Advanced Imaging in the Diagnosis and Response Assessment of High-Grade Glioma: AJR Expert Panel Narrative Review.

This AJR Expert Panel Narrative explores the current status of advanced MRI and PET techniques for the post-therapeutic response assessment of high-grade adult-type gliomas, focusing on ongoing clinical controversies in current practice. Discussed techniques that complement conventional MRI and aid the differentiation of recurrent tumor from post-treatment effects include DWI and diffusion tensor imaging; perfusion MRI techniques including dynamic susceptibility contrast (DSC), dynamic contrast-enhanced MRI, and arterial spin labeling; MR spectroscopy including assessment of 2-hydroxyglutarate (2HG) concentration; glucose- and amino acid (AA)-based PET; and amide proton transfer imaging. Updated criteria for Response Assessment in Neuro-Oncology are presented. Given the abundant supporting clinical evidence, the panel supports a recommendation that routine response assessment after HGG treatment should include perfusion MRI, particularly given the development of a consensus recommended DSC-MRI protocol. Although published studies support 2HG MRS and AA PET, these techniques' widespread adoption will likely require increased availability (for 2HG MRS) or increased insurance funding in the United States (for AA PET). The article concludes with a series of consensus opinions from the author panel, centered on the clinical integration of the advanced imaging techniques into posttreatment surveillance protocols.

Identification of magnetic resonance imaging features for the prediction of molecular profiles of newly diagnosed glioblastoma.

PURPOSE: We predicted molecular profiles in newly diagnosed glioblastoma patients using magnetic resonance (MR) imaging features and explored the associations between imaging features and major molecular alterations. METHODS: This retrospective study included patients with newly diagnosed glioblastoma and available next-generation sequencing results. From preoperative MR imaging, Visually AcceSAble Rembrandt Images (VASARI) features, volumetric parameters, and apparent diffusion coefficient (ADC) values were obtained. First, univariate random forest was performed to identify gene abnormalities that could be predicted by imaging features with high accuracy and stability. Next, multivariate random forest was trained to predict the selected genes in the discovery cohort and was validated in the external cohort. Univariable logistic regression was performed to further explore the associations between imaging features and genes. RESULTS: Univariate random forest identified nine genes predicted by imaging features, with high accuracy and stability. The multivariate random forest model showed excellent performance in predicting IDH and PTPN11 mutations in the discovery cohort, which were validated in the external validation cohorts (areas under the receiver operator characteristic curve [AUCs] of 0.855 for IDH and 0.88 for PTPN11). ATRX loss and EGFR mutation were predicted with AUCs of 0.753 and 0.739, respectively, whereas PTEN could not be reliably predicted. Based on univariable logistic regression analyses, IDH, ATRX, and TP53 were clustered according to their shared imaging features, whereas EGFR and CDKN2A/B were clustered in the opposite direction. CONCLUSIONS: MR imaging features are related to specific molecular alterations and can be used to predict molecular profiles in patients with newly diagnosed glioblastoma.

Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial.

BACKGROUND: Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients. METHODS: The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3-21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549-BRAF fusion or the BRAFV600E [Val600Glu] mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m2 twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101. FINDINGS: Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% [95% CI 18-57]) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72-45·59). In stratum 3, ten (40% [21-61]) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14-51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]). No treatment-realted deaths were reported. INTERPRETATION: Selumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1. FUNDING: National Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca.

Location of subventricular zone recurrence and its radiation dose predicts survival in patients with glioblastoma.

Glioblastomas are aggressive brain tumors that frequently recur in the subventricular zone (SVZ) despite maximal treatment. The purpose of this study was to evaluate imaging patterns of subventricular progression and impact of recurrent subventricular tumor involvement and radiation dose to patient outcome. Retrospective review of 50 patients diagnosed with glioblastoma and treated with surgery, radiation, and concurrent temozolomide from January 2012 to June 2013 was performed. Tumors were classified based on location, size, and cortical and subventricular zone involvement. Survival was compared based on recurrence type, distance from the initial enhancing tumor (local ≤ 2 cm, distant > 2 cm), and the radiation dose at the recurrence site. Progression of enhancing subventricular tumor was common at both local (58%) and distant (42%) sites. Median survival was better after local SVZ recurrence than distant SVZ recurrence (8.7 vs. 4.3 months, p = 0.04). Radiation doses at local SVZ recurrence sites recurrence averaged 57.0 ± 4.0 Gy compared to 44.7 ± 6.7 Gy at distant SVZ recurrence sites (p = 0.008). Distant subventricular progression at a site receiving ≤ 45 Gy predicted worse subsequent survival (p = 0.05). Glioblastomas frequently recurred in the subventricular zone, and patient survival was worse when enhancing tumor occurred at sites that received lower radiation doses. This recurrent disease may represent disease undertreated at the time of diagnosis, and further study is needed to determine if improved treatment strategies, such as including the subventricular zone in radiation fields, could improve clinical outcomes.

