalling. Opsoclonus-myoclonus syndrome is a rare autoimmune phenotype demonstrating a disturbance in the humoral immune response mostly seen in the context of paraneoplastic or postinfectious states, although its pathophysiology is incompletely understood. We report the first three children described with AGS demonstrating transient opsoclonus and myoclonus after irritability and/or developmental regression, suggesting a pathological association. We describe the presentation, clinical features, progress, cerebrospinal fluid (CSF) inflammatory markers, electroencephalogram (EEG), and magnetic resonance imaging (MRI) findings in these children. Two patients had developmental regression but demonstrated a positive response to JAK1/2 inhibition clinically and on serial examination of CSF inflammatory markers. These findings suggest that AGS should be considered in children presenting with opsoclonus-myoclonus, and that the association between AGS and opsoclonus-myoclonus further supports the role of immune dysregulation as causal in the rare neurological phenomenon opsoclonus and myoclonus. What this paper adds There is a phenotypic association between opsoclonus-myoclonus syndrome and Aicardi-Goutières syndrome. There is clinical evidence of immune dysregulation in the pathogenesis of opsoclonus and myoclonus.

Ruxolitinib in Aicardi-Goutières syndrome.

Aicardi-Goutières Syndrome (AGS) is a monogenic leukodystrophy with pediatric onset, clinically characterized by a variable degree of neurologic impairment. It belongs to a group of condition called type I interferonopathies that are characterized by abnormal overproduction of interferon alpha, an inflammatory cytokine which action is mediated by the activation of two of the four human Janus Kinases. Thanks to an ever-increasing knowledge of the molecular basis and pathogenetic mechanisms of the disease, Janus Kinase inhibitors (JAKIs) have been proposed as a treatment option for selected interferonopathies. Here we reported the 24 months follow-up of the fifth AGS patient treated with ruxolitinib described so far in literature. The treatment was globally well tolerated; clinical examinations and radiological images demonstrated a progressively improving course. It is however to note that patients presenting with mild and spontaneously improving course have been reported. Large natural history studies on AGS spectrum are strongly required in order to get a better understanding of the results emerging from ongoing therapeutic trials on such rare disease.

Understanding Pediatric Neuroimmune Disorder Conflicts: A Neuroradiologic Approach in the Molecular Era.

Neuroimmune disorders in children are a complex group of inflammatory conditions of the central nervous system with diverse pathophysiologic mechanisms and clinical manifestations. Improvements in antibody analysis, genetics, neuroradiology, and different clinical phenotyping have expanded knowledge of the different neuroimmune disorders. The authors focus on pediatric-onset myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease, which is a new entity in the spectrum of inflammatory demyelinating diseases, distinct from both multiple sclerosis (MS) and anti-aquaporin-4 (AQP4) antibody neuromyelitis optica spectrum disorders (NMOSDs). The authors review the importance of an optimized antibody-detection assay, the frequency of MOG antibodies in children with acquired demyelinating syndrome (ADS), the disease course, the clinical spectrum, proposed diagnostic criteria, and neuroimaging of MOG antibody-associated disease. Also, they outline differential diagnosis from other neuroimmune disorders in children according to the putative primary immune mechanism. Finally, they recommend a diagnostic algorithm for the first manifestation of ADS or relapsing ADS that leads to four demyelinating syndromes: MOG antibody-associated disease, AQP4 antibody NMOSDs, MS, and seronegative relapsing ADS. This diagnostic approach provides a framework for the strategic role of neuroradiology in diagnosis of ADS and decision making, to optimize patient care and treatment outcome in concert with clinicians. Online supplemental material is available for this article. ©RSNA, 2020.

Intracerebral large artery disease in Aicardi-Goutières syndrome with TREX1 mutation: a case report.

We report a patient diagnosed with Aicardi-Goutières syndrome (AGS) with homozygous TREX1 gene mutation. Her magnetic resonance angiography (MRA) showed intracerebral large artery disease, which was rarely reported in the past in TREX1 AGS patients. Her younger sister also had homozygous TREX1 gene mutation and died of necrotizing enterocolitis. Intracerebral large artery involvement has been seen as a particular feature of SAMHD1-related disease. Our patient also had arthropathy, which is a finding more commonly mentioned in SAMHD1-related diseases. The observations in our case may contribute to our understanding of the pathogenetic mechanism of TREX1 AGS, involving the intracerebral large arteries, arthropathy, and possibly the gastrointestinal tract.

