A Contemporary Approach to Intraoperative Evaluation in Neuropathology.

CONTEXT.­: Although the basic principles of intraoperative diagnosis in surgical neuropathology have not changed in the last century, the last several decades have seen dramatic changes in tumor classification, terminology, molecular classification, and modalities used for intraoperative diagnosis. As many neuropathologic intraoperative diagnoses are performed by general surgical pathologists, awareness of these recent changes is important for the most accurate intraoperative diagnosis. OBJECTIVE.­: To describe recent changes in the practice of intraoperative surgical neuropathology, with an emphasis on new entities, tumor classification, and anticipated ancillary tests, including molecular testing. DATA SOURCES.­: The sources for this review include the fifth edition of the World Health Organization Classification of Tumours of the Central Nervous System, primary literature on intraoperative diagnosis and newly described tumor entities, and the authors' clinical experience. CONCLUSIONS.­: A significant majority of neuropathologic diagnoses require ancillary testing, including molecular analysis, for appropriate classification. Therefore, the primary goal for any neurosurgical intraoperative diagnosis is the identification of diagnostic tissue and the preservation of the appropriate tissue for molecular testing. The intraoperative pathologist should seek to place a tumor in the most accurate diagnostic category possible, but specific diagnosis at the time of an intraoperative diagnosis is often not possible. Many entities have seen adjustments to grading criteria, including the incorporation of molecular features into grading. Awareness of these changes can help to avoid overgrading or undergrading at the time of intraoperative evaluation.

Neuropathologic Features in Chronic Methamphetamine Use.

ABSTRACT: Methamphetamine is a psychostimulant that exerts its euphoric and stimulant effects by increasing cytosolic monoamine concentration at the nerve terminal. In addition to its known systemic cardiovascular effects, there is compelling evidence to suggest a direct neurotoxic effect of methamphetamine; however, the existing body of literature includes very few human tissue studies. This exploratory analysis used postmortem human brain specimens to examine histologic and immunohistochemical features associated with chronic methamphetamine use. This retrospective cohort study included 60 decedents who were autopsied at the University of Iowa Hospitals and Clinics between the years 2015 and 2021. Logistic regression models demonstrated no definite pathologic changes in the hippocampi of individuals with a history of chronic methamphetamine use. Decedents with a history of methamphetamine use had a marginally increased odds of basal ganglia arteriosclerosis, which did not reach statistical significance (odds ratio, 3.33; 95% confidence interval, 0.6-19.2; P = 0.17), which may be independent of the systemic hypertensive effects of methamphetamine. Future studies that include targeted examination of brain regions of interest, such as the basal ganglia and specifically the striatum, may prove revealing.

The neuropathologic findings in a case of progressive cavitating leukoencephalopathy due to NDUFV1 pathogenic variants.

Pathogenic variants in the NDUFV1 gene, which codes for complex I of the mitochondrial respiratory chain, have been associated with a variety of clinical phenotypes, including a progressive cavitating leukoencephalopathy. The neuropathology of NDUFV1-associated leukoencephalopathy is not well-described. We present a report of a 24-year-old female with two pathogenic variants in the NDUFV1 gene, together with antemortem skeletal muscle biopsy and postmortem neuropathologic examination. Autopsy neuropathology showed a cavitating leukoencephalopathy with extensive white matter involvement, regions of active demyelination, and sparing of the subcortical U-fibers. Muscle biopsy showed subtle but distinct histologic abnormalities by light microscopy, and ultrastructural analysis demonstrated mitochondrial abnormalities including abnormal subsarcolemmal mitochondrial accumulation, electron-dense inclusions, and enlarged mitochondria with abnormal cristae. Our report is the first comprehensive description of the neuropathology in a patient with compound heterozygous variants in the NDUFV1 gene and progressive cavitating leukoencephalopathy. This case is evidence of pathogenicity of one NDUFV1 variant (c.565 T > C, p.S189P), which has not been previously described as pathogenic. These findings, in combination with the ultrastructural abnormalities in the mitochondria by electron microscopy, support the mitochondrial nature of the pathology. Together, this case highlights the link between mitochondrial abnormalities and demyelinating processes in the central nervous system (CNS).

COVID-19-associated necrotizing encephalopathy presenting without active respiratory symptoms: a case report with histopathology.

Acute necrotizing encephalopathy (ANE) is a rare complication of coronavirus disease 2019 (COVID-19) secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The condition is typically diagnosed based on characteristic neuroimaging findings in the context of active viral respiratory symptoms. We present a rare case of COVID-19-associated ANE presenting with expressive aphasia and encephalopathy in the absence of active respiratory symptoms. Initial evaluation revealed bilateral thalamic lesions and a mild neutrophilic-predominant pleocytosis on cerebrospinal fluid analysis, the latter of which has not been described in previously published cases. Presence of these atypical features prompted extensive diagnostic evaluation. Metagenomic next-generation sequencing on cerebrospinal fluid did not detect the presence of pathogenic nucleic acids. Thalamic biopsy revealed perivascular neutrophilic inflammation suggestive of small vessel vasculitis with surrounding hemorrhage and necrosis. Ultimately, the diagnosis was made following detection of SARS-CoV-2 serologies and after exclusion of alternative etiologies. The patient was successfully treated with a short course of high-dose methylprednisolone with favorable outcome.

