Quantifying Putative Retinal Gliosis in Preclinical Alzheimer's Disease.

Purpose: Neuroinflammation plays a significant role in the pathology of Alzheimer's disease (AD). Mouse models of AD and postmortem biopsy of patients with AD reveal retinal glial activation comparable to central nervous system immunoreactivity. We hypothesized that the surface area of putative retinal gliosis observed in vivo using en face optical coherence tomography (OCT) imaging will be larger in patients with preclinical AD versus controls. Methods: The Spectralis II instrument was used to acquire macular centered 20 × 20 and 30 × 25-degrees spectral domain OCT images of 76 participants (132 eyes). A cohort of 22 patients with preclinical AD (40 eyes, mean age = 69 years, range = 60-80 years) and 20 control participants (32 eyes, mean age = 66 years, range = 58-82 years, P = 0.11) were included for the assessment of difference in surface area of putative retinal gliosis and retinal nerve fiber layer (RNFL) thickness. The surface area of putative retinal gliosis and RNFL thickness for the nine sectors of the Early Treatment Diabetic Retinopathy Study (ETDRS) map were compared between groups using generalized linear mixed models. Results: The surface area of putative retinal gliosis was significantly greater in the preclinical AD group (0.97 ± 0.55 mm2) compared to controls (0.68 ± 0.40 mm2); F(1,70) = 4.41, P = 0.039; Cohen's d = 0.61. There was no significant difference between groups for RNFL thickness in the 9 ETDRS sectors, P > 0.05. Conclusions: Our analysis shows greater putative retinal gliosis in preclinical AD compared to controls. This demonstrates putative retinal gliosis as a potential biomarker for AD-related neuroinflammation.

Vitrectomy and tumor endoresection for the diagnosis and treatment of focal nodular retinal gliosis.

We report the case of a 60-year-old woman who presented with metamorphopsia and progressive vision loss in the right eye. Fundus examination revealed an elevated, white-yellow mass in the peripheral inferotemporal retina, with massive retinal exudation, proliferative vitreoretinopathy, and retinal detachment. Pars plana vitrectomy with tumor endoresection was performed, and a complete excisional biopsy of the lesion was obtained by removing the tumor through the anterior chamber. Histopathological analysis of the specimen confirmed a diagnosis of peripheral, focal, nodular retinal gliosis. Postoperatively, visual function improved greatly, with no recurrence of the disease at 12 months' follow-up. Focal nodular retinal gliosis is a rare, non-neoplastic proliferation of retinal glial cells, with a vascular component. In our case, surgical treatment with pars plana vitrectomy facilitated accurate diagnosis and resulted in effective management of the retinal tumor and associated complications.

[Disorders of the visual system following vitreoretinal and macular surgery]. / Störungen des visuellen Systems nach vitreoretinaler und makulärer Chirurgie.

The visual system is highly complex. Monocular or binocular disorders can develop, for example during tractive alterations of the macula, such as in epimacular membranes, and result in symptoms, such as double vision, aniseikonia or metamorphopsia. These symptoms are also observed following vitreomacular or vitreoretinal surgery, especially after treatment of large retinal detachment involving the macular area using pars plana vitrectomy or scleral buckle surgery but also as a result of vitreomacular interventions, such as membrane peeling in epimacular gliosis. Some patients have preoperatively existing latent conditions, which are not explicitly addressed during routine preoperative diagnostics. For patients and surgeons it is worth noting that these troublesome symptoms are often manifested in patients with good restoration of best corrected visual acuity following vitreomacular surgery. In such cases, patients tend to be dissatisfied with the surgical result despite good visual acuity. Treatment of postoperative metamorphopsia, aniseikonia and double vision is often difficult. In clinical studies, the maximum depth of tractive retinal folds has been described as a reliable morphological biomarker for the occurrence of metamorphopsia in epimacular gliosis. As metamorphopsia tends to postoperatively resolve slowly and even persist in ca. 30% of cases, this biomarker can have an impact on preoperative consulting and postoperative monitoring. Persistent binocular discomfort is often treatable by exact refraction correction and by applying a vertical and, if necessary, a horizontal prism. This often requires patience on the part of both the patient and the physician but is mostly successful due to fusion and adaptability.

