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Relapsing White Matter Disease and Subclinical Optic Neuropathy: From the National Multiple Sclerosis Society Case Conference Proceedings

O'Neill, Kimberly A; Dugue, Andrew; Abreu, Nicolas J; Balcer, Laura J; Branche, Marc; Galetta, Steven; Graves, Jennifer; Kister, Ilya; Magro, Cynthia; Miller, Claire; Newsome, Scott D; Pappas, John; Rucker, Janet; Steigerwald, Connolly; William, Christopher M; Zamvil, Scott S; Grossman, Scott N; Krupp, Lauren B
A 16-year-old adolescent boy presented with recurrent episodes of weakness and numbness. Brain MRI demonstrated subcortical, juxtacortical, and periventricular white matter T2 hyperintensities with gadolinium enhancement. CSF was positive for oligoclonal bands that were not present in serum. Despite treatment with steroids, IV immunoglobulins, plasmapheresis, and rituximab, he continued to have episodes of weakness and numbness and new areas of T2 hyperintensity on imaging. Neuro-ophthalmologic examination revealed a subclinical optic neuropathy with predominant involvement of the papillomacular bundle. Genetic evaluation and brain biopsy led to an unexpected diagnosis.
PMID: 38181317
ISSN: 2332-7812
CID: 5628442

Occipital Nocardia Abscess Presenting With Positive Visual Phenomenon and Quadrantanopsia

Fein, Alexander S; Kelly, Sean M; Louie, Eddie; Young, Matthew G; Jain, Rajan; William, Christopher M; Galetta, Steven L; Grossman, Scott N
A 74-year-old man with chronic obstructive pulmonary disease, glaucoma, and Stage IIIB squamous cell lung cancer experienced several minutes of flashing lights in his right visual hemifield, followed by onset of a right visual field defect. On examination, the patient had a right homonymous hemianopsia that was most dense inferiorly by confrontation testing. Emergent CT scan of the head revealed a 2.5 × 3 cm hypodensity in the left occipital lobe, which was interpreted as an acute stroke. Continuous EEG monitoring captured left posterior quadrant seizures that were temporally correlated to the positive visual phenomena. Subsequent MRI of the brain with and without contrast revealed a conglomerate of centrally necrotic and peripherally enhancing mass lesions. On biopsy, a thick purulent material was drained and Gram stain of the sample revealed gram-positive beaded rods, which speciated to Nocardia farcinica. The patient was treated with a six-week course of intravenous meropenem and a one-year course of oral trimethroprim-sulfamethoxazole. On follow-up, the patient experienced resolution of the right visual field deficit.
PMID: 37440372
ISSN: 1536-5166
CID: 5537712

Recurrent TRAK1::RAF1 Fusions in pediatric low-grade gliomas

Benhamida, Jamal K; Harmsen, Hannah J; Ma, Deqin; William, Christopher M; Li, Bryan K; Villafania, Liliana; Sukhadia, Purvil; Mullaney, Kerry A; Dewan, Michael C; Vakiani, Efsevia; Karajannis, Matthias A; Snuderl, Matija; Zagzag, David; Ladanyi, Marc; Rosenblum, Marc K; Bale, Tejus A
Fusions involving CRAF (RAF1) are infrequent oncogenic drivers in pediatric low-grade gliomas, rarely identified in tumors bearing features of pilocytic astrocytoma, and involving a limited number of known fusion partners. We describe recurrent TRAK1::RAF1 fusions, previously unreported in brain tumors, in three pediatric patients with low-grade glial-glioneuronal tumors. We present the associated clinical, histopathologic and molecular features. Patients were all female, aged 8 years, 15 months, and 10 months at diagnosis. All tumors were located in the cerebral hemispheres and predominantly cortical, with leptomeningeal involvement in 2/3 patients. Similar to previously described activating RAF1 fusions, the breakpoints in RAF1 all occurred 5' of the kinase domain, while the breakpoints in the 3' partner preserved the N-terminal kinesin-interacting domain and coiled-coil motifs of TRAK1. Two of the three cases demonstrated methylation profiles (v12.5) compatible with desmoplastic infantile ganglioglioma (DIG)/desmoplastic infantile astrocytoma (DIA) and have remained clinically stable and without disease progression/recurrence after resection. The remaining tumor was non-classifiable; with focal recurrence 14 months after initial resection; the patient remains symptom free and without further recurrence/progression (5 months post re-resection and 19 months from initial diagnosis). Our report expands the landscape of oncogenic RAF1 fusions in pediatric gliomas, which will help to further refine tumor classification and guide management of patients with these alterations.
PMID: 37399073
ISSN: 1750-3639
CID: 5539042

