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Myxopapillary ependymomas (MPE) are considered benign (World Health Organization (WHO) grade I) neoplasms with favorable prognosis. However, malignant behavior occurs in a small subset. To our knowledge, only five anaplastic MPEs have been reported without consensus on diagnostic criteria. We retrieved 14 anaplastic MPEs from the pathology archives of six institutions. Each tumor included at least two of the following features: ≥5 mitoses per 10 high power fields, Ki-67 labeling index (LI) ≥10%, microvascular proliferation (MVP) and spontaneous necrosis. These features were typically encountered in the foci of hypercellularity and reduced mucin. There were eight male and six female patients (age range 6–57 years, median = 16.5). Ten tumors displayed anaplasia at initial resection, and 4 were anaplastic at a second surgery for recurrence (ranging from 9 months to 14 years following initial resection). The Ki-67 LI ranged between 8% and 40% in the anaplastic foci and

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly encountered in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. A small group of ATRT stands out clinically, because these tumors are located in the sellar region of adults. To investigate if sellar region ATRT in adults represents a molecular distinct entity, we characterized molecular alterations in 7 sellar region ATRTs in adults as compared with 150 pediatric ATRTs and 47 pituitary adenomas using SMARCB1 sequencing, multiplex ligation-dependent probe amplification and fluorescence in situ hybridization as well as DNA methylation profiling. The median age of the 6 female and 1 male patients was 56 years. On histopathologic examination, all tumors were malignant rhabdoid tumors showing loss of SMARCB1/INI1 protein expression. Two cases displayed compound heterozygous SMARCB1 point mutations, 3 cases showed heterozygous SMARCB1 deletions with point mutations of the other allele and 1 case a homozygous SMARCB1 deletion; in 1 case, underlying SMARCB1 alterations could not be identified. On unsupervised hierarchical cluster analysis of DNA methylation profiles, sellar region ATRTs did not form a distinct group, but clustered with ATRT-MYC, 1 of 3 recently described molecular subgroups of ATRT. On analysis of DNA methylation array intensity data, only 1 sellar region ATRT showed characteristic features of pediatric ATRT-MYC, that is, major copy number losses affecting the SMARCB1 region. In conclusion, these results suggest that sellar region ATRTs in adults form a clinically distinct entity with a different mutational spectrum, but epigenetic similarities with pediatric ATRTs of the ATRT-MYC subgroup.

Increased overall survival for patients with glioma brain tumours is associated with mutations in the metabolic regulator isocitrate dehydrogenase 1 (IDH1). Gliomas develop within a mechanically challenged microenvironment that is characterized by a dense extracellular matrix (ECM) that compromises vascular integrity to induce hypoxia and activate HIF1α. We found that glioma aggression and patient prognosis correlate with HIF1α levels and the stiffness of a tenascin C (TNC)-enriched ECM. Gain- and loss-of-function xenograft manipulations demonstrated that a mutant IDH1 restricts glioma aggression by reducing HIF1α-dependent TNC expression to decrease ECM stiffness and mechanosignalling. Recurrent IDH1-mutant patient gliomas had a stiffer TNC-enriched ECM that our studies attributed to reduced miR-203 suppression of HIF1α and TNC mediated via a tension-dependent positive feedback loop. Thus, our work suggests that elevated ECM stiffness can independently foster glioblastoma aggression and contribute to glioblastoma recurrence via bypassing the protective activity of IDH1 mutational status.

While immunotherapy may offer promising new approaches for high grade meningiomas, little is currently known of the immune landscape in meningiomas. We sought to characterize the immune microenvironment and a potentially targetable antigen mesothelin across WHO grade I-III cases of meningiomas, and how infiltrating immune populations relate to patient outcomes. Immunohistochemistry was performed on tissue microarrays constructed from 96 meningioma cases. The cohort included 16 WHO grade I, 62 WHO grade II, and 18 WHO grade III tumors. Immunohistochemistry was performed using antibodies against CD3, CD8, CD20, CD68, PD-L1, and mesothelin. Dual staining using anti-PD-L1 and anti-CD68 antibodies was performed, and automated cell detection and positive staining detection algorithms were utilized. Greater degree of PD-L1 expression was found in higher grade tumors. More specifically, higher grade tumors contained increased numbers of intratumoral CD68-, PD-L1+ cells (p = 0.022), but did not contain higher numbers of infiltrating CD68+, PD-L1+ cells (p = 0.30). Higher PD-L1+/CD68- expression was independently predictive of worse overall survival in our cohort when accounting for grade, performance status, extent of resection, and recurrence history (p = 0.014). Higher expression of PD-L1+/CD68- was also present in tumors that had undergone prior radiotherapy (p = 0.024). Approximately quarter of meningiomas overexpressed mesothelin to levels equivalent to those found in pancreatic carcinomas and malignant mesotheliomas. The association with poor survival outcomes in our study suggests that PD-L1 may play a significant biologic role in the aggressive phenotype of higher grade meningiomas. Thus, immunotherapeutic strategies such as checkpoint inhibition may have clinical utility in PD-L1 overexpressing meningiomas.

