Type I astrocytes and microglia induce a cytokine response in an encephalitic murine coronavirus infection.

The pathogenesis of viral infections involves an immune response by cytokines, causing a deleterious effect on organ function, in addition to tissue destruction due to viral replication. Clinical symptoms and laboratory findings of the human coronavirus disease COVID-19, caused by the novel coronavirus SARS CoV-2, indicate cytokine involvement. Our laboratory showed that an experimental murine coronavirus (MHV-A59) can be transmitted into the brain by intranasal or intracerebral exposure and that neurovirulence is mediated by cytokine secretion. In this study we investigated which cells in the brain produce cytokines, thus functioning as the brain's innate immune system. Using tissue cultures of microglia, and clonal populations of astrocytes, we found that microglia and type I astrocytes (but not types II and III), produced pro-inflammatory cytokines in response to MHV-A59 infection. A molecularly closely related, non-encephalitic strain of the virus (MHV-2) caused in vitro infection, but without cytokine induction. Furthermore, immunofluorescence and immunohistochemistry revealed that type I astrocytes and microglia have perivascular foot processes necessary for the formation of the perivascular glymphatic system, the anatomical site of the brain's innate immune system. Cytokine secretion by type I astrocytes and microglia, as part of the brain's glymphatic and innate immune system, contributes to the pathogenesis of an encephalitic coronavirus infection, and indicates the rationale for anti-cytokine therapies for COVID-19.

Ischemic Optic Neuropathy Secondary to Intravascular Lymphoma.

BACKGROUND: To describe a case of optic neuropathy associated with intravascular lymphoma (IVL). METHODS: Case report and review of the literature. RESULTS: A case of asymmetric binocular vision loss is described, preceded by transient vision loss. Associated optic perineural enhancement and enhancing and diffusion-positive cortical lesions were observed on magnetic resonance imaging. Biopsy of the cerebellum revealed exclusively intraluminal neoplastic B-cells consistent with IVL. CONCLUSIONS: Patients with IVL may rarely present with optic nerve involvement, presumably due to small vessel occlusion. The presentation may mimic features of anterior ischemic optic neuropathy including an acute onset and disc edema. Although optic nerve enhancement and associated white matter lesions may suggest optic neuritis, enhancement of the optic nerve sheath, as in this case, has a wide differential diagnosis, which includes giant cell arteritis. IVL should be considered in atypical cases of optic neuropathy accompanied by enhancing, diffusion-positive brain lesions that are not within a specific vascular territory.

Novel activating BRAF fusion identifies a recurrent alternative mechanism for ERK activation in pediatric Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm characterized by constitutive activation of extracellular signal-regulated kinase (ERK). Genomic characterization has identified activating point mutations including mutually exclusive BRAFV600E and activating MAP2K1 mutations to be responsible for ERK activation in a majority of pediatric LCH patients. Here, we report the discovery of a novel BRAF kinase fusion, PACSIN2-BRAF, in a child with multisystem LCH. This is the second reported case of an activating BRAF kinase fusion and indicates a recurrent pathologic mechanism. Genomic evaluation for activating kinase fusions should be strongly considered in pediatric LCH patients lacking more common mutations.

Middle Meningeal Artery Embolization as Treatment for Chronic Subdural Hematoma: A Case Series.

BACKGROUND: Traditional treatment for symptomatic subdural hematoma (SDH) has been surgical evacuation, but recurrence rates are high and patients often harbor complex medical comorbidities. Growth and recurrence is thought to be due to the highly friable nature of the vascularized membrane that forms after initial injury. There have been reported cases of middle meningeal artery (MMA) embolization for treatment of recurrent SDH after surgical evacuation with the goal of eliminating the arterial supply to this vascularized membrane. OBJECTIVE: To present the first known case series of MMA embolization as upfront treatment for symptomatic chronic SDHs that have failed conservative management in lieu of surgical evacuation. METHODS: Five patients with symptomatic chronic SDHs underwent MMA embolization using PVA microparticles at our institution. Size of SDH was recorded in maximum diameter and total volume. RESULTS: Four patients underwent unilateral and 1 underwent bilateral MMA embolization successfully. All cases had significant reduction in total volume of SDH at longest follow-up scan: 81.4 to 13.8 cc (7 wk), 48.5 to 8.7 cc (3 wk), 31.7 and 88 to 0 and 17 cc (14 wk, bilateral), 79.3 to 24.2 cc (8 wk), and 53.5 to 0 cc (6 wk). All patients had symptomatic relief with no complications. Histologic analysis of the chronic SDH membrane in a separate patient that required surgery revealed rich neovascularization with many capillaries and few small arterioles. CONCLUSION: MMA embolization could present a minimally invasive and low-risk initial treatment alternative to surgery for symptomatic chronic SDH when clinically appropriate.