Clinical Validation of Stimulated Raman Histology for Rapid Intraoperative Diagnosis of Central Nervous System Tumors

Movahed-Ezazi, Misha; Nasir-Moin, Mustafa; Fang, Camila; Pizzillo, Isabella; Galbraith, Kristyn; Drexler, Steven; Krasnozhen-Ratush, Olga A; Shroff, Seema; Zagzag, David; William, Christopher; Orringer, Daniel; Snuderl, Matija
Stimulated Raman histology (SRH) is an ex vivo optical imaging method that enables microscopic examination of fresh tissue intraoperatively. The conventional intraoperative method uses frozen section analysis, which is labor and time intensive, introduces artifacts that limit diagnostic accuracy, and consumes tissue. SRH imaging allows rapid microscopic imaging of fresh tissue, avoids tissue loss, and enables remote telepathology review. This improves access to expert neuropathology consultation in both low- and high-resource practices. We clinically validated SRH by performing a blinded, retrospective two-arm telepathology study to clinically validate SRH for telepathology at our institution. Using surgical specimens from 47 subjects, we generated a data set composed of 47 SRH images and 47 matched whole slide images (WSIs) of formalin-fixed, paraffin-embedded tissue stained with hematoxylin and eosin, with associated intraoperative clinicoradiologic information and structured diagnostic questions. We compared diagnostic concordance between WSI and SRH-rendered diagnoses. Also, we compared the 1-year median turnaround time (TAT) of intraoperative conventional neuropathology frozen sections with prospectively rendered SRH-telepathology TAT. All SRH images were of sufficient quality for diagnostic review. A review of SRH images showed high accuracy in distinguishing glial from nonglial tumors (96.5% SRH vs 98% WSIs) and predicting final diagnosis (85.9% SRH vs 93.1% WSIs). SRH-based diagnosis and WSI-permanent section diagnosis had high concordance (κ = 0.76). The median TAT for prospectively SRH-rendered diagnosis was 3.7 minutes, approximately 10-fold shorter than the median frozen section TAT (31 minutes). The SRH-imaging procedure did not affect ancillary studies. SRH generates diagnostic virtual histologic images with accuracy comparable to conventional hematoxylin and eosin-based methods in a rapid manner. Our study represents the largest and most rigorous clinical validation of SRH to date. It supports the feasibility of implementing SRH as a rapid method for intraoperative diagnosis complementary to conventional pathology laboratory methods.
PMID: 37201685
ISSN: 1530-0285
CID: 5508102

Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors-A prospective study and guidelines for clinical testing

Galbraith, Kristyn; Vasudevaraja, Varshini; Serrano, Jonathan; Shen, Guomiao; Tran, Ivy; Abdallat, Nancy; Wen, Mandisa; Patel, Seema; Movahed-Ezazi, Misha; Faustin, Arline; Spino-Keeton, Marissa; Roberts, Leah Geiser; Maloku, Ekrem; Drexler, Steven A; Liechty, Benjamin L; Pisapia, David; Krasnozhen-Ratush, Olga; Rosenblum, Marc; Shroff, Seema; Boué, Daniel R; Davidson, Christian; Mao, Qinwen; Suchi, Mariko; North, Paula; Hopp, Amanda; Segura, Annette; Jarzembowski, Jason A; Parsons, Lauren; Johnson, Mahlon D; Mobley, Bret; Samore, Wesley; McGuone, Declan; Gopal, Pallavi P; Canoll, Peter D; Horbinski, Craig; Fullmer, Joseph M; Farooqui, Midhat S; Gokden, Murat; Wadhwani, Nitin R; Richardson, Timothy E; Umphlett, Melissa; Tsankova, Nadejda M; DeWitt, John C; Sen, Chandra; Placantonakis, Dimitris G; Pacione, Donato; Wisoff, Jeffrey H; Teresa Hidalgo, Eveline; Harter, David; William, Christopher M; Cordova, Christine; Kurz, Sylvia C; Barbaro, Marissa; Orringer, Daniel A; Karajannis, Matthias A; Sulman, Erik P; Gardner, Sharon L; Zagzag, David; Tsirigos, Aristotelis; Allen, Jeffrey C; Golfinos, John G; Snuderl, Matija
BACKGROUND/UNASSIGNED:Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. METHODS/UNASSIGNED:We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. RESULTS/UNASSIGNED:Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. CONCLUSIONS/UNASSIGNED:DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.
PMID: 37476329
ISSN: 2632-2498
CID: 5536102