Distal myopathies are a group of clinically and pathologically overlapping muscle diseases that are genetically complex and can represent a diagnostic challenge. Laing early-onset distal myopathy (MPD1) is a form of distal myopathy caused by mutations in the MYH7 gene, which encodes the beta myosin heavy chain protein expressed in type 1 skeletal muscle fibers and cardiac myocytes. Here, we present a case of genetically confirmed MPD1 with a typical clinical presentation but distinctive light microscopic and ultrastructural findings on muscle biopsy. A 39-year-old professional male cellist presented with a bilateral foot drop that developed by age 8; analysis of the family pedigree showed an autosomal dominant pattern of inheritance. The physical exam demonstrated bilateral weakness of ankle dorsiflexors, toe extensors and finger extensors; creatine kinase level was normal. Biopsy of the quadriceps femoris muscle showed predominance and hypotrophy of type 1 fibers, hybrid fibers with co-expression of slow and fast myosin proteins (both in highly atrophic and normal size range), moth-eaten fibers and mini-cores, lack of rimmed vacuoles and rare desmin-positive eosinophilic sarcoplasmic inclusions. In addition to these abnormalities often observed in MPD1, the biopsy demonstrated frequent clefted fibers with complex sarcolemmal invaginations; on ultrastructural examination, these structures closely mimicked myotendinous junctions but were present away from the tendon and were almost exclusively found in type 1 fibers. Sequencing analysis of the MYH7 gene in the index patient and other affected family members demonstrated a previously described heterozygous c.4522_4524delGAG (p.Glu1508del) mutation. This case widens the pathologic spectrum of MPD1 and highlights the pathologic and clinical variability that can accompany the same genetic mutation, suggesting a significant role for modifier genes in MPD1 pathogenesis.

Lower-grade (World Health Organization Grades II and III) gliomas vary widely in clinical behavior and are classified as astrocytic, oligodendroglial, or mixed. Anaplasia depends greatly on mitotic activity, with CDKN2A loss considered as the most common mechanism for cell cycle dysregulation. We investigated whether loss of the CDKN2A gene is associated with overall survival across pathologically and genetically defined glioma subtypes. After adjustment for IDH mutation, sex, and age, CDKN2A deletion was strongly associated with poorer overall survival in astrocytomas but not in oligodendrogliomas or oligoastrocytomas. Molecular classification of astrocytomas by IDH mutation, TP53 mutation, and /or ATRX loss of expression revealed that CDKN2A loss in IDH/TP53 mutated tumors was strongly associated with worse overall survival. CDKN2A loss in IDH mutated tumors with ATRX loss was only weakly associated with worse overall survival. These findings suggest that CDKN2A testing may provide further clinical aid in lower-grade glioma substratification beyond IDH mutation and 1p19q codeletion status, particularly in IDH/TP53 mutated astrocytomas.

SummaryThe evolutionary history of tumor cell populations can be reconstructed from patterns of genetic alterations. In contrast to stable genetic events, epigenetic states are reversible and sensitive to the microenvironment, prompting the question whether epigenetic information can similarly be used to discover tumor phylogeny. We examined the spatial and temporal dynamics of DNA methylation in a cohort of low-grade gliomas and their patient-matched recurrences. Genes transcriptionally upregulated through promoter hypomethylation during malignant progression to high-grade glioblastoma were enriched in cell cycle function, evolving in parallel with genetic alterations that deregulate the G1/S cell cycle checkpoint. Moreover, phyloepigenetic relationships robustly recapitulated phylogenetic patterns inferred from somatic mutations. These findings highlight widespread co-dependency of genetic and epigenetic events throughout brain tumor evolution.