Transtubular excisional biopsy as a rescue for a non-diagnostic stereotactic needle biopsy-case report and literature review.

Stereotactic needle biopsy, a standard of care for acquiring deep-seated pathology, has limitations and risks in some situations. We present an uncommon case with basal ganglia dematiaceous mycetoma. Due to the firm consistency of the lesion, the initial stereotactic needle biopsy failed to provide a diagnosis. In a second operation, transtubular excisional biopsy was successfully performed to remove the entire mycetoma. We reviewed recent case series of transtubular approaches to deep-seated brain lesions and suggest this method could be a rescue for a non-diagnostic stereotactic needle biopsy and even may be the approach of choice in some cases.

An Acute Disseminated Encephalomyelitis-Like Illness in the Elderly: Neuroimaging and Neuropathology Findings.

INTRODUCTION: Acute disseminated encephalomyelitis (ADEM) is a rare demyelinating disease of the central nervous system (CNS) that classically occurs in children and adolescents. It characteristically presents with acute inflammation, resulting in demyelination, often following an infectious disease. ADEM has been described in adult patients, but the incidence in the adult and especially elderly population is low. CASES: We describe five older adults (age 57 to 85) who presented with acute neurological symptoms. Three patients presented with an infectious illness preceding the event, 4 patients were encephalopathic, and oligoclonal bands (OCBs) were negative in all tested cases. The clinical scenario and imaging studies suggested alternative diagnoses, such as metastasis, primary CNS tumor, or stroke. Two patients had contrast enhancing lesions, two other patients had lesions with restricted diffusion on diffusion-weighted imaging. Neuropathologic diagnostic from biopsy or autopsy was eventually conclusive, showing perivascular zones of myelin loss with relative axonal sparing in all five cases. CONCLUSION: Each of these patients was found to have pathological findings of acute demyelination on tissue diagnosis, suggesting ADEM or ADEM-like disease. The initial presentation and imaging was pointing toward other diagnoses. Broad differential diagnosis is important, especially for older patients, and pathological proof might be warranted for a conclusive diagnosis.

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): an epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway.

Epileptogenic tumors affecting children and young adults are a morphologically diverse collection of neuroepithelial neoplasms that, as a group, exhibit varying levels of glial and/or neuronal differentiation. Recent advances in molecular profiling technology, including comprehensive DNA sequencing and methylation analysis, have enabled the application of more precise and biologically relevant classification schemes to these tumors. In this report, we describe a morphologically and molecularly distinct epileptogenic neoplasm, the polymorphous low-grade neuroepithelial tumor of the young (PLNTY), which likely accounts for a sizable portion of oligodendroglioma-like tumors affecting the pediatric population. Characteristic microscopic findings most notably include infiltrative growth, the invariable presence of oligodendroglioma-like cellular components, and intense immunolabeling for cluster of differentiation 34 (CD34). Moreover, integrative molecular profiling reveals a distinct DNA methylation signature for PLNTYs, along with frequent genetic abnormalities involving either B-Raf proto-oncogene (BRAF) or fibroblast growth factor receptors 2 and 3 (FGFR2, FGFR3). These findings suggest that PLNTY represents a distinct biological entity within the larger spectrum of pediatric, low-grade neuroepithelial tumors.

Imaging findings of spinal brown tumors: a rare but important cause of pathologic fracture and spinal cord compression.

Brown tumors rarely develop in the spine, and neurological compromise is exceedingly uncommon. There is a growing body of literature describing brown tumors that involve the spine, but few emphasize the radiographic findings. In the present case, we illustrate the development and progression of biopsy-proven brown tumors leading to neurological compromise through radiographs, computed tomography, magnetic resonance, and nuclear imaging acquired over a 4-year span.

CD1a Reactivity in Non-neoplastic Adenohypophysis.

Within the differential diagnosis of patients presenting with sellar or suprasellar lesions is Langerhans cell histiocytosis (LCH). CD1a staining is frequently used to identify the presence of an abnormal proliferation of Langerhans cells on histologic sections and contributes to the diagnosis of LCH. Here, we report that the MTB-1 monoclonal antibody against the CD1a antigen reacts to native adenohypophyseal epithelial cells. We show that immunohistochemistry for CD1a exhibits strong positivity in all autopsy and surgically resected non-neoplastic adenohypophysis tested. Thus, CD1a positivity by itself should be interpreted with caution, and we recommend the routine use of a panel of stains including CD1a, Langerin, and synaptophysin in conjunction with morphologic analysis before a diagnosis of LCH is rendered. In addition, we find that pituitary adenomas fail to stain for CD1a prompting consideration of the utility of this stain as a marker for non-neoplastic gland.