MRI Features and IDH Mutational Status of Grade II Diffuse Gliomas: Impact on Diagnosis and Prognosis.

OBJECTIVE: Grade II diffuse gliomas (DGs) with isocitrate dehydrogenase (IDH) mutations are associated with better prognosis than their IDH wild-type counterparts. We sought to determine the MRI characteristics associated with IDH mutational status and ascertain whether MRI considered in combination with IDH mutational status can better predict the clinical outcomes of grade II DGs. MATERIALS AND METHODS: Preoperative MRI examinations were retrospectively studied for qualitative tumor characteristics, including location, extent, cortical involvement, margin sharpness, cystic component, mineralization or hemorrhage, and contrast enhancement. Quantitative diffusion and perfusion metrics were also assessed. Logistic regression and ROC analyses were used to evaluate the relationship between MRI features and IDH mutational status. The association between IDH mutational status, 1p19q codeletion, MRI features, extent of resection, and clinical outcomes was assessed by Kaplan-Meier and Cox proportional hazards models. RESULTS: Of 100 grade II DGs, 78 were IDH mutant and 22 were IDH wild type. IDH wild-type tumors were associated with older age, multifocality, brainstem involvement, lack of cystic change, and a lower apparent diffusion coefficient (ADC). Multivariable regression showed that age older than 45 years as well as low minimum ADC (ADCmin), mean ADC, and maximum ADC values were independently associated with IDH mutational status. Of these, an ADCmin threshold of 0.9 × 10-3 mm2/s or less provided the greatest sensitivity and specificity (91% and 76%, respectively) in defining IDH wild-type grade II DGs. Combining low ADCmin with IDH wild-type status conferred worse outcomes than did IDH wild-type status alone. CONCLUSION: IDH wild-type grade II DGs are associated with a lower ADC and poor clinical outcomes. Combining IDH mutational status and ADC may allow more accurate prediction of clinical outcomes for patients with grade II DGs.

PET/MRI: Where might it replace PET/CT?

Simultaneous positron emission tomography and MRI (PET/MRI) is a technology that combines the anatomic and quantitative strengths of MR imaging with physiologic information obtained from PET. PET and computed tomography (PET/CT) performed in a single scanning session is an established technology already in widespread and accepted use worldwide. Given the higher cost and complexity of operating and interpreting the studies obtained on a PET/MRI system, there has been question as to which patients would benefit most from imaging with PET/MRI versus PET/CT. In this article, we compare PET/MRI with PET/CT, detail the applications for which PET/MRI has shown promise and discuss impediments to future adoption. It is our hope that future work will prove the benefit of PET/MRI to specific groups of patients, initially those in which PET/CT and MRI are already performed, leveraging simultaneity and allowing for greater degrees of multiparametric evaluation. LEVEL OF EVIDENCE: 5 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2017;46:1247-1262.

Early tumor growth between initial resection and radiotherapy of glioblastoma: incidence and impact on clinical outcomes.

Early tumor growth, or increased contrast-enhancing tumor not related to evolving post-surgical injury, in the interval between surgical resection and initiation of radiotherapy has implications for treatment planning and clinical outcomes. In this study we evaluated the incidence of early tumor growth, correlated tumor growth with survival outcome measures, and assessed predictors of early tumor growth in glioblastoma. We reviewed the records of patients with newly-diagnosed glioblastoma who underwent surgical resection and chemoradiotherapy at our institution. Patients with preoperative, immediate postoperative, and preradiotherapy MRI were included. Conventional MRI and DWI features were assessed. The correlation between early tumor growth and extent of resection with survival was assessed with Kaplan-Meier analysis. Logistic regression was carried out to evaluate predictors of early tumor growth. Of 140 included patients, sixty-seven cases (48%) had new or increased contrast enhancement attributed to early tumor growth. Median progression free survival (PFS) and overall survival (OS) were shorter in patients with early tumor growth compared to those without early tumor growth (p < 0.001 for both). Additionally, PFS and OS were longer in patients who underwent gross total resection of enhancing tumor (p = 0.016 and <0.001, respectively). Of the evaluated predictors of early growth, subtotal resection was most likely to result in early growth (p < 0.001). Imaging evidence of early tumor growth is often observed at preradiotherapy MRI and is associated with shorter survival. Gross total resection of contrast enhancing tumor decreases likelihood of early tumor growth.