Pilocytic astrocytoma is a low-grade glioma that affects mostly children and young adults and can occur anywhere in the central nervous system. Pilocytic astrocytoma of the optic nerve is an equally indolent subtype that is occasionally associated with neurofibromatosis type 1. In earlier studies, this subtype was considered within the larger category of 'optic pathway glioma,' which included infiltrating astrocytomas and other hypothalamic tumors. However, there have been suggestions that gliomas in the optic nerve, and especially pilocytic astrocytoma of the optic nerve, are biologically different from tumors within the hypothalamus and other parts of the optic tract. Furthermore, the recent discovery of BRAF duplication and fusion with the KIAA1549 gene is reported to be more typical for posterior fossa tumors, and the rate of this aberration is not well known in pilocytic astrocytoma of the optic nerve. To determine the distinction of pilocytic astrocytoma of the optic nerve from pilocytic astrocytoma of the posterior fossa and to investigate the prevalence of BRAF aberrations, we reviewed the clinicopathological and molecular features of all such patients in our institution. Our study demonstrates that BRAF duplication is more frequent in posterior fossa tumors compared with pilocytic astrocytoma of the optic nerve (P=0.011). However, the rates of phospho-MAPK1 and CDKN2A expression were high in both pilocytic astrocytoma of the optic nerve and posterior fossa pilocytic astrocytoma, suggesting that the MAPK pathway is active in these tumors. Our study supports the notion that BRAF duplication is more typical of posterior fossa pilocytic astrocytoma and that molecular alterations other than KIAA1549 fusion may underlie MAPK pathway activation in pilocytic astrocytoma of the optic nerve.

Glioblastomas (GBM) are aggressive brain tumors that inevitably recur despite surgical resection, chemotherapy, and radiation. The degree to which recurrent GBM retains its initial immunophenotype is incompletely understood. We generated tissue microarrays of paired initial and posttreatment GBM (3 pairs positive and 17 negative for IDH1 R132H ) from the same patients and made comparisons in the IDH1 R132H -negative group for immunohistochemical and gene expression differences between primary and recurrent tumors. In initial tumors, immunopositivity for Ki-67 in > 20% of tumor cells was associated with shorter progression-free and overall survival. Recurrent tumors showed decreased staining for CD34 suggesting lower vessel density. A subset of tumors showed increased staining for markers associated with the mesenchymal gene expression pattern, including CD44, phosphorylated STAT3, and YKL40. Recurrent tumors with the greatest increase in mesenchymal marker expression had rapid clinical progression, but no difference in overall survival after second surgery. Comparison of protein and gene expression data from the same samples revealed a poor correlation. A subset of tumors (15%) showed loss of neurofibromin protein in both initial and recurrent tumors. These data support the notion that GBM progression is associated with a shift toward a mesenchymal phenotype in a subset of tumors and this may portend a more aggressive behavior.

Amyloid precursor protein (APP) vesicle movement by kinesin-1 and cytoplasmic dynein exhibits kinesin-1–dependent velocity. Our data also suggest that kinesin-1 and cytoplasmic dynein motors assemble in stable mixtures on APP vesicles and that their direction and velocity are controlled at least in part by dynein IC., Bidirectional axonal transport driven by kinesin and dynein along microtubules is critical to neuronal viability and function. To evaluate axonal transport mechanisms, we developed a high-resolution imaging system to track the movement of amyloid precursor protein (APP) vesicles in Drosophila segmental nerve axons. Computational analyses of a large number of moving vesicles in defined genetic backgrounds with partial reduction or overexpression of motor proteins enabled us to test with high precision existing and new models of motor activity and coordination in vivo. We discovered several previously unknown features of vesicle movement, including a surprising dependence of anterograde APP vesicle movement velocity on the amount of kinesin-1. This finding is largely incompatible with the biophysical properties of kinesin-1 derived from in vitro analyses. Our data also suggest kinesin-1 and cytoplasmic dynein motors assemble in stable mixtures on APP vesicles and their direction and velocity are controlled at least in part by dynein intermediate chain.