Clinical, Pathological, and Molecular Characteristics of Diffuse Spinal Cord Gliomas

Garcia, Mekka R; Feng, Yang; Vasudevaraja, Varshini; Galbraith, Kristyn; Serrano, Jonathan; Thomas, Cheddhi; Radmanesh, Alireza; Hidalgo, Eveline T; Harter, David H; Allen, Jeffrey C; Gardner, Sharon L; Osorio, Diana S; William, Christopher M; Zagzag, David; Boué, Daniel R; Snuderl, Matija
Diffuse spinal cord gliomas (SCGs) are rare tumors associated with a high morbidity and mortality that affect both pediatric and adult populations. In this retrospective study, we sought to characterize the clinical, pathological, and molecular features of diffuse SCG in 22 patients with histological and molecular analyses. The median age of our cohort was 23.64 years (range 1-82) and the overall median survival was 397 days. K27M mutation was significantly more prevalent in males compared to females. Gross total resection and chemotherapy were associated with improved survival, compared to biopsy and no chemotherapy. While there was no association between tumor grade, K27M status (p = 0.366) or radiation (p = 0.772), and survival, males showed a trend toward shorter survival. K27M mutant tumors showed increased chromosomal instability and a distinct DNA methylation signature.
PMID: 35997552
ISSN: 1554-6578
CID: 5338172

Proteomic differences in hippocampus and cortex of sudden unexplained death in childhood

Leitner, Dominique F; William, Christopher; Faustin, Arline; Askenazi, Manor; Kanshin, Evgeny; Snuderl, Matija; McGuone, Declan; Wisniewski, Thomas; Ueberheide, Beatrix; Gould, Laura; Devinsky, Orrin
Sudden unexplained death in childhood (SUDC) is death of a child over 1 year of age that is unexplained after review of clinical history, circumstances of death, and complete autopsy with ancillary testing. Multiple etiologies may cause SUDC. SUDC and sudden unexpected death in epilepsy (SUDEP) share clinical and pathological features, suggesting some similarities in mechanism of death and possible abnormalities in hippocampus and cortex. To identify molecular signaling pathways, we performed label-free quantitative mass spectrometry on microdissected frontal cortex, hippocampal dentate gyrus (DG), and cornu ammonis (CA1-3) in SUDC (n = 19) and pediatric control cases (n = 19) with an explained cause of death. At a 5% false discovery rate (FDR), we found differential expression of 660 proteins in frontal cortex, 170 in DG, and 57 in CA1-3. Pathway analysis of altered proteins identified top signaling pathways associated with activated oxidative phosphorylation (p = 6.3 × 10-15, z = 4.08) and inhibited EIF2 signaling (p = 2.0 × 10-21, z = - 2.56) in frontal cortex, and activated acute phase response in DG (p = 8.5 × 10-6, z = 2.65) and CA1-3 (p = 4.7 × 10-6, z = 2.00). Weighted gene correlation network analysis (WGCNA) of clinical history indicated that SUDC-positive post-mortem virology (n = 4/17) had the most significant module in each brain region, with the top most significant associated with decreased mRNA metabolic processes (p = 2.8 × 10-5) in frontal cortex. Additional modules were associated with clinical history, including fever within 24 h of death (top: increased mitochondrial fission in DG, p = 1.8 × 10-3) and febrile seizure history (top: decreased small molecule metabolic processes in frontal cortex, p = 8.8 × 10-5) in all brain regions, neuropathological hippocampal findings in the DG (top: decreased focal adhesion, p = 1.9 × 10-3). Overall, cortical and hippocampal protein changes were present in SUDC cases and some correlated with clinical features. Our studies support that proteomic studies of SUDC cohorts can advance our understanding of the pathogenesis of these tragedies and may inform the development of preventive strategies.
PMID: 35333953
ISSN: 1432-0533
CID: 5200692

