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.

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.

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.

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".

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.

Phase I/II study of oral erlotinib for treatment of relapsed/refractory glioblastoma multiforme and anaplastic astrocytoma.

We evaluated the safety and survival benefits of orally administered erlotinib monotherapy for patients with relapsed/refractory glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA). A dose escalation schedule was administered with a starting dose of 150 mg/day for the first cycle (28 days), followed by 100 mg twice daily for 14 days, and 150 mg twice daily for another 14 days. Assuming no dose limiting toxicities were observed, dosage was maintained at 150 mg BID for 10 more cycles. Disease and tumor responses were assessed after every other cycle; toxicity assessments were conducted for a minimum of 10 weeks. Patients discontinued use of enzyme-inducing anticonvulsants (EIAED) and started non-EIAEDs. Patients with previous erlotinib exposure were ineligible. Eleven patients were enrolled: 8 (73%) GBM; 3 (27%) AA. Adverse events limited study accrual, originally intended to accrue 43 patients. Nine patients (90%) experienced rash within the first 2 cycles: 7 (64%) within cycle 1; 6 (60%) reported diarrhea within the first 2 cycles. Median progress-free survival (PFS) and overall survival (OS) was 1.9 months and 6.9 months. All patients showed disease progression while on the drug. Despite the sample size, the toxicity of erlotinib supersedes any marginal benefit it as a monotherapy for relapsed/refractory GBM/AA.

Pineal parenchymal tumor of intermediate differentiation with papillary features: a continuum of primary pineal tumors?

Pineal parenchymal tumors comprise a rare group of primary neoplasms of the pineal gland. We describe a case involving a 29-year-old woman who presented with signs and symptoms of hydrocephalus secondary to a pineal region tumor obstructing the third ventricle. Surgical resection was performed and pathological analysis revealed a novel diagnosis consistent with a pineal parenchymal tumor of intermediate differentiation (PPTID) with transition to a papillary tumor of the pineal region (PTPR). To our knowledge, this particular pineal region tumor pathology has not yet been reported in the literature and highlights the continuum with which primary pineal tumors exist. We provide a review of the existing literature on pineal region tumors, specifically PTPR and PPTID, and offer insight into the management of these rare neoplasms.

Activation of the cholinergic anti-inflammatory system by nicotine attenuates neuroinflammation via suppression of Th1 and Th17 responses.

The alpha7 nicotinic acetylcholine receptor (nAChR) was recently described as an anti-inflammatory target in both macrophages and T cells. Its expression by immune cells may explain the epidemiological data claiming a negative link between cigarette smoking and several inflammatory diseases. In this study, we determined the immunological effects of alpha7 nAChR activation by nicotine. Our results indicate that the alpha7 nAChR is expressed on the surface of CD4(+) T cells and that this expression is up-regulated upon immune activation. Nicotine reduced T cell proliferation in response to an encephalitogenic Ag, as well as the production of Th1 (TNF-alpha and IFN-gamma) and Th17 cytokines (IL-17, IL-17F, IL-21, and IL-22). IL-4 production was increased in the same setting. Attenuation of the Th1 and Th17 lineages was accompanied by reduced T-bet (50%) and increased GATA-3 (350%) expression. Overall, nicotine induced a shift to the Th2 lineage. However, alpha7(-/-)-derived T cells were unaffected by nicotine. Furthermore, nicotine reduced NF-kappaB-mediated transcription as measured by IL-2 and IkappaB transcription. In vivo, administration of nicotine (2 mg/kg s.c.) suppressed the severity of CD4(+) T cell-mediated disease experimental autoimmune encephalomyelitis. alpha7(-/-) mice were refractory to nicotine treatment, although disease severity in those animals was reduced, due to impairment in Ag presentation. Accordingly, CD4(+) and CD11b(+) cells infiltration into the CNS, demyelination, and axonal loss were reduced. Our data implicate a role for the alpha7 nAChR in immune modulation and suggest that alpha7 nAChR agonists may be effective in the treatment of inflammatory disorders.

Pituitary carcinoma diagnosed on fine needle aspiration: Report of a case and review of pathogenesis.