Meningiomas represent the most common intracranial tumor in adults, and treatment options are currently limited for recurrent high grade meningiomas. While immunotherapy may offer promising new approaches for these tumors, little is known of the immune landscape in meningiomas. We sought to characterize the immune microenvironment across WHO grade I-III cases of meningiomas, and how infiltrating immune populations relate to patient outcomes. Immunohistochemistry was performed on tissue microarrays constructed from 96 meningioma cases. The cohort included 16 WHO grade I, 62 WHO grade II, and 18 WHO grade III tumors. Immunohistochemistry was performed using antibodies against CD3, CD8, CD20, CD68 and the immunomodulatory molecule, PD-L1. Dual staining using anti-PD-L1 and anti-CD68 antibodies was performed using fluorescence-conjugated secondary antibodies. Automated cell detection and positive staining detection algorithms were applied using StrataQuest software (Tissuegnostics, Vienna). Greater degree of PD-L1 expression was found in higher grade tumors. Higher grade tumors contained increased numbers of intratumoral CD68-, PD-L1+ cells (p = 0.022), but not double positive CD68 + , PD-L1+ infiltrating cells. Higher PD-L1 expression was independently predictive of worse overall survival in our cohort when accounting for grade, performance status, extent of resection, and recurrence history in a multivariate Cox proportional hazards model (p = 0.021). Partitioning analysis revealed >7.76% PD-L1-positive cells as the most significant cut-off predicting worse overall survival. Higher expression of PD-L1 was also present in tumors that had undergone prior radiotherapy (p = 0.041). There was no correlation between degree of PD-L1 expression and fractions of infiltrating CD3 + , CD8 + , CD20+ or CD68+ cells. CD3, CD8, CD20 or CD68 subpopulations were also not associated with survival outcomes. The association with decreased overall survival in our study suggests that PD-L1 may play a significant biologic role in the aggressive phenotype of higher grade meningiomas. Thus, immunotherapeutic agents may have clinical utility in PD-L1 overexpressing meningiomas.

Pilocytic astrocytoma (PA) is the most common astrocytic neoplasm of childhood. Patients have an extremely favorable prognosis after surgical resection, qualifying tumors for a grade I designation by the World Health Organization. The molecular data on PA support a key role for the BRAF oncogene in the pathogenesis of these tumors, with the KIAA1549-BRAF fusion being the most common alteration identified in sporadic cases, particularly those occurring in the posterior fossa. Constitutive activation of BRAF leads to downstream activation of the MEK/MAPK/ERK/p16 pathway, which interestingly is also used by cells to activate oncogene-induced senescence (OIS). In fact, the presence of an active OIS pathway might explain the periods of dormancy or spontaneous regression or both, that can be seen in PA. In addition to reviewing the historical evolution, clinicopathologic, predictive, prognostic, and molecular features of PA, we discuss current therapeutic strategies and the caveats that should be considered for the development of therapies that could be used to more effectively treat challenging cases. Individualized treatment requires identification of the type of MAPK alteration, as several alterations in BRAF have been described in addition to the KIAA1549-BRAF fusion. Combination regimens would also appear crucial to achieve tumor eradication and prevent the development of drug resistance. Balancing mitogen-activated protein kinases (MAPK) pathway inhibition with abrogation of an active OIS should be carefully considered as well to preserve any existing protective pathways. Importantly, PAs are largely indolent tumors, and care should be taken to avoid overtreatment, as aggressive therapy could cause more harm than good.

The pilocytic astrocytoma is predominantly a tumor of childhood and the most common type of circumscribed astrocytoma. The indolent nature of this tumor allows for prolonged survival for most patients, rendering the disease a rather “chronic” one, with potential long-term sequelae that are occasionally related to treatment. Two critical features of this tumor are its tendency to remain dormant, or involute even after subtotal resection, and the exceptional anaplastic transformation, sometimes following adjuvant therapy. The biological behavior of pilocytic astrocytoma can often be related to molecular alterations in the MAPK pathway.

