Application of the condensed protocol for the NIA-AA guidelines for the neuropathological assessment of Alzheimer's disease in an academic clinical practice.

AIMS: In response to concerns regarding resource expenditures required to implement fully the 2012 National Institute on Aging and the Alzheimer's Association (NIA-AA) Sponsored Guidelines for the neuropathological assessment of Alzheimer's disease (AD), we previously developed a sensitive and cost-reducing condensed protocol (CP) at the University of Washington (UW) Alzheimer's Disease Research Center (ADRC) that consolidated the recommended NIA-AA protocol into fewer cassettes requiring fewer immunohistochemical stains. The CP was not designed to replace NIA-AA protocols, but instead to make the NIA-AA criteria accessible to clinical and forensic neuropathology practices where resources limit full implementation of NIA-AA guidelines. METHODS AND RESULTS: In this regard, we developed practical criteria to instigate CP sampling and immunostaining, and applied these criteria in an academic clinical neuropathological practice. During the course of 1 year, 73 cases were sampled using the CP; of those, 53 (72.6%) contained histological features that prompted CP work-up. We found that the CP resulted in increased identification of AD and Lewy body disease neuropathological changes from what was expected using a clinical history-driven work-up alone, while saving approximately $900 per case. CONCLUSIONS: This study demonstrates the feasibility and cost-savings of the CP applied to a clinical autopsy practice, and highlights potentially unrecognised neurodegenerative disease processes in the general ageing community.

Localized crystal-storing histiocytosis of the posterior fossa.

Crystal-storing histiocytosis (CSH) is an uncommon histiocytic proliferation reported to involve diverse organs and tissues, but involvement of the central nervous system (CNS) is rare. In most cases CSH is identified in association with underlying lymphoproliferative, plasma cell diseases or rarely with various inflammatory or infectious conditions. CSH is characterized by the cytoplasmic accumulation of crystalline material in histiocytes, most commonly of kappa immunoglobulin light chain. We report a unique case of localized CSH involving the left cerebellum and caudal brain stem in a young man with a history of gout but without known lymphoproliferative or plasma cell disorders. Awareness of this entity is important diagnostically, but also to ensure appropriate management and follow-up, particularly in the absence of apparent underlying malignancy.

Surgery for very large and giant intracranial aneurysms: Results and complications.

BACKGROUND: Results of and the complications encountered during surgery for very large and giant intracranial aneurysms are illustrated. OBJECTIVE: To analyze a consecutive series of patients with very large and giant aneurysms treated with microsurgery. METHODS: This retrospective study included seventy six very large and giant aneurysms which were managed by clipping and bypass technique. Sixty two (82%) aneurysms were located in anterior circulation, and 14 (18%) aneurysms were located in posterior circulation. The bypasses performed included local bypasses, extra-intracranial bypasses, double bypasses and combination techniques of external carotid-internal carotid (EC-IC) bypass and local bypasses. RESULTS: 73 patients with 76 aneurysms were treated over 13 years. There were 44 very large and 32 giant aneurysms. Twenty-four patients presented with subarachnoid hemorrhage [SAH] (32%) while forty nine patients with 52 aneurysms (68%) were unruptured. These 73 patients underwent 63 bypass procedures with aneurysm occlusion and 13 clipping procedures. Out of 62 anterior circulation aneurysms, bypass surgery was performed in 49 patients while 13 underwent clipping. In posterior circulation aneurysms, all patients were treated with bypass procedures with proximal occlusion or trapping. In the ruptured group, 16 (67%) patients had postoperative modified Rankin Scale (mRs) 0-2, six patients (25%) had mRs 3-5, and two patients (8.4%) died. In the unruptured group, 45 patients (87%) had mRs 0-2, 3 patients (6%) had mRs 3-5, and four patients (7.6%) died. CONCLUSIONS: In this large series of very large and giant aneurysms treated with microsurgical clipping and bypasses, excellent results were obtained in the long term, in regards to aneurysm occlusion, functional status, and graft patency. Our experience will be very useful to other neurosurgeons who treat these complex lesions.

An Incidental Finding of Choroidal Ganglioneuronal Hamartoma in a Patient With Neurofibromatosis Type 1.

A 42-year-old man with neurofibromatosis type 1 underwent a giant facial neurofibroma resection and enucleation of the right eye. He was found to have a diffusely thickened and cellular choroid containing individual or small clusters of large ganglion and medium-sized neuronal cells. The nomenclature of this lesion is difficult; however, the term choroidal ganglioneuronal hamartoma has been favored due to the lack of proliferative activity and diffuse nature of the lesion arguing against a neoplastic etiology. This case highlights an interesting presentation of neurofibromatosis type I.