Quantitative multi-modal MR imaging as a non-invasive prognostic tool for patients with recurrent low-grade glioma.

Low-grade gliomas can vary widely in disease course and therefore patient outcome. While current characterization relies on both histological and molecular analysis of tissue resected during surgery, there remains high variability within glioma subtypes in terms of response to treatment and outcome. In this study we hypothesized that parameters obtained from magnetic resonance data would be associated with progression-free survival for patients with recurrent low-grade glioma. The values considered were derived from the analysis of anatomic imaging, diffusion weighted imaging, and 1H magnetic resonance spectroscopic imaging data. Metrics obtained from diffusion and spectroscopic imaging presented strong prognostic capability within the entire population as well as when restricted to astrocytomas, but demonstrated more limited efficacy in the oligodendrogliomas. The results indicate that multi-parametric imaging data may be applied as a non-invasive means of assessing prognosis and may contribute to developing personalized treatment plans for patients with recurrent low-grade glioma.

Serial analysis of 3D H-1 MRSI for patients with newly diagnosed GBM treated with combination therapy that includes bevacizumab.

Interpretation of changes in the T1- and T2-weighted MR images from patients with newly diagnosed glioblastoma (GBM) treated with standard of care in conjunction with anti-angiogenic agents is complicated by pseudoprogression and pseudoresponse. The hypothesis being tested in this study was that 3D H-1 magnetic resonance spectroscopic imaging (MRSI) provides estimates of levels of choline, creatine, N-acetylaspartate (NAA), lactate and lipid that change in response to treatment and that metrics describing these characteristics are associated with survival. Thirty-one patients with newly diagnosed GBM and being treated with radiation therapy (RT), temozolomide, erlotinib and bevacizumab were recruited to receive serial MR scans that included 3-D lactate edited MRSI at baseline, mid-RT, post-RT and at specific follow-up time points. The data were processed to provide estimates of metrics representing changes in metabolite levels relative to normal appearing brain. Cox proportional hazards analysis was applied to examine the relationship of these parameters with progression free survival (PFS) and overall survival (OS). There were significant reductions in parameters that describe relative levels of choline to NAA and creatine, indicating that the treatment caused a decrease in tumor cellularity. Changes in the levels of lactate and lipid relative to the NAA from contralateral brain were consistent with vascular normalization. Metabolic parameters from the first serial follow-up scan were associated with PFS and OS, when accounting for age and extent of resection. Integrating metabolic parameters into the assessment of patients with newly diagnosed GBM receiving therapies that include anti-angiogenic agents may be helpful for tracking changes in tumor burden, resolving ambiguities in anatomic images caused by non-specific treatment effects and for predicting outcome.

Multicenter phase 1 trial of intraventricular immunochemotherapy in recurrent CNS lymphoma.

UNLABELLED: Recurrent CNS lymphoma continues to be associated with poor outcomes in the rituximab era. Although IV rituximab mediates superior disease control of systemic non-Hodgkin lymphoma (NHL), it fails to completely eliminate the risk of meningeal recurrence, likely due to minimal CNS penetration. Given that rituximab acts synergistically with chemotherapy, we conducted the first phase 1 study of intraventricular immunochemotherapy in patients with recurrent CNS NHL. Fourteen patients received 10 mg or 25 mg intraventricular rituximab twice weekly for 4 weeks, with rituximab administered as monotherapy during the first treatment each week and rituximab administered in combination with methotrexate (MTX) during the second treatment each week. More than 150 doses were administered without serious toxicity. In a population with high-refractory CNS NHL, 75% of patients achieved complete cytologic responses and 43% achieved an overall complete response in CSF and/or brain parenchyma. Two patients achieved a first complete response of CNS NHL with intraventricular rituximab/MTX, including 1 with CNS lymphoma refractory to high-dose systemic and intrathecal MTX plus IV rituximab. We conclude that intraventricular rituximab in combination with MTX is feasible and highly active in the treatment of drug-resistant CNS NHL that is refractory or unresponsive to IV rituximab. KEY POINTS: Phase I study showed that intraventricular rituximab plus methotrexate is feasible and active in the treatment of refractory CNS lymphoma.