Autoimmune glial fibrillary acidic protein astrocytopathy in children: a retrospective study.

OBJECTIVE: To describe the clinical features of autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy in children. METHOD: Data from 11 pediatric patients with autoimmune GFAP astrocytopathy were retrospectively analyzed. RESULTS: All of the patients showed encephalitis and meningoencephalitis or meningoencephalomyelitis with or without myelitis. 45.4% of the patients had fever, 27.3% headaches, 18.2% dizziness, 18.2% drowsiness, and 18.2% mental disorders. Cerebrospinal fluid (CSF) was detected in all patients. The white blood cell counts (WBC) (90.9%), lactic dehydrogenase levels (72.7%), protein level (36.4%), and adenosine deaminase activity (ADA) level (27.3%) were elevated, and the CSF glucose levels (72.7%) were slightly reduced. Nine patients (90%) were found to have brain abnormalities, of which five (50.0%) patients had abnormal symmetrical laminar patterns or line patterns hyperintensity lesions on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images in the basal ganglia, hypothalamus, subcortical white matter and periventricular white matter. The linear radial enhancement pattern of the cerebral white matter was only seen in two patients, with the most common being abnormal enhancement of leptomeninges (50%). Five patients had longitudinally extensive spinal cord lesions. CONCLUSION: The findings of pediatric patients with autoimmune GFAP astrocytopathy are different from previous reports.

Histopathological assessments reveal retinal vascular changes, inflammation, and gliosis in patients with lethal COVID-19.

PURPOSE: The purpose of this study is to assess for histopathological changes within the retina and the choroid and determine the long-term sequelae of the SARS-CoV-2 infection. METHODS: Eyes from seven COVID-19-positive and six similar age-matched control donors with a negative test for SARS-CoV-2 were assessed. Globes were evaluated ex vivo with macroscopic, SLO and OCT imaging. Macula and peripheral regions were processed for Epon embedding and immunocytochemistry. RESULTS: Fundus analysis shows hemorrhagic spots and increased vitreous debris in several of the COVID-19 eyes compared to the controls. OCT-based measurements indicated an increased trend in retinal thickness in the COVID-19 eyes; however, the difference was not statistically significant. Histology of the retina showed presence of hemorrhages and central cystoid degeneration in several of the donors. Whole mount analysis of the retina labeled with markers showed changes in retinal microvasculature, increased inflammation, and gliosis in the COVID-19 eyes compared to the controls. The choroidal vasculature displayed localized changes in density and signs of increased inflammation in the COVID-19 samples. CONCLUSIONS: In situ analysis of the retinal tissue suggests that there are severe subclinical abnormalities that could be detected in the COVID-19 eyes. This study provides a rationale for evaluating the ocular physiology of patients that have recovered from COVID-19 infections to further understand the long-term effects caused by this virus.

EPIDERMAL GROWTH FACTOR RECEPTOR EXPRESSION IN A CASE OF FOCAL NODULAR GLIOSIS OF THE RETINA.

PURPOSE: To describe the immunohistochemical profile in a case with focal nodular gliosis (FNG) of the retina. METHODS: A 56-year-old female patient presented with vitreoretinal tractional syndrome with FNG of the retina. After resection of the retinal tumor tissue during the 25-G pars plana vitrectomy, immunohistochemistry using anti-epidermal growth factor receptor (EGFR), p-53, Ki67, glial fibrillary acid protein (GFAP), CD34, and vascular endothelial growth factor antibodies was performed in the excised tissue of the FNG of the retina. RESULTS: Histopathological analysis of the tumor led to a diagnosis of FNG of the retina. Spindle cells of the tumor exhibited strong positive staining for glial fibrillary acid protein, and there was local staining for CD34 in the endothelial cells in the blood vessels. The epidermal growth factor receptor and vascular endothelial growth factor immunoreactivity were strongly observed in the endothelial cells. CONCLUSION: This study demonstrated epidermal growth factor receptor expression in eyes with FNG of the retina. Oncogenic epidermal growth factor receptor might trigger and amplify the expression and function of endothelial vascular endothelial growth factor.