Distal myopathies are a group of clinically and pathologically overlapping muscle diseases that are genetically complex and can represent a diagnostic challenge. Laing early-onset distal myopathy (MPD1) is a form of distal myopathy caused by mutations in the MYH7 gene, which encodes the beta myosin heavy chain protein expressed in type 1 skeletal muscle fibers and cardiac myocytes. Here, we present a case of genetically confirmed MPD1 with a typical clinical presentation but distinctive light microscopic and ultrastructural findings on muscle biopsy. A 39-year-old professional male cellist presented with a bilateral foot drop that developed by age 8; analysis of the family pedigree showed an autosomal dominant pattern of inheritance. The physical exam demonstrated bilateral weakness of ankle dorsiflexors, toe extensors and finger extensors; creatine kinase level was normal. Biopsy of the quadriceps femoris muscle showed predominance and hypotrophy of type 1 fibers, hybrid fibers with co-expression of slow and fast myosin proteins (both in highly atrophic and normal size range), moth-eaten fibers and mini-cores, lack of rimmed vacuoles and rare desmin-positive eosinophilic sarcoplasmic inclusions. In addition to these abnormalities often observed in MPD1, the biopsy demonstrated frequent clefted fibers with complex sarcolemmal invaginations; on ultrastructural examination, these structures closely mimicked myotendinous junctions but were present away from the tendon and were almost exclusively found in type 1 fibers. Sequencing analysis of the MYH7 gene in the index patient and other affected family members demonstrated a previously described heterozygous c.4522_4524delGAG (p.Glu1508del) mutation. This case widens the pathologic spectrum of MPD1 and highlights the pathologic and clinical variability that can accompany the same genetic mutation, suggesting a significant role for modifier genes in MPD1 pathogenesis.

A 29-year-old pregnant woman developed progressively worsening encephalopathy, left hemiparesis, and hemodynamic instability over a 6-week period. Initial brain MRI and work-up for infectious and autoimmune causes were normal, although elevated IgG and oligoclonal bands were seen on analysis of the cerebrospinal fluid (CSF). After uncomplicated spontaneous delivery of a preterm healthy infant, her condition worsened. Repeat brain MRI demonstrated generalized volume loss and evidence of corticospinal tract degeneration. She underwent a brain biopsy, which showed characteristic viral inclusions of the type seen in subacute sclerosing panencephalitis (SSPE). The diagnosis was confirmed by immunohistochemistry and electron microscopy, and additional CSF analysis also showed markedly elevated IgG titer for measles. Sequence analysis of the nucleoprotein gene N-450 demonstrated a close relationship to the sequences of viruses in genotype D7. This case documents an ~ 6-month progression to death of SSPE in a pregnant woman.

Beta-adrenergic receptors and the cyclic AMP signaling pathway play an important role in neuronal plasticity and in learning and memory and are known to change with aging. We examined the effects of β-adrenergic stimulation paired with 5-Hz low frequency stimulation (LFS) of Schaffer collateral-commissural afferents on population spike amplitude in area CA1 of hippocampal slices from young (3 mo) and aged (22 mo) Fischer 344 rats. Application of the β-adrenergic agonist isoproterenol (1 μM) for 10 min followed immediately by 3 min LFS produced long-lasting potentiation in young hippocampi, but the magnitude of potentiation in aged rats was significantly attenuated and was not long-lasting. In slices prepared from young rats, long-term potentiation (LTP) induced by this protocol occludes subsequent attempts to produce conventional high frequency stimulation-induced LTP, and vice versa, suggesting that these two forms of potentiation share one or more molecular mechanisms. Age-related differences in response to LFS alone were not observed, but significant differences in response to β-adrenergic stimulation were apparent. Similarly, significant age-related differences in response to direct activation of adenylate cyclase with forskolin (10 μM) were observed. In both age groups, this enhancement produced by isoproterenol or forskolin is only transient, returning to baseline within 60 or 90 min, respectively. Taken together, these studies of adenylate cyclase-mediated forms of potentiation in area CA1 suggest that there is an age-related defect, either upstream or downstream of adenylate cyclase activation, in this important signaling system. Such changes may contribute to the compromised performance on memory tasks that is often observed with normal aging.