Spontaneous MRI improvement and absence of cerebral calcification in Aicardi-Goutières syndrome: Diagnostic and disease-monitoring implications.

BACKGROUND: Aicardi-Goutières syndrome (AGS) is a rare genetic leukoencephalopathy related to inappropriate activation of type I interferon. Neuroradiological findings are typically characterized by white matter abnormalities, cerebral atrophy and cerebral calcification. The disease usually manifests itself during the first year of life in the form of an initial "encephalitic-like" phase followed by a chronic phase of stabilization of the neurological signs. Recently new therapeutic strategies have been proposed aimed at blocking the abnormal activation of the interferon cascade. MATERIALS AND METHODS: We reviewed clinical and MRI findings in three young RNASEH2B-mutated patients studied with serial CT and MRI studies. RESULTS: All three patients presented clinical and MRI features consistent with AGS but, very unexpectedly, an improving neuroradiological course. In patient 1, the MRI improvement was noted some months after treatment with high-dose steroid and IVIg treatment; in patients 2 and 3 it occurred spontaneously. Patient 2 did not show cerebral calcification on CT images. CONCLUSIONS: Our series highlights the possibility of spontaneous neuroradiological improvement in AGS2 patients, as well as the possibility of absence of cerebral calcification in AGS. The study underlines the need for extreme caution when using MRI as an outcome measure in therapeutic trials specific for this disease. MRI follow-up studies in larger series are necessary to describe the natural course of AGS.

Clinical Heterogeneity in Patients with Glutamate Decarboxylase Antibody.

OBJECTIVE: To explore the diversity and clinical features of anti-glutamate decarboxylase (GAD) antibody-associated neurological diseases. METHODS: Clinical data of a series of 5 patients positive for anti-GAD antibodies were retrospectively analyzed. RESULTS: All 5 patients were female, with a median age of 41.5 years (range 19-60 years). Their neurological symptoms included stiff-person syndrome (SPS), encephalitis, myelitis, cramp, visual loss, and paresthesia. Three patients (60%) were diagnosed with tumors, 2 cases of thymic tumor and 1 of breast cancer. On immunohistochemistry for tumor pathology, expression of GAD65 was found only in 1 patient. Four patients (80%) had abnormal brain MRI findings. All patients received immunotherapy and improved significantly after treatment, but 4 (80%) then experienced a relapse. CONCLUSIONS: Neurological manifestations in anti-GAD-positive patients are diverse and include SPS, encephalitis, myelitis, cramp, visual loss, and paresthesia.

FDG-PET in Cotard syndrome before and after treatment: can functional brain imaging support a two-factor hypothesis of nihilistic delusions?

Introduction: Cotard syndrome is a neuropsychiatric entity recognised by the presence of nihilistic delusions. Although different models have been proposed for the development of monothematic delusions, including Cotard syndrome, functional neuroanatomical models are lacking.Methods: A case report of a 19-year old male with autoimmune encephalitis and Cotard syndrome, in whom Positron Emission Tomography (18F-FDG-PET) scans were performed before and after successful treatment with electroconvulsive therapy (ECT), is presented. Literature review on brain imaging is provided to discuss a functional neuroanatomical model of Cotard syndrome, in accordance with the two-factor theory of delusions.Results: The patient's 18F-FDG-PET showed marked insular and prefrontal metabolic abnormalities. Except for insular hypometabolism, metabolic abnormalities improved after ECT. Previously reported structural neuroimaging studies in Cotard syndrome showed a predominance of right hemisphere lesions, in which frontal lobes were more frequently involved, followed by parietal and temporal lesions. Functional neuroimaging studies reported abnormalities in frontoparietal circuits as well as midline structures included in the "default mode network".Conclusions: Abnormalities in the functioning of the insular cortex and the prefrontal cortex could be related to the development of nihilistic delusions when a two-factor theory of delusions is considered.

Imaging in Autoimmune Neurology.