Epiretinal Membrane from Uncontrolled Gliosis After Inverted ILM Flap Technique for Idiopathic Macular Hole.

We describe two cases with epiretinal membrane (ERM) from uncontrolled gliosis seen after multilayered inverted internal limiting membrane (ILM) flap technique for full thickness macular hole (FTMH). Two patients with FTMH who had undergone surgery with inverted ILM flap technique were examined by serial optical coherence tomography scans to evaluate the course of multilayered ILM flaps seen as foveal hyperreflective lesions postoperatively. We observed excessive uncontrolled gliosis over these hyperreflective ILM flaps with ERM formation, along with worsening metamorphopsia and best-corrected visual acuity. Case 1 underwent a repeat surgery for ERM. We report excessive uncontrolled gliosis as a rare complication of multilayered inverted ILM flap technique for FTMH. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:663-665.].

Yet another utility for isocitrate dehydrogenase.1: Can it serve as an immunomarker to assess tumor margins in gliomas?

BACKGROUND: Isocitrate dehydrogenase-1 (IDH1) mutation is now an established early event in gliomagenesis. The ability to detect this mutation by several techniques including immunohistochemistry makes it a significant marker for diagnosing and prognosticating gliomas. This study was done to assess the expression of mutant IDH1 in different grades of gliomas and evaluate its utility in differentiating reactive gliosis from glioma and defining surgical margins of these tumors in the operative specimens. MATERIALS AND METHODS: A total of fifty cases including equal number of Grade I, II, III, and IV gliomas and gliosis were included in the study. Formalin-fixed, paraffin-embedded tissue sections from these lesions were immunostained with IDH1 and Ki-67 antibody, and percentage of tumor cells that stained positive with these markers was assessed. RESULTS: Grades II, III, and IV showed consistent immunopositivity for IDH1. No immunostaining was noted in Grade I glioma and gliosis. Mean Ki-67 labeling index correlated with grades of gliomas with low activity in Grade I and high activity in Grade IV. Individual tumor cells infiltrating into adjacent normal brain parenchyma also stained positive with IDH1 antibody. CONCLUSION: Immunostaining for IDH1 mutation can be utilized as a reliable marker in the precise diagnosis of diffuse gliomas and also in objective assessment of surgical margins to differentiate gliomas from gliosis.

Prolonged inflammation leads to ongoing damage after spinal cord injury.

The pathogenesis of spinal cord injury (SCI) remains poorly understood and treatment remains limited. Emerging evidence indicates that post-SCI inflammation is severe but the role of reactive astrogliosis not well understood given its implication in ongoing inflammation as damaging or neuroprotective. We have completed an extensive systematic study with MRI, histopathology, proteomics and ELISA analyses designed to further define the severe protracted and damaging inflammation after SCI in a rat model. We have identified 3 distinct phases of SCI: acute (first 2 days), inflammatory (starting day 3) and resolution (>3 months) in 16 weeks follow up. Actively phagocytizing, CD68+/CD163- macrophages infiltrate myelin-rich necrotic areas converting them into cavities of injury (COI) when deep in the spinal cord. Alternatively, superficial SCI areas are infiltrated by granulomatous tissue, or arachnoiditis where glial cells are obliterated. In the COI, CD68+/CD163- macrophage numbers reach a maximum in the first 4 weeks and then decline. Myelin phagocytosis is present at 16 weeks indicating ongoing inflammatory damage. The COI and arachnoiditis are defined by a wall of progressively hypertrophied astrocytes. MR imaging indicates persistent spinal cord edema that is linked to the severity of inflammation. Microhemorrhages in the spinal cord around the lesion are eliminated, presumably by reactive astrocytes within the first week post-injury. Acutely increased levels of TNF-alpha, IL-1beta, IFN-gamma and other pro-inflammatory cytokines, chemokines and proteases decrease and anti-inflammatory cytokines increase in later phases. In this study we elucidated a number of fundamental mechanisms in pathogenesis of SCI and have demonstrated a close association between progressive astrogliosis and reduction in the severity of inflammation.