The clonal evolution of tumor cell populations can be reconstructed from patterns of genetic alterations. In contrast, tumor epigenetic states, including DNA methylation, are reversible and sensitive to the tumor microenvironment, presumably precluding the use of epigenetics to discover tumor phylogeny. Here we examined the spatial and temporal dynamics of DNA methylation in a clinically and genetically characterized cohort of IDH1-mutant low-grade gliomas and their patient-matched recurrences. WHO grade II gliomas are diffuse, infiltrative tumors that frequently recur and may undergo malignant progression to a higher grade with a worse prognosis. The extent to which epigenetic alterations contribute to the evolution of low-grade gliomas, including malignant progression, is unknown. While all gliomas in the cohort exhibited the hypermethylation signature associated with IDH1 mutation, low-grade gliomas that underwent malignant progression to high-grade glioblastoma (GBM) had a unique signature of DNA hypomethylation enriched for active enhancers, as well as sites of age-related hypermethylation in the brain. Genes with promoter hypomethylation and concordant transcriptional upregulation during evolution to GBM were enriched in cell cycle function, evolving in concert with genetic alterations that deregulate the G1/S cell cycle checkpoint. Despite the plasticity of tumor epigenetic states, phyloepigenetic trees robustly recapitulated phylogenetic trees derived from somatic mutations in the same patients. These findings highlight widespread co-dependency of genetic and epigenetic events throughout the clonal evolution of initial and recurrent glioma.

Tumor-to-tumor metastasis of breast carcinoma to meningioma is a rare phenomenon. It is likely underdiagnosed given the relatively high prevalence and comorbidity of these two primary tumor types, the lack of standardized methodologies for its diagnosis, and the tendency to obfuscate this lesion with simple meningioma or cerebral metastasis of breast carcinoma. Careful histopathologic study of the resected meningioma is the cornerstone of diagnosis of these lesions, although certain conventional radiological features along with specialized modalities may clue the diagnosis. Vigilance for this lesion is appropriate in selected patients with known breast cancer or meningioma, as the two are often coexistent in the same patient, permitting tumor-to-tumor metastasis. Detection of this rare disease process may alter the treatment plan and prognosis. Here, we report a case of breast carcinoma-to-meningioma metastasis in a patient who developed subacute neurological decline while undergoing long-term treatment of her primary, late-stage breast cancer.

Neurodegeneration induced by abnormal hyperphosphorylation and aggregation of the microtubule-associated protein tau defines neurodegenerative tauopathies. Destabilization of microtubules by loss of tau function and filament formation by toxic gain of function are two mechanisms suggested for how abnormal tau triggers neuronal loss. Recent experiments in kinesin-1 deficient mice suggested that axonal transport defects can initiate biochemical changes that induce activation of axonal stress kinase pathways leading to abnormal tau hyperphosphorylation. Here we show using Drosophila and mouse models of tauopathies that reductions in axonal transport can exacerbate human tau protein hyperphosphorylation, formation of insoluble aggregates and tau-dependent neurodegeneration. Together with previous work, our results suggest that non-lethal reductions in axonal transport, and perhaps other types of minor axonal stress, are sufficient to induce and/or accelerate abnormal tau behavior characteristic of Alzheimer's disease and other neurodegenerative tauopathies. Fil: Falzone, Tomas Luis. University of California at San Diego; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina Fil: Gunawardena, Shermali. University of California at San Diego; Estados Unidos. State University of New York; Estados Unidos Fil: McCleary, David. University of California at San Diego; Estados Unidos Fil: Reis, Gerald F.. University of California at San Diego; Estados Unidos Fil: Goldstein, Lawrence S. B.. University of California at San Diego; Estados Unidos

Background Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome with both genetic and acquired causes characterized by elevated cytokine levels, hyperinflammation, and overactivation of lymphocytes and macrophages. It is typically a systemic disease with variable degrees of CNS involvement. Cases with predominantly central nervous system (CNS) involvement are very rare, with the vast majority of these occurring in infants and young children. This report documents a case of adult-onset CNS-HLH involving a middle-aged man. Case presentation A 55 year-old man developed progressive left hemiparesis and aphasia over the course of several months. Brain MRI showed multifocal, mass-like enhancing lesions with increased susceptibility consistent with blood products. An extensive workup for infectious, autoimmune, and neoplastic etiologies was significant only for a markedly elevated serum ferritin at 1456 ng/mL. Two brain biopsies showed a non-specific inflammatory process. The patient was treated empirically with steroids and plasmapheresis, but he continued to suffer a progressive neurological decline and died one year after onset of neurological symptoms. Autopsy revealed profound histiocytic infiltration, perivascular lymphocytosis, and emperipolesis, compatible with CNS-HLH. Conclusion This case report describes an exceedingly rare presentation of an adult patient with CNS predominant HLH. This diagnosis should be considered in the differential diagnosis of adults presenting with progressive brain lesions, even in the absence of typical systemic signs of HLH.