Blinded Review of Hippocampal Neuropathology in Sudden Unexplained Death in Childhood Reveals Inconsistent Observations and Similarities to Explained Pediatric Deaths

Leitner, Dominique F; McGuone, Declan; William, Christopher; Faustin, Arline; Askenazi, Manor; Snuderl, Matija; Guzzetta, Melissa; Jarrell, Heather S; Maloney, Katherine; Reichard, Ross; Smith, Colin; Weedn, Victor; Wisniewski, Thomas; Gould, Laura; Devinsky, Orrin
AIMS/OBJECTIVE:Hippocampal findings are implicated in the pathogenesis of sudden unexplained death in childhood (SUDC), although some studies have identified similar findings in sudden explained death in childhood (SEDC) cases. We blindly reviewed hippocampal histology in SUDC and SEDC controls. METHODS:Hippocampal H&E slides (n=67; 36 SUDC, 31 controls) from clinical and forensic collaborators were evaluated by 9 blinded reviewers: 3 board-certified forensic pathologists, 3 neuropathologists, and 3 dual-certified neuropathologist/forensic pathologists. RESULTS:Among nine reviewers, about 50% of hippocampal sections were rated as abnormal (SUDC 52.5%, controls 53.0%), with no difference by cause of death (COD) (p=0.16) or febrile seizure history (p=0.90). There was little agreement among nine reviewers on whether a slide was within normal range (Fleiss' kappa=0.014, p=0.47). Within reviewer groups, there were no findings more frequent in SUDC compared to controls, with variability in pyramidal neuron and dentate gyrus findings. Across reviewer groups, there was concordance for bilamination and granule cell loss. Neither SUDC (51.2%) nor control (55.9%) slides were considered contributory to determining COD (p=0.41). CONCLUSIONS:The lack of an association of hippocampal findings in SUDC and controls, as well as inconsistency of observations by multiple blinded reviewers, indicates discrepancy with previous studies and an inability to reliably identify hippocampal malformation associated with sudden death (HMASD). These findings underscore a need for larger studies to standardize evaluation of hippocampal findings, identify the range of normal variation and, changes unrelated to SUDC or febrile seizures. Molecular studies may help identify novel immunohistological markers that inform on COD.
PMID: 34164845
ISSN: 1365-2990
CID: 4918622

Clinical value of DNA methylation in practice: A prospective molecular neuropathology study [Meeting Abstract]

Galbraith, Kristyn; Shen, Guomiao; Serrano, Jonathan; Vasudevaraja, Varshini; Tran, Ivy; Movahed-Ezazi, Misha; Harter, David; Hidalgo, Eveline; Wisoff, Jeffrey; Orringer, Daniel; Placantonakis, Dimitris; Gardner, Sharon; William, Christopher; Zagzag, David; Allen, Jeffrey; Sulman, Erik; Golfinos, John; Snuderl, Matija
ISSN: 0022-3069
CID: 5244322

Clinical Validation of Stimulated Raman Histology for Rapid Intraoperative Diagnosis of CNS Tumors [Meeting Abstract]

Movahed-Ezazi, Misha; Nasir-moin, Mustafa; Fang, Camila; Pizzillo, Isabella; Galbraith, Kristyn; Krasnozhen, Olga; Schroff, Seema; Drexler, Steven; William, Christopher; Zagzag, David; Orringer, Daniel; Snuderl, Matija
ISSN: 0022-3069
CID: 5244332