TERT Promoter Mutation Analysis to Distinguish Glioma From Gliosis.

Among the most challenging diagnostic issues in surgical neuropathology is the distinction between scant infiltration by diffuse gliomas and reactive gliosis. The best documented ancillary marker to establish a definitive diagnosis of glioma in this setting is the identification of hotspot mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) genes, which is limited, however, by the low prevalence of these mutations in gliomas of elderly adults. Since telomerase reverse transcriptase (TERT) promoter mutations are present in the vast majority of IDH-wildtype diffuse gliomas, we hypothesized that combined analysis of IDH and TERT might overcome these limitations. For this purpose, we analyzed a series of non-neoplastic and neoplastic CNS samples for the prevalence of TERT hotspot mutations. TERT mutations were identified in none out of 58 (0%) reactive gliosis samples, and in 91 out of 117 (78%) IDH-wildtype gliomas. Based on a series of 200 consecutive diffuse gliomas, we found that IDH mutation analysis alone had a sensitivity of 28% (63% and 12%, respectively, in patients below and above age of 50) for detection of gliomas, whereas a combined analysis of IDH and TERT was 85% sensitive (87% and 84%, respectively, below and above age of 50). In sum, our findings suggest that TERT promoter mutation analysis contributes favorably to a molecular panel in cases equivocal for glioma versus gliosis on morphological grounds, especially in patients above age of 50, in which IDH analysis alone performs poorly.

HIV-Negative Cryptococcal Meningoencephalitis Results in a Persistent Frontal-Subcortical Syndrome.

Twenty-seven previously healthy (of 36 consecutive eligible patients), HIV-negative cryptococcal meningoencephalitis (CM) patients underwent comprehensive neuropsychological evaluation during the late post-treatment period (1.3-4 years post diagnosis), assessing attention, language, learning, memory, visuospatial, executive function, information processing, psychomotor functioning, as well as mood symptoms. Seven of eight domains (all except attention) showed increased percentages of CM patients scoring in the less than 16th percentile range compared to standardized normative test averages, adjusted for education level and age. Comparison with a matched archival dataset of mild cognitive impairment/Alzheimer's disease patients showed that CM patients exhibited relative deficits in psychomotor and executive function with fewer deficits in memory and learning, consistent with a frontal-subcortical syndrome. MRI evaluation at the time of testing demonstrated an association of lower neuropsychological functioning with ventriculomegaly. These studies suggest that CM should be included in the list of treatable causes of dementia in neurological work ups. Future studies are needed to identify diagnostic and treatment regimens that may enhance neurological function after therapy.

Usefulness and safety from stereotactic biopsy in posterior fossa lesions in adult patients.

BACKGROUND: Stereotactic biopsy has been reported as a useful and safety procedure in pediatric patients. In adult patients exist more controversy because a greater number of diagnostic options. OBJECTIVE: To demonstrate its usefulness and safety in adult patients with posterior fossa pathology. METHOD: From 2006-2014, 23 patients were operated from posterior fossa. Variables: age, gender, state, pre- and postoperative diagnosis, stereotactic device, location and complications. RESULTS: 52.2% females and 47.8% males. The location was ponto-mesencephalic 43.5%, cerebellum 39.1%, bulbar 13% and pineal region 4.3%. The preoperative diagnosis was brainstem glioma 78.2%, lymphoma 8.7%, and meningioma, metastasis and abscess 4.3% each one. In 73.9% Zamorano-Dujovni device was used and in 26.1% the CRW. The definitive diagnosis was pilocytic astrocytoma 17.4%, diffuse astrocytoma 13%, inflammatory response 13%, anaplastic astrocytoma 8.7%, gliosis 8.7%, glioblastoma, neuroectodermic primitive tumor, germinoma, pineocytoma and cryptococcosis 4.3% each one. In 17.4% there was no diagnosis. The preoperative diagnosis was concordant in 43.5%. One transient deficit and one pin displacement 4.3% were present. 91.4% without complications. CONCLUSIONS: It is a useful, necessary and safety procedure in adult patients.