Pituitary carcinoma (PC) is a very rare entity (0.2% of all pituitary tumors), with only about 140 cases reported in English literature. There are no reliable histological, immunohistochemical or ultrastructural features distinguishing pituitary adenoma (PA) from PC. By definition, a diagnosis of PC is made after a patient with PA develops non-contiguous central nervous system (CNS) or systemic metastases. To date, only three cases of PC have been reportedly diagnosed on fine needle aspiration (FNA). Two of the reported cases were diagnosed on FNA of the cervical lymph nodes and one on FNA of the vertebral bone lesion. Herein, we present a case of PC, diagnosed on FNA of the liver lesion. In this case, we describe cytologic features of PC and compare them to histologic features of the tumor in the pituitary. Clinical behavior of tumor, pathogenesis of metastasis and immunochemical and prognostic markers will also be described.

Large congenital melanotic nevi in an extremity with neurocutaneous melanocytosis.

A 14-day-old boy presented with a large congenital melanocytic nevus over his left thigh with approximately 17 satellite nevi distributed over the rest of his skin surface. Six weeks later, he developed generalized tonic-clonic seizures and additional satellite nevi became apparent (n > 20). A subsequent brain magnetic resonance imaging demonstrated right temporal T1 hyperintense signal abnormality. At 4 months of age the patient underwent a lumbar puncture that was normal without evidence of melanocytes or tumor. Nevertheless, a few days later he underwent resection of his right medial temporal lesion which demonstrated melanocytosis in the temporal lobe as well as melanocytosis in subependymal areas in other parts of the brain and ventricles, confirming the suspected diagnosis of neurocutaneous melanocytosis. Our case supports previous studies that conclude that the number of satellite nevi is a greater predictor of neurocutaneous melanocytosis than is the location of large congenital melanocytic nevus. In our case, cerebrospinal fluid studies were not reliable even in the face of florid neurocutaneous melanocytosis involving the leptomeninges and ventricles.

Suppression of neuroinflammation and immunomodulation by the acetylcholinesterase inhibitor rivastigmine.

In this study we determined the influence of cholinergic up-regulation by rivastigmine, an acetylcholinesterase inhibitor, on central nervous system inflammation. Neuroinflammation was induced in experimental autoimmune encephalomyelitis (EAE). Rivastigmine markedly ameliorated clinical symptoms of EAE and the spatial memory deficits induced by EAE. It also reduced demyelination, microglia activation and axonal damage. Rivastigmine decreased the reactivity of encephalitogenic T-cells and the production of pro-inflammatory cytokines (TNF-alpha, IFN-gamma and IL-17) without affecting IL-10 production. These effects were abolished by alpha7 nicotinic acetylcholine receptor antagonists. Antigen presentation was also affected by this treatment. Thus, rivastigmine treatment had immunomodulatory activity in EAE.

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.

Effect of DAB(389)IL-2 immunotoxin on the course of experimental autoimmune encephalomyelitis in Lewis rats.

Activated T cells express the high affinity interleukin 2 receptor (IL-2R also CD25) that binds interleukin 2 (IL-2) and transduces signals important for the proliferation and survival of these cells. We investigated the effect of the genetically engineered immunotoxin DAB(389)IL-2 on experimental autoimmune encephalomyelitis (EAE), an autoimmune disease of the central nervous system (CNS) mediated by activated myelin-reactive T cells. EAE is the most commonly used animal model of the human disease multiple sclerosis (MS). DAB(389)IL-2 is a recombinant fusion product made of a portion of diphtheria toxin, which contains binding and translocation components of the toxin linked to IL-2. The diphtheria toxin targets and kills cells expressing the high affinity IL-2 receptor and has been successfully used in several autoimmune and neoplastic conditions. We observed a significant suppression of guinea-pig spinal cord homogenate (gpSCH)-MBP induced active EAE in Lewis rats at 2 x 1,600 kU of DAB(389)IL-2 given on days 7 and 9 post-immunization and complete suppression with the same dose on days 7, 8 and 9 or 7, 8, 9 and 10 after immunization during the active disease period. There were reduced mononuclear cell infiltrates of CD4(+), CD8(+), CD25(+) and alphabetaTCR(+) T cells in the spinal cord of treated rats. However, treatment at day 11 or 12 post-immunization led to severe, fatal disease. The toxin added to cultures in vitro or injected in vivo suppressed antigen- and mitogen-induced T cell proliferation. DAB(389)IL-2 treatment in vivo or exposure of encephalitogenic T cells in vitro prior to transfer did have a significant inhibitory effect on adoptive transfer EAE. Our data demonstrate that DAB(389)IL-2 immunotoxin can suppress active and passive EAE if applied at specific, early time points, but can have negative consequences at later time points.

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.

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.