CXCL13 plus interleukin 10 is highly specific for the diagnosis of CNS lymphoma.

Establishing the diagnosis of focal brain lesions in patients with unexplained neurologic symptoms represents a challenge. The goal of this study is to provide evidence supporting functional roles for CXC chemokine ligand (CXCL)13 and interleukin (IL)-10 in central nervous system (CNS) lymphomas and to evaluate the utility of each as prognostic and diagnostic biomarkers. We demonstrate for the first time that elevated CXCL13 concentration in cerebrospinal fluid (CSF) is prognostic and that CXCL13 and CXCL12 mediate chemotaxis of lymphoma cells isolated from CNS lymphoma lesions. Expression of the activated form of Janus kinase 1 supported a role for IL-10 in prosurvival signaling. We determined the concentration of CXCL13 and IL-10 in CSF of CNS lymphoma patients and control cohorts including inflammatory and degenerative neurologic disease in a multicenter study involving 220 patients. Bivariate elevated CXCL13 plus IL-10 was 99.3% specific for primary and secondary CNS lymphoma, with sensitivity significantly greater than reference standard CSF tests. These results identify CXCL13 and IL-10 as potentially important biomarkers of CNS lymphoma that merit further evaluation and support incorporation of CXCL13 and IL-10 into diagnostic algorithms for the workup of focal brain lesions in which lymphoma is a consideration.

Performance of Apparent Diffusion Coefficient Values and Conventional MRI Features in Differentiating Tumefactive Demyelinating Lesions From Primary Brain Neoplasms.

OBJECTIVE: Tumefactive demyelinating lesions (TDLs) remain one of the most common brain lesions to mimic a brain tumor, particularly primary CNS lymphoma (PCNSL) and high-grade gliomas. The purpose of our study was to evaluate the ability of apparent diffusion coefficient (ADC) values and conventional MRI features to differentiate TDLs from PCNSLs and high-grade gliomas. MATERIALS AND METHODS: Seventy-five patients (24 patients with TDLs, 28 with PCNSLs, and 23 with high-grade gliomas) with 168 brain lesions (70 TDLs, 68 PCNSLs, and 30 high-grade gliomas) who underwent DWI before surgery or therapy were included in the study. Minimum ADC (ADC(min)) and average ADC (ADC(avg)) values were calculated for each lesion. ANOVA and ROC analyses were performed. ROC analyses were also performed for the presence of incomplete rim enhancement and for the number of lesions. Multiple-variable logistic regression with ROC analysis was then performed to evaluate performance in multiple-variable models. RESULTS: ADC(min) was statistically significantly higher (p < 0.01) in TDLs (mean, 0.886; 95% CI, 0.802-0.931) than in PCNSLs (0.547; 95% CI, 0.496-0.598) and high-grade gliomas (0.470; 95% CI, 0.385-0.555). (All ADC values in this article are reported in units of × 10(-3) mm(2)/s.) ADC(avg) was statistically significantly higher (p < 0.01) in TDLs (mean, 1.362; 95% CI, 1.268-1.456) than in PCNSLs (0.990; 95% CI, 0.919-1.061) but not in high-grade gliomas (1.216; 95% CI, 1.074-1.356). Multiple-variable models showed statistically significant individual effects and superior diagnostic performance on ROC analysis. CONCLUSION: TDLs can be diagnosed on preoperative MRI with a high degree of specificity; MRI features of incomplete rim enhancement, high ADC values, and a large number of lesions individually increase the probability and diagnostic confidence that a lesion is a TDL.

Adult-onset central nervous system hemophagocytic lymphohistiocytosis: a case report.

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.

Apparent diffusion coefficient in glioblastoma with PNET-like components, a GBM variant.

Glioblastoma (GBM) with primitive neuroectodermal tumor (PNET)-like (GBM-PNET) components is a rare variant of GBM. Recent studies describe PNET-like clinical behavior in these patients-with significantly increased propensity for CSF dissemination and a benefit of "PNET-like" chemotherapy. The imaging appearance of GBM-PNET is not well-described and given areas of marked cellularity in the PNET components one might expect significantly reduced diffusion on MRI. The purpose of this study is to quantitatively evaluate the diffusion characteristics in GBM-PNET and compare them with conventional GBMs. Nine patients with surgical specimens yielding GBM-PNET were identified from the UCSF Pathology files. MR images of these patients were reviewed retrospectively. DWI (diffusion-weighted imaging) sequences were analyzed with multiple regions of interests placed within the tumor, and ADC (apparent diffusion coefficient) values were measured. Results were compared to previously published ADC values in pathology-proven conventional GBM cases from our institution. Reduced ADC was seen in GBM-PNET (mean 581 × 10(-6) mm(2)/s, range 338-817) compared to previously published mean of 1,030 × 10(-6) mm(2)/s in the enhancing components of conventional GBMs. We report substantially reduced ADC values in GBM-PNETs compared to conventional GBMs. If demonstrated in a larger sample, when areas of marked reduced diffusion are seen in a suspected GBM, MRI may appropriately direct tissue sampling and can advocate a thorough search for PNET-like components on histopathology. These patients may have a higher chance of developing CSF dissemination and may benefit from "PNET-like" platinum-based chemotherapy.