The Neuropathology of 1p36 Deletion Syndrome: An Autopsy Case Series.

1p36 deletion syndrome is the most common terminal deletion syndrome, manifesting clinically as abnormal facies and developmental delay with frequent cardiac, skeletal, urogenital, and renal abnormalities. Limited autopsy case reports describe the neuropathology of 1p36 deletion syndrome. The most extensive single case report described a spectrum of abnormalities, mostly related to abnormal neuronal migration. We report the largest published series of 1p36 autopsy cases, with an emphasis on neuropathologic findings. Our series consists of 3 patients: 2 infants (5-hours old and 23-days old) and 1 older child (11 years). Our patients showed abnormal cortical gyration together with a spectrum of neuronal migration abnormalities, including heterotopias and hippocampal abnormalities, as well as cerebellar hypoplasia. Our findings thus support the role of neuronal migration defects in the pathogenesis of cognitive defects in 1p36 deletion syndrome and broaden the reported neuropathologic spectrum of this common syndrome.

Brain Histopathology of Adult Decedents After Extracorporeal Membrane Oxygenation.

OBJECTIVE: To test the hypothesis that brain injury is more common and varied in patients receiving extracorporeal membrane oxygenation (ECMO) than radiographically observed, we described neuropathology findings of ECMO decedents and associated clinical factors from 3 institutions. METHODS: We conducted a retrospective multicenter observational study of brain autopsies from adult ECMO recipients. Pathology findings were examined for correlation with demographics, clinical data, ECMO characteristics, and outcomes. RESULTS: Forty-three decedents (n = 13 female, median age 47 years) received autopsies after undergoing ECMO for acute respiratory distress syndrome (n = 14), cardiogenic shock (n = 14), and cardiac arrest (n = 15). Median duration of ECMO was 140 hours, most decedents (n = 40) received anticoagulants; 60% (n = 26) underwent venoarterial ECMO, and 40% (n = 17) underwent venovenous ECMO. Neuropathology was found in 35 decedents (81%), including microhemorrhages (37%), macrohemorrhages (35%), infarctions (47%), and hypoxic-ischemic brain injury (n = 17, 40%). Most pathology occurred in frontal neocortices (n = 43 occurrences), basal ganglia (n = 33), and cerebellum (n = 26). Decedents with hemorrhage were older (median age 57 vs 38 years, p = 0.01); those with hypoxic brain injury had higher Sequential Organ Failure Assessment scores (8.0 vs 2.0, p = 0.04); and those with infarction had lower peak Paco2 (53 vs 61 mm Hg, p = 0.04). Six of 9 patients with normal neuroimaging results were found to have pathology on autopsy. The majority underwent withdrawal of life-sustaining therapy (n = 32, 74%), and 2 of 8 patients with normal brain autopsy underwent withdrawal of life-sustaining therapy for suspected neurologic injury. CONCLUSION: Neuropathological findings after ECMO are common, varied, and associated with various clinical factors. Further study on underlying mechanisms is warranted and may guide ECMO management.

Medical Examiner Review of the Characteristics of Fire-Related Homicides.

While fire-related deaths are regularly encountered by medical examiners, fire-related homicides are relatively uncommon. Although some large retrospective studies of fire-related deaths have been performed, few large studies have specifically reviewed fire-related homicides. Autopsy, scene investigation, and ancillary studies were reviewed for 38 fire-related homicides evaluated at the Wayne County Medical Examiner's Office in Detroit, Michigan. The largest proportion of cases were inhalation-related deaths in dwelling fires (n = 21, 55%), followed by deaths from thermal injury after immolation (n = 8, 21%) and traumatic death with contemporaneous or subsequent immolation (n = 8, 21%). There was one case of postmortem immolation. Although carboxyhemoglobin (COHb) levels played a significant role in evaluation of these cases, no single factor was diagnostic of a particular cause or manner of death. Fire-related homicides present unique diagnostic challenges because multiple insults frequently contribute to the cause death. Death at the scene and COHb level above 10% are the most useful factors in establishing smoke and soot inhalation as the cause of death. Some autopsy findings are helpful in establishing or ruling out smoke and soot inhalation as contributing to or sole cause of death, but an evaluation of the entire circumstances and autopsy findings is necessary.

Multiple system atrophy pathology is associated with primary Sjögren's syndrome.