Joubert syndrome: brain and spinal cord malformations in genotyped cases and implications for neurodevelopmental functions of primary cilia.

Joubert syndrome (JS) is an autosomal recessive ciliopathy characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability. The brain is malformed, with severe vermian hypoplasia, fourth ventriculomegaly, and "molar tooth" appearance of the cerebral and superior cerebellar peduncles visible as consistent features on neuroimaging. Neuropathological studies, though few, suggest that several other brain and spinal cord structures, such as the dorsal cervicomedullary junction, may also be affected in at least some patients. Genetically, JS is heterogeneous, with mutations in 13 genes accounting for approximately 50% of patients. Here, we compare neuropathologic findings in five subjects with JS, including four with defined mutations in OFD1 (2 siblings), RPGRIP1L, or TCTN2. Characteristic findings in all JS genotypes included vermian hypoplasia, fragmented dentate and spinal trigeminal nuclei, hypoplastic pontine and inferior olivary nuclei, and nondecussation of corticospinal tracts. Other common findings, seen in multiple genotypes but not all subjects, were dorsal cervicomedullary heterotopia, nondecussation of superior cerebellar peduncles, enlarged arcuate nuclei, hypoplastic reticular formation, hypoplastic medial lemnisci, and dorsal spinal cord disorganization. Thus, while JS exhibits significant neuropathologic as well as genetic heterogeneity, no genotype-phenotype correlations are apparent as yet. Our findings suggest that primary cilia are important for neural patterning, progenitor proliferation, cell migration, and axon guidance in the developing human brain and spinal cord.

Primary Intracranial Brainstem Malignant Melanoma: A Technical Case Report.

BACKGROUND AND IMPORTANCE: Primary intracranial malignant melanomas (PIMMs) are quite rare, comprising 1% of melanomas and 0.07% of intracranial tumors. PIMMs have been reported in a variety of intracranial locations, but there has only been 1 reported instance of PIMM occurring in the brainstem. In this study, we describe the second reported case of primary pontine malignant melanoma and its treatment. CLINICAL PRESENTATION: A 40-year-old man presented with right hemiparesis, diplopia, and dysarthria. MRI demonstrated a hemorrhagic, expansile, and heterogeneously enhancing lesion in the left pons with edema extending to the left thalamus and posterior limb of the internal capsule. Surgical resection was performed through a transpetrosal approach. Pathology resulted as malignant melanoma immunopositive for BRAF V600E mutation. Complete oncological workup revealed no other lesions; thus, he was diagnosed with PIMM of the brainstem. CONCLUSION: We report a rare case of primary pontine malignant melanoma in which microsurgical resection resulted in dramatic clinical improvement despite the challenging location. This is only the second reported case of brainstem PIMM. More patients with longer-term follow-up will be necessary to determine the best treatment approach.

Neuronal migration disorders in microcephalic osteodysplastic primordial dwarfism type I/III.

Microcephalic osteodysplastic primordial dwarfism (MOPD) is a rare microlissencephaly syndrome, with at least two distinct phenotypic and genetic types. MOPD type II is caused by pericentrin mutations, while types I and III appear to represent a distinct entity (MOPD I/III) with variably penetrant phenotypes and unknown genetic basis. The neuropathology of MOPD I/III is little understood, especially in comparison to other forms of lissencephaly. Here, we report postmortem brain findings in an 11-month-old female infant with MOPD I/III. The cerebral cortex was diffusely pachygyric, with a right parietal porencephalic lesion. Histologically, the cortex was abnormally thick and disorganized. Distinct malformations were observed in different cerebral lobes, as characterized using layer-specific neuronal markers. Frontal cortex was severely disorganized and coated with extensive leptomeningeal glioneuronal heterotopia. Temporal cortex had a relatively normal 6-layered pattern, despite cortical thickening. Occipital cortex was variably affected. The corpus callosum was extremely hypoplastic. Brainstem and cerebellar malformations were also present, as well as old necrotic foci. Findings in this case suggest that the cortical malformation in MOPD I/III is distinct from other forms of pachygyria-lissencephaly.

The Future of Skull Base Surgery: A View Through Tinted Glasses.