ANTECEDENTES: La biopsia por estereotaxia ha sido reportada como segura y útil en pediatría. En adultos es más controvertida debido a la mayor diversidad de opciones diagnósticas. OBJETIVO: Demostrar su utilidad y seguridad en pacientes adultos con patología de fosa posterior. MÉTODO: En 2006-2014 se operaron 23 pacientes de fosa posterior. Variables: edad, sexo, diagnóstico preoperatorio y posoperatorio, estereotáctico, localización y complicaciones. RESULTADOS: 52.2% mujeres y 47.8% hombres. La localización fue la región pontomesencefálica en el 43.5%, el cerebelo en el 39.1%, bulbar en el 13% y pineal en el 4.3%. El diagnóstico preoperatorio fue glioma de tallo en el 78.2%, linfoma en el 8.7% y meningioma, metástasis y absceso en el 4.3% cada uno. En el 73.9% se utilizó el sistema Zamorano-Dujovni y en el 26.1% el CRW. El diagnóstico definitivo fue astrocitoma pilocítico en el 17.4%, astrocitoma difuso en el 13%, respuesta inflamatoria en el 13%, astrocitoma anaplásico en el 8.7%, gliosis en el 8.7%, y glioblastoma, tumor neuroectodérmico primitivo, germinoma, pineoctioma y criptococosis en el 4.3% cada uno. En el 17.4% no hubo diagnóstico. El diagnóstico preoperatorio fue concordante en el 43.5%. Hubo un déficit transitorio y un desplazamiento de uno de los pinchos en el 4.3% de los casos. En el 91.4% no hubo complicaciones. CONCLUSIONES: Es un procedimiento útil, necesario y seguro en pacientes adultos.

Review on Retinal Gliosis Illustrated with a Series of Massive Glioses and Focal Nodular Gliosis Cases in Regard to Potential Pitfalls of Ocular Reactive Tumor-like Lesions of this Type.

This paper presents a review on retinal gliosis illustrated by series of three cases of patients (a 39-year-old man and a 35-year-old woman with massive retinal gliosis (MRG) and a 51-year-old man with truly focal nodular gliosis of retina) with intraocular tumor-like masses and loss of vision, who recently suffered from painful inflammation of eyeball and who classically had a history of remote ocular trauma, onset of blindness early in lifetime or gradual but progressive loss of sight. The diagnosis of this pathological entity is given for the lesions that are composed of GFAP strongly positive, elongated, fusiform cells consistent with fibrillary astrocytes. As illustrated in cases from our pathological practice, PAS gave positive patchy disseminated reaction in form of cellular densely purplish granules in minority of cells representing glycogen storing. This feature could be consistent with PAS-positive Müller cells that also constitute retinal gliosis as one of cellular components of normal retina that is induced to reactive proliferation. Thus, the paper presents histological background and differential diagnosis of the entity.

Reactive gliosis mimicking tumor recurrence - a case series documenting MRI abnormalities and neuropathological correlates.