BACKGROUNDOur objective was to investigate whether primary Sjögren's syndrome (pSS) is associated with multiple system atrophy (MSA).METHODSWe performed a retrospective cohort study assessing (a) rates of MSA in a cohort of patients with pSS and (b) rates of pSS in a cohort of patients with MSA. These data were compared with rates in respective control groups. We additionally reviewed the neuropathologic findings in 2 patients with pSS, cerebellar degeneration, parkinsonism, and autonomic dysfunction.RESULTSOur cohort of 308 patients with pSS had a greater incidence of MSA compared with 4 large population-based studies and had a significantly higher prevalence of at least probable MSA (1% vs. 0%, P = 0.02) compared with 776 patients in a control cohort of patients with other autoimmune disorders. Our cohort of 26 autopsy-proven patients with MSA had a significantly higher prevalence of pSS compared with a cohort of 115 patients with other autopsy-proven neurodegenerative disorders (8% vs. 0%, P = 0.03). The 2 patients we described with pSS and progressive neurodegenerative disease showed classic MSA pathology at autopsy.CONCLUSIONOur findings provide evidence for an association between MSA and pSS that is specific to both pSS, among autoimmune disorders, and MSA, among neurodegenerative disorders. The 2 cases we describe of autopsy-proven MSA support that MSA pathology can explain neurologic disease in a subset of patients with pSS. These findings together support the hypothesis that systemic autoimmune disease plays a role in neurodegeneration.FUNDINGThe Michigan Brain Bank is supported in part through NIH grant P30AG053760.

Sudden Death Due to Calcifying Pseudoneoplasm of the Neuraxis: A Case Report and a Review of Sudden Death Due to Undiagnosed Central Nervous System Mass Lesions.

We present a case of a 22-year-old man who died unexpectedly after a seizure due to a previously undiagnosed calcifying pseudoneoplasm of the neuraxis (CAPNON). Calcifying pseudoneoplasm of the neuraxis is a rare entity, and this is, to our knowledge, the first described case of sudden death due to CAPNON. Sudden death due to undiagnosed central nervous system mass lesions is rare, and most cases are attributable to hemorrhage, hydrocephalus, or increased intracranial pressure due to mass effect. Seizure is a rare cause of sudden death due to central nervous system mass lesions. This case highlights that mass lesions may cause sudden death due to seizure, even without other pathologic evidence of a cause of death, such as hemorrhage or edema. Furthermore, benign, reactive, and low-grade mass lesions may cause sudden death due to seizure. Seizure should remain in the autopsy differential as a cause of death, even where there is no pathologically evident mechanism by which a mass lesion caused death.

Cardiac Involvement in Sarcoidosis Deaths in Wayne County, Michigan: A 20-Year Retrospective Study.

BACKGROUND: Sarcoidosis is a disease of unknown etiology characterized by the formation of noncaseating, nonnecrotizing granulomas in various organ systems. METHODS: Reviews of 84 cases of natural death with sarcoidosis between the years 1996 and 2017 autopsied at Wayne County. RESULTS: The median age of decedents was 44 years (29 - 59 years of age). Blacks comprised 95% of the cohort, and 52% were female. Sarcoidosis or direct sequelae were the cause of death in 79% of cases. Twenty-nine percent of patients had a documented history of sarcoidosis and 70% of patients had evidence of systemic sarcoidosis. The most common sites of involvement were lungs or hilar lymph nodes (92%), heart (45%), liver (39%), and spleen (30%). Decedents with cardiac involvement were more likely to have no documented history of sarcoidosis (87% vs. 59%, p=0.004), more likely to have died of a sarcoidosis-related cause (97% vs. 65%, p<0.001), and died at a younger mean age (41 years vs. 46 years, p=0.001). In addition, individuals with cardiac involvement commonly had concurrent multiorgan involvement including lungs (90%), lymph nodes (38%), liver (40%), spleen (32%), and kidneys (7%). CONCLUSIONS: Cardiac sarcoidosis is a uniquely poor prognostic factor and carries an increased risk of sudden death as shown by a disproportionate representation among medical examiner cases of sarcoidosis. Our findings suggest that approximately 40% may have asymptomatic cardiac involvement. The distribution of sarcoidosis within our cohort suggests that there is potentially a large undiagnosed and/or underdiagnosed demographic within large urban centers, such as Detroit, Michigan.

Relationship Between 24-Hour Ambulatory Blood Pressure and Cognitive Function in Community-Living Older Adults: The UCSD Ambulatory Blood Pressure Study.

BACKGROUND: Twenty-four-hour ambulatory blood pressure (BP) patterns have been associated with diminished cognitive function in hypertensive and very elderly populations. The relationship between ambulatory BP patterns and cognitive function in community-living older adults is unknown. METHODS: We conducted a cross-sectional study in which 24-hour ambulatory BP, in-clinic BP, and cognitive function measures were obtained from 319 community-living older adults. RESULTS: The mean age was 72 years, 66% were female, and 13% were African-American. We performed linear regression with performance on the Montreal Cognitive Assessment (MoCA) as the primary outcome and 24-hour BP patterns as the independent variable, adjusting for age, sex, race/ethnicity, education, and comorbidities. Greater nighttime systolic dipping (P = 0.046) and higher 24-hour diastolic BP (DBP; P = 0.015) were both significantly associated with better cognitive function, whereas 24-hour systolic BP (SBP), average real variability, and ambulatory arterial stiffness were not. CONCLUSIONS: Higher 24-hour DBP and greater nighttime systolic dipping were significantly associated with improved cognitive function. Future studies should examine whether low 24-hour DBP and lack of nighttime systolic dipping predict future cognitive impairment.