In the present report, we have broadly outlined the potential advances in the field of skull base surgery, which might occur within the next 20 years based on the many areas of current research in biology and technology. Many of these advances will also be broadly applicable to other areas of neurosurgery. We have grounded our predictions for future developments in an exploration of what patients and surgeons most desire as outcomes for care. We next examined the recent developments in the field and outlined several promising areas of future improvement in skull base surgery, per se, as well as identifying the new hospital support systems needed to accommodate these changes. These include, but are not limited to, advances in imaging, Raman spectroscopy and microscopy, 3-dimensional printing and rapid prototyping, master-slave and semiautonomous robots, artificial intelligence applications in all areas of medicine, telemedicine, and green technologies in hospitals. In addition, we have reviewed the therapeutic approaches using nanotechnology, genetic engineering, antitumor antibodies, and stem cell technologies to repair damage caused by traumatic injuries, tumors, and iatrogenic injuries to the brain and cranial nerves. Additionally, we have discussed the training requirements for future skull base surgeons and stressed the need for adaptability and change. However, the essential requirements for skull base surgeons will remain unchanged, including knowledge, attention to detail, technical skill, innovation, judgment, and compassion. We believe that active involvement in these rapidly evolving technologies will enable us to shape some of the future of our discipline to address the needs of both patients and our profession.

Distribution of 4-hydroxynonenal-protein conjugates as a marker of lipid peroxidation and parameter of malignancy in astrocytic and ependymal tumors of the brain.

AIMS AND BACKGROUND: Lipid peroxidation (LPO) is an autocatalytic process caused by oxidative stress. It results in the production of 4-hydroxynonenal (HNE), which plays a crucial role in hypoxic brain injury, neuronal degeneration and apoptosis. The aim of this study was to evaluate the expression of HNE in 120 astrocytic and 40 ependymal tumors in relation to tumor type, grade of malignancy, angiogenesis, and presence of necrosis and apoptosis. METHODS: Immunohistochemical staining was performed using a monoclonal antibody for the detection of HNE-modified proteins. RESULTS: HNE-protein adducts were found in all tumors. The incidence of HNE-immunopositive tumor cells increased with increasing grades of malignancy. Significantly higher HNE expression was found in tumor cells of glioblastomas multiforme than in cells of pilocytic astrocytomas (P < 0.005), and in anaplastic ependymomas than in benign ependymomas (P < 0.01). HNE-immunopositive tumor cells were distributed more diffusely than in perivascular locations (P < 0.05). Pronounced HNE-protein adducts were detected in mitotic, necrotic, and apoptotic cells. HNE was expressed in the endothelium of almost all tumor vessels, but its expression in the walls of the vessels was significantly higher in diffuse and anaplastic astrocytomas than in pilocytic astrocytomas and glioblastomas multiforme (P < 0.05). The number of microvessels containing HNE in their endothelium and walls was significantly associated with the grade of malignancy in both astrocytic (P < 0.001) and ependymal tumors (P < 0.05), although microvessels in pilocytic astrocytomas were significantly more numerous (P < 0.05) than in diffuse astrocytomas. CONCLUSIONS: LPO seems to be a common pathological process in astrocytic and ependymal glial tumors, proportional to the level of malignancy and neovascularization. Therefore, HNE might be involved in the damage of brain cells and the induction of malignancy.

Malformations of Cerebral Cortex Development: Molecules and Mechanisms.

Malformations of cortical development encompass heterogeneous groups of structural brain anomalies associated with complex neurodevelopmental disorders and diverse genetic and nongenetic etiologies. Recent progress in understanding the genetic basis of brain malformations has been driven by extraordinary advances in DNA sequencing technologies. For example, somatic mosaic mutations that activate mammalian target of rapamycin signaling in cortical progenitor cells during development are now recognized as the cause of hemimegalencephaly and some types of focal cortical dysplasia. In addition, research on brain development has begun to reveal the cellular and molecular bases of cortical gyrification and axon pathway formation, providing better understanding of disorders involving these processes. New neuroimaging techniques with improved resolution have enhanced our ability to characterize subtle malformations, such as those associated with intellectual disability and autism. In this review, we broadly discuss cortical malformations and focus on several for which genetic etiologies have elucidated pathogenesis.

Intraoperative assessment of skull base tumors using stimulated Raman scattering microscopy.

Intraoperative consultations, used to guide tumor resection, can present histopathological findings that are challenging to interpret due to artefacts from tissue cryosectioning and conventional staining. Stimulated Raman histology (SRH), a label-free imaging technique for unprocessed biospecimens, has demonstrated promise in a limited subset of tumors. Here, we target unexplored skull base tumors using a fast simultaneous two-channel stimulated Raman scattering (SRS) imaging technique and a new pseudo-hematoxylin and eosin (H&E) recoloring methodology. To quantitatively evaluate the efficacy of our approach, we use modularized assessment of diagnostic accuracy beyond cancer/non-cancer determination and neuropathologist confidence for SRH images contrasted to H&E-stained frozen and formalin-fixed paraffin-embedded (FFPE) tissue sections. Our results reveal that SRH is effective for establishing a diagnosis using fresh tissue in most cases with 87% accuracy relative to H&E-stained FFPE sections. Further analysis of discrepant case interpretation suggests that pseudo-H&E recoloring underutilizes the rich chemical information offered by SRS imaging, and an improved diagnosis can be achieved if full SRS information is used. In summary, our findings show that pseudo-H&E recolored SRS images in combination with lipid and protein chemical information can maximize the use of SRS during intraoperative pathologic consultation with implications for tissue preservation and augmented diagnostic utility.