The aim of this study is to identify, in our center, all cases of foreign-body reactions to hemostatic agents or other prostheses resulting in a radiological suspicion of tumor recurrence. We interrogated our internal database to identify all such cases and systematically evaluated the MRI brain scans of patients: (i) at the time of initial tumor diagnosis, (ii) postoperatively, (iii) and at the time of suspected tumor recurrence. In addition, we reviewed each patient's operative notes and reviewed the histology of all cases following a second surgical intervention. In total, we identified 8 patients, 7 of whom had a WHO grade II glioma at initial surgery. We did not identify any distinguishing radiological abnormalities from the initial diagnostic brain scan to the suspected recurrence, and histologically all cases were characterized by extensive gliosis; with both macrophages and reactive astrocytes present throughout. The cause of gliosis was identified as being relating to hemostatic agents in 4 cases; in the other 4 cases, the foreign-body reaction was presumed to be caused be materials used in a craniotomy or cranioplasty. This study highlights the difficulty in radiologically diagnosing a foreign-body reaction and also identifies that such a gliotic reaction may occur as a consequence of exogenous materials used in a craniotomy or cranioplasty.
.

Mitogen-activated protein kinase in gliosis and pilocytic astrocytoma.

Pilocytic astrocytoma (PA), featuring activation of the mitogen-activated protein kinase (MAPK) pathway, is the most common tumor of the pediatric central nervous system. However, it remains unknown whether MAPK activation is present in the reactive gliosis of non-neoplastic lesions. Therefore, we investigated the expression of MAPK in reactive gliosis associated with cavernous angiomas. Immunohistochemical expression and the extent of BRAF, ERK, p38, and JNK were investigated in 10 patients with gliosis surrounding cavernous angiomas (GS group) and 10 patients with PA (PA group). Evaluation of these parameters was scored as 0, none; 1, scarce; 2, moderate; 3, global. In the GS group, histopathologic features of PA (piloid cells, Rosenthal fibers, microcysts with eosinophilic granular bodies) were identified. Expression of ERK, and p38 was shown in all patients in the GS and PA group. Expression of BRAF was identified in 5 patients (50%) in the GS group and in 8 (80%) in the PA group. The mean score of BRAF expression in the PA group was significantly higher than that in the GS group (p = 0.019). Reactive gliosis may resemble PA in histological findings and MAPK activation. Therefore, PA could be indistinguishable from reactive gliosis with classic histopathologic and/or immunohistochemical methods.
.

[Watchful waiting as a therapeutic principle for diseases of the vitreoretinal interface]. / "Zuwarten" als therapeutisches Prinzip bei Erkrankungen der vitreoretinalen Grenzfläche.

Elective surgery of the vitreoretinal interface is currently the most common reason for vitrectomy in Germany. The evaluation and correct interpretation of spectral domain optical coherence tomography (SD-OCT) images is of great importance but the indications for vitrectomy in macular surgery should be based more on patient symptoms and not only the OCT findings. Watchful waiting is highlighted as an alternative therapeutic option in individual patients. This article addresses a number of aspects and discrepancies between findings and patients' level of suffering based on binocular symptoms. Postoperative retinal thickening and irregular surface of the macula after peeling operations may still allow excellent function and often require no therapeutic measures. The difficulties in differentiating between cystoid macular edema after cataract operations with simultaneous epiretinal gliosis and gliosis as the cause of macular edema are highlighted.

Elimination of huntingtin in the adult mouse leads to progressive behavioral deficits, bilateral thalamic calcification, and altered brain iron homeostasis.

Huntington's Disease (HD) is an autosomal dominant progressive neurodegenerative disorder characterized by cognitive, behavioral and motor dysfunctions. HD is caused by a CAG repeat expansion in exon 1 of the HD gene that is translated into an expanded polyglutamine tract in the encoded protein, huntingtin (HTT). While the most significant neuropathology of HD occurs in the striatum, other brain regions are also affected and play an important role in HD pathology. To date there is no cure for HD, and recently strategies aiming at silencing HTT expression have been initiated as possible therapeutics for HD. However, the essential functions of HTT in the adult brain are currently unknown and hence the consequence of sustained suppression of HTT expression is unpredictable and can potentially be deleterious. Using the Cre-loxP system of recombination, we conditionally inactivated the mouse HD gene homologue at 3, 6 and 9 months of age. Here we show that elimination of Htt expression in the adult mouse results in behavioral deficits, progressive neuropathological changes including bilateral thalamic calcification, and altered brain iron homeostasis.