The University of California San Francisco Adult Longitudinal Post-Treatment Diffuse Glioma (UCSF-ALPTDG) MRI Dataset.

"Just Accepted" papers have undergone full peer review and have been accepted for publication in Radiology: Artificial Intelligence. This article will undergo copyediting, layout, and proof review before it is published in its final version. Please note that during production of the final copyedited article, errors may be discovered which could affect the content. The University of California San Francisco Adult Longitudinal Post-Treatment Diffuse Glioma (UCSF-ALPTDG) MRI dataset is a publicly available annotated dataset featuring multimodal brain MRIs from 298 patients with diffuse gliomas taken at two consecutive follow-ups (596 scans total), with corresponding clinical history and expert voxelwise annotations. ©RSNA, 2024.

Comparison of DSC-MRI post-processing techniques in predicting microvascular histopathology in patients newly diagnosed with GBM.

PURPOSE: To evaluate which common post-processing method applied to gradient-echo DSC-MRI data, acquired with a single gadolinium injection and low flip-angle, most accurately reflects microvascular histopathology for patients with de novo, treatment-naive glioblastoma multiforme (GBM). MATERIALS AND METHODS: Seventy-two tissue samples were collected from 35 patients with treatment-naive GBM. Sample locations were co-registered to preoperative gradient-echo dynamic susceptibility contrast (DSC) MRI acquired with 35° flip-angle and 0.1 mmol/kg gadolinium. Estimates of blood volume and leakiness at each sample location were calculated using four common postprocessing methods (leakage-corrected nonlinear gamma-variate, non-parametric, scaled MR-signal, and unscaled MR-signal). Tissue sample microvascular morphology was characterized using Factor VIII immunohistochemical analysis. A random-effects regression model, adjusted for repeated measures and contrast-enhancement (CE), identified whether MR parameter estimates significantly predicted IHC findings. RESULTS: Elevated blood volume estimates from nonlinear and non-parametric methods significantly predicted increased microvascular hyperplasia. Abnormal microvasculature existed beyond the CE-lesion and was significantly reflected by increased blood volume from nonlinear, non-parametric, and scaled MR-signal analysis. CONCLUSION: This study provides histopathological support for both non-parametric and nonlinear post-processing of low flip-angle DSC-MRI for characterizing microvascular hyperplasia within GBM. Non-parametric analysis with a single gadolinium injection may be a particularly useful strategy clinically, as it requires less computational expense and limits gadolinium exposure.

Clinical Reasoning: A 22-Year-Old Man With Multifocal Brain and Osseous Lesions.

The evaluation of patients with disseminated processes with CNS and osseous involvement is often challenging. A 22-year-old healthy man developed left-sided weakness, paresthesias, and neck pain over several weeks. On clinical examination, he was noted to have decreased right eye visual acuity, left-sided pyramidal weakness and numbness, and bilateral hyperreflexia. MRI revealed multifocal widespread abnormalities: nonenhancing lesions throughout the infratentorial brain, pituitary gland, right frontal lobe, and optic nerves, in addition to an enhancing intramedullary cervical spinal cord lesion, extensive nodular leptomeningeal enhancement of the spine, and numerous enhancing bony lesions throughout the vertebrae and iliac bones. CSF analysis was notable for normal opening pressure, protein 465 mg/dL, glucose 21 mg/dL, and normal cell count. Extensive serum and CSF analysis for infectious, inflammatory, and neoplastic etiologies was unrevealing, and the diagnosis was ultimately revealed after additional staining of tissue biopsy specimen from sacral and cerebellar biopsies. This case highlights the differential diagnoses for widely disseminated disease affecting the CNS and bones and informs pediatric and adult clinicians of important recent developments regarding this diagnostic entity.