A De Novo Mouse Model of C11orf95-RELA Fusion-Driven Ependymoma Identifies Driver Functions in Addition to NF-κB.

The majority of supratentorial ependymomas (ST-ependymomas) have few mutations but frequently display chromothripsis of chromosome 11q that generates a fusion between C11orf95 and RELA (RELAFUS). Neural stem cells transduced with RELAFUSex vivo form ependymomas when implanted in the brain. These tumors display enhanced NF-κB signaling, suggesting that this aberrant signal is the principal mechanism of oncogenesis. However, it is not known whether RELAFUS is sufficient to drive de novo ependymoma tumorigenesis in the brain and, if so, whether these tumors also arise from neural stem cells. We show that RELAFUS drives ST-ependymoma formation from periventricular neural stem cells in mice and that RELAFUS-induced tumorigenesis is likely dependent on a series of cell signaling pathways in addition to NF-κB.

Cytomegalovirus (CMV) in gastrointestinal mucosal biopsies: should a pathologist perform CMV immunohistochemistry if the clinician requests it?

Cytomegalovirus (CMV) causes clinically significant gastrointestinal (GI) injury. CMV inclusions can be identified on routine hematoxylin and eosin (H&E) stain, but immunohistochemistry (IHC) is also available for identifying CMV in tissue. The advent of accountable care organization models of care bring into question whether it is cost-effective for immunohistochemistry to be performed upfront at the request of clinicians and whether the quality of viral detection is compromised when the diagnosis of CMV is predicated on histologic review. In this study, a retrospective review of GI biopsies with CMV evaluations was performed. There were 449 cases with clinical requests to rule out CMV and 238 CMV analyses initiated by the pathologist without a clinical request. Among the cases that included a clinician's request, 37 had CMV detected. Immunostaining was performed on 26 cases, while a diagnosis based on readily identifiable viral inclusions on H&E-stained slides was made in 11. Among pathologist-initiated work-ups, 15 were CMV+, 3 of which had inclusions identified by H&E only. Among 38 CMV cases for which IHC had been performed, 27 had overt viral inclusions obvious on H&E. Seventy-two cases revealed uninflamed GI mucosa, and although a clinical concern about CMV infection was present, a CMV IHC work-up was not initially performed; all were negative for CMV by IHC and H&E. Clinical suspicion for CMV has a high yield for CMV detection, but "upfront" testing is likely unnecessary. Careful histopathologic review by a pathologist remains critical in the efficient and cost-effective detection of CMV.

A case of malignant peripheral nerve sheath tumor of the hypoglossal nerve after stereotactic radiosurgery treatment.

Objectives Hypoglossal schwannomas are rare. Surgical resection has been the standard treatment modality. Radiosurgery has been increasingly used for treatment. Radiation-associated secondary malignancy/malignant transformation has not been documented in the literature for the treatment of nonvestibular schwannomas. Setting The patient was a 52-year-old man with an enlarging high cervical/skull base lesion 8.5 years after CyberKnife treatment of a presumed vagal schwannoma. A decision was made for surgical resection, and the tumor was found to originate from the hypoglossal nerve intraoperatively. Final pathology diagnosis was malignant peripheral nerve sheath tumor. Results Patient had a gross total resection. Three months after resection, he received fractionated radiation of 50 Gy in 25 fractions and a boost gamma knife radiosurgery of 10 Gy to the 50% isodose surface. He remained tumor free on repeat magnetic resonance imaging 9 months after the resection. Conclusion Although extremely rare, radiation treatment of nonvestibular schwannomas can potentially cause malignant transformation.

Clinicopathologic assay of 15 tumor resections in a family with neurofibromatosis type 2.

The objective of this study is the management of multiple family members with multiple neurofibromatosis type 2 (NF2) related tumors of the skull base that can be challenging, on purely technical, decision-making, and ethical levels. These issues are addressed in this manuscript based on an experience treating an unique large family with NF2. A retrospective chart review was performed, reviewing clinical, radiological, surgical, and pathological data. A unique family of 17 siblings, whose father was the proband as a sporadic mutation is reported. Over a 4-month period, five of eight affected siblings underwent 12 procedures for resection of 15 different NF2-related tumors. This single family experience of NF2-related skull base tumors underscores the importance of preservation of function and quality of life as the major determinants of treatment success.