Autoimmune disorders are becoming increasingly recognized within the broader field of neurology. The discovery of multiple, novel, neutrally targeted autoantibodies over the past decade and their translation into commercially available testing, in particular, has aided in the more rapid diagnosis of these disorders. When considering imaging in autoimmune neurologic disorders, it is important, when possible, to visualize the autoimmune process itself, as well as to make sure that the patient does not have an associated malignancy driving the overall process. Positron emission tomographic scans can aid in the detection of small tumors with limited spread, as well as in the visualization of autoimmune processes affecting the brain and/or spinal cord. In autoimmune disorders of the central nervous system, imaging abnormalities can appear within the limbic system, extralimbic areas, and spinal cord. Such imaging abnormalities can serve as objective markers to follow over time to assess patients' responses to treatment. It is important to recognize that overlapping syndromes (for instance, both demyelinating and autoimmune or both infectious and autoimmune) exist and that inflammatory disorders can leave behind sequelae that can be recognized on subsequent imaging. Work is currently underway to develop more specific imaging techniques for autoimmune neurologic disorders.

Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease.

We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.

Late diagnosis and atypical brain imaging of Aicardi-Goutières syndrome: are we failing to diagnose Aicardi-Goutières syndrome-2?

Aicardi-Goutières syndrome (AGS) is a rare disorder with in utero or postnatal onset of encephalopathy and progressive neurological deterioration. The seven genetic subtypes of AGS are associated with abnormal type I interferon-mediated innate immune response. Most patients with AGS present with progressive microcephaly, spasticity, and cognitive impairment. Some, especially those with type 2 (AGS2), manifest milder phenotypes, reduced childhood mortality, and relative preservation of physical and cognitive abilities. In this report, we describe two siblings (sister and brother) diagnosed with AGS2 in their second decade, who exhibited static encephalopathy since 1 year of age with spastic quadriplegia and anarthria but preserved intellect. Both were homozygous for the common pathogenic RNASEH2B allele (c.529G>A, p.Ala177Thr). Rather than manifesting calcifications and leukoencephalopathy, both had increased iron signal in the basal ganglia. Our report broadens the clinical and imaging spectrum of AGS2 and emphasizes the importance of including AGS2 in the differential diagnosis of idiopathic spastic cerebral palsy. WHAT THIS PAPER ADDS: We identified two siblings (sister and brother) with atypical Aicardi-Goutières syndrome type 2 due to RNASEH2B mutation. Manifestations included spastic quadriplegia and anarthria but preserved intellect and increased iron signal in the basal ganglia. RNASEH2B-related Aicardi-Goutières syndrome type 2 can have present with a variable phenotype, including idiopathic spastic cerebral palsy.

Aicardi-Goutières syndrome: unusual neuro-radiological manifestations.

Aicardi-Goutières syndrome (AGS) is one of the expanding group of inherited congenital infection like syndromes. Here, we describe the detailed clinical and imaging findings of two sibs with AGS. Each shows scattered periventricular intracranial calcifications, severe global delay, seizures, microcephaly and spasticity. Interestingly, chilblains were observed in the two sisters as well as their parents and a paternal uncle. The brain MRI of the older sister showed marked ventricular dilatation as a result of unusual associated porencephalic cysts. Unexpectedly, unilateral cerebellar hypoplasia was also noted. In comparison, her younger sister displayed the classic atrophic changes and white matter loss of AGS. The diagnosis of AGS was confirmed by sequence analysis, which identified a previously reported homozygous RNASEH2B mutation, c.554 T > G (p.V185G). Parents were heterozygous for the same mutation. Further molecular analysis excluded mutations in potentially related manifestations of COL4A1 gene. This is the first report of chilblains associated with heterozygous RNASEH2B mutation. Further, the brain imaging findings appear particularly interesting, which until now has not been reported in any AGS patient. We discuss the possible reasons for this unusual presentation.

Infectious and inflammatory diseases of the central nervous system-the spectrum of imaging findings and differential diagnosis.

The infectious and inflammatory diseases of the central nervous system (CNS) including the brain and spine can present with a wide spectrum of clinical symptoms, locations, and appearance. The purpose of this exhibit is to review the different patterns of their presentations, to illustrate their imaging characteristics and techniques, and to discuss their clinical features and pathology so that the correct diagnosis can be made and prompt intervention can be initiated on a timely fashion.