VZV, temporal arteritis, and clinical practice: False positive immunohistochemical detection due to antibody cross-reactivity.

Varicella Zoster Virus (VZV) antigen has been reported to be present in the majority of temporal artery biopsies with implications for antiviral treatment in patients with giant cell arteritis. Using immunohistochemistry with VZV antibodies we found reactivity present in diverse myocyte types (smooth, skeletal and cardiac), diverse arteries (including temporal, coronary, and vertebral) and diverse clinical settings. This phenomenon is likely due to shared epitopes between VZV proteins and muscle elements and not due to actual VZV infection. We conclude that VZV immunohistochemistry should be used with caution for screening of VZV infection in the setting of temporal artery biopsies.

Pituitary adenoma-neuronal choristoma is a pituitary adenoma with ganglionic differentiation.

The presence of ganglion cells within an endocrine pituitary tumor has been named hamartoma, choristoma, gangliocytoma, or most recently pituitary adenoma-neuronal choristoma (PANCH). The presence of neuronal differentiation in regular pituitary adenomas has been previously suggested, however, its origin, the extent of its presence, and the relationship between the neuronal elements and the pituitary adenoma remain uncertain. Thus, to further explore the neuronal potential of pituitary tumors, we used immunohistochemistry on pituitary tumors of different grades, with a neuronal antigen protein (NeuN) antibody as a specific marker for mature neuronal differentiation. We found NeuN expression in 26.47% (9/34) cases of pituitary tumors without ganglionic differentiation (7 adenomas, 1 atypical adenoma and 1 pituitary carcinoma), in addition to NeuN expression in pituitary adenomas with ganglionic cells (2/2). Thus, neuronal expression is an innate property of pituitary adenomas. We propose that the rare presence of ganglionic cells in pituitary adenomas is not the result of a separate lesion or "collision sellar tumors", as previously suggested, but a ganglionic neuronal differentiation in an endocrine neoplasm. The ganglionic cells may be arising from uncommitted stem/progenitor cells that contain both neuronal and endocrine properties. A label of "pituitary adenoma with ganglionic differentiation" would better reflect the dual differentiation in a neuroendocrine tumor than the current label "PANCH".

Direct Invasion of the Optic Nerves, Chiasm, and Tracts by Cryptococcus neoformans in an Immunocompetent Host.

Cryptococcus spp is a common fungal infection and frequent cause of meningitis in immunocompromised patients; however, immunocompetent patients are also at risk of infection. Visual loss often occurs via elevated intracranial hypertension but can rarely occur through direct optic nerve, chiasm, or tract invasion. We report a case of a 38-year-old woman who presented with decreased acuity in both eyes. She had generalized visual field constriction in the right eye and temporal hemianopsia in the left eye. Magnetic resonance imaging of the brain and orbits showed multiple areas of ill-defined enhancement in the optic chiasm and tracts as well as in the diaphragmatic sella, prepontine and interpeduncular cisterns, and along cranial nerves VI, VII, and VIII bilaterally. Initial cerebrospinal fluid (CSF) showed 34 white blood cells, hypoglycorrhachia, and negative cryptococcal antigen and bacterial and fungal cultures. A transphenoidal biopsy of the dura and pituitary gland was unremarkable. Empiric steroids resulted in marked improvement in visual acuity in both eyes, but while tapering steroids, she developed rapid visual loss bilaterally. Repeat CSF performed 6 weeks later demonstrated a cryptococcal antigen titer of 1:512. Retroactive staining of the pituitary biopsy was positive for mucicarmine, a component of the polysaccharide capsule of Cryptococcus spp. After induction therapy with amphotericin B and flucytosine and 1 year of fluconazole, her visual acuity was 20/20 in both eyes. In summary, Cryptococcus can affect immunocompetent patients and often presents with insidious, chronic meningitis. Visual loss is common in cryptococcal meningitis but usually results from fulminant papilledema related to elevated intracranial pressure. In rare cases, direct nerve or chiasm infiltration by the fungus results in vision loss.

Parasellar xanthogranulomas.

OBJECT: Xanthogranulomas are rare inflammatory masses most often found in the skin and eye. The incidence of intracranial xanthogranulomas is 1.6%-7%, with those found in the sellar and parasellar region being exceedingly rare and their etiology controversial. Sellar and parasellar xanthogranulomas are rarely reported in the western hemisphere, and their incidence in Western countries is unknown. METHODS: A prospectively acquired database of all endonasal endoscopic transsphenoidal surgeries performed at Weill Cornell Medical College was queried. Patients with histologically confirmed xanthogranulomas who were diagnosed and treated between 2003 and 2013 were included in the study. Patient history, demographic data, histological findings, and surgical approach were also evaluated. RESULTS: A total of 643 endonasal endoscopic procedures had been performed at the time of this study. Four patients (0.6%) were identified as having a histologically confirmed xanthogranuloma of the parasellar region, compared with an incidence of 6.7% for craniopharyngioma (CP) and 2% for Rathke cleft cyst (RCC). The most common symptom was visual loss, followed by headache. Preoperative diagnosis was CP in all cases. All patients underwent extended endonasal endoscopic transsphenoidal surgery with gross-total resection. Two patients developed panhypopituitarism after surgery. There were no CSF leaks. The mean follow-up was 61 months, at which time there were no recurrences. The key histological features differentiating xanthogranulomas from CPs were accumulation of foamy macrophages, multinucleated foreign body giant cells, cholesterol clefts, and hemosiderin deposits without stratified squamous epithelium. These histological features appear commonly as part of the spectrum of a secondary inflammatory response in an RCC. CONCLUSIONS: Parasellar xanthogranulomas most closely approximate CPs clinically but pathological evidence may suggest an RCC origin. Gross-total resection can be achieved through extended endonasal endoscopic transsphenoidal approaches, and is curative.

Toxicity evaluation of prolonged convection-enhanced delivery of small-molecule kinase inhibitors in naïve rat brainstem.

PURPOSE: Convection-enhanced delivery (CED), a local drug delivery technique, is typically performed as a single session and drug concentrations therefore decline quickly post CED. Prolonged CED (pCED) overcomes this problem by performing a long-term infusion to maintain effective drug concentrations for an extended period. The purpose of the current study was to assess the toxicity of using pCED to deliver single and multi-drug therapy in naïve rat brainstem. METHODS: Sixteen rats underwent pCED of three small-molecule kinase inhibitors in the pons. Single and multi-drug combinations were delivered continuously for 7 days using ALZET mini-osmotic pumps (model 2001, rate of 1 µl/h). Rats were monitored daily for neurological signs of toxicity. Rats were sacrificed 10 days post completion of infusion, and appropriate tissue sections were analyzed for histological signs of toxicity. RESULTS: Two rats exhibited signs of neurological deficits, which corresponded with diffuse inflammation, necrosis, and parenchymal damage on histological analysis. The remaining rats showed no neurological or histological signs of toxicity. CONCLUSION: The neurological deficits in the two rats were likely due to injury from physical force, such as cannula movement post insertion and subsequent encephalitis. The remaining rats showed no toxicity and therefore brainstem targeting using pCED to infuse single and multi-drug therapy was well tolerated in these rats.

Amyloid ß-Related Central Nervous System Angiitis Presenting With an Isolated Seizure.

Amyloid beta-related angiitis (ABRA) of the central nervous system (CNS) is a very rare inflammatory disorder that causes destruction of CNS arteries and subsequent neuronal injury. Most patients with ABRA are old and present with cognitive dysfunction and stroke; however, some patients may present atypically. In this article, we report a 44-year-old man who presented with a first-time seizure but was otherwise neurologically intact and denied any headache. Brain MRI showed right hemispheric and bilateral medial frontal lobe hyperintensities and microhemorrhages that were most suspicious for a mass lesion. An extensive diagnostic evaluation including CSF analysis and catheter angiography was unremarkable. A brain biopsy with specific stains for amyloid surprisingly demonstrated ABRA and led to immunosuppressive treatment. The patient has remained neurologically intact and seizure-free 1 year after presentation. This case demonstrates that ABRA can occur in young patients without headache or neurologic deficits, and should be considered in patients with new-onset seizures and mass lesions. It also reinforces the need to consider a brain biopsy in patients with idiopathic brain lesions and negative non-invasive testing, as it is virtually impossible to confirm the diagnosis of ABRA otherwise.

Glioblastoma-arteriovenous fistula complex: imaging characteristics and treatment considerations.

Although a certain degree of arteriovenous shunting may be expected in glioblastoma, to our knowledge, the coexistence of a glioblastoma and arteriovenous fistula has not been previously reported. In this case report, we present such a lesion and discuss its diagnosis with a multimodal imaging approach. Additionally, we discuss treatment considerations for such a lesion.