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Refereed/Peer-reviewed Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer’s disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic, genetic, and clinical data were compiled from 13 high-quality community- and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese–American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1 years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n = 5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementia—broadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n = 6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with “frequent” neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage > 1 (associated with cognitive impairment). In the subset of individuals with Thal Aβ phase = 0 (lacking detectable Aβ plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC in advanced age. LATE-NC was seen in almost 40% of participants and often, but not always, coexisted with Alzheimer’s disease neuropathology.

Dementia with Lewy bodies (DLB) is clinically diagnosed when patients develop dementia less than a year after parkinsonism onset. Age is the primary risk factor for DLB and mitochondrial health influences ageing through effective oxidative phosphorylation (OXPHOS). Patterns of stable polymorphisms in the mitochondrial genome (mtDNA) alter OXPHOS efficiency and define individuals to specific mtDNA haplogroups. This study investigates if mtDNA haplogroup background affects clinical DLB risk and neuropathological disease severity. 360 clinical DLB cases, 446 neuropathologically confirmed Lewy body disease (LBD) cases with a high likelihood of having DLB (LBD-hDLB), and 910 neurologically normal controls had European mtDNA haplogroups defined using Agena Biosciences MassARRAY iPlex technology. 39 unique mtDNA variants were genotyped and mtDNA haplogroups were assigned to mitochondrial phylogeny. Striatal dopaminergic degeneration, neuronal loss, and Lewy body counts were also assessed in different brain regions in LBD-hDLB cases. Logistic regression models adjusted for age and sex were used to assess associations between mtDNA haplogroups and risk of DLB or LBD-hDLB versus controls in a case-control analysis. Additional appropriate regression models, adjusted for age at death and sex, assessed associations of haplogroups with each different neuropathological outcome measure. No mtDNA haplogroups were significantly associated with DLB or LBD-hDLB risk after Bonferroni correction.Haplogroup H suggests a nominally significant reduced risk of DLB (OR=0.61, P=0.006) but no association of LBD-hDLB (OR=0.87, P=0.34). The haplogroup H observation in DLB was consistent after additionally adjusting for the number of APOE ε4 alleles (OR=0.59, P=0.004). Haplogroup H also showed a suggestive association with reduced ventrolateral substantia nigra neuronal loss (OR=0.44, P=0.033). Mitochondrial haplogroup H may be protective against DLB risk and neuronal loss in substantia nigra regions in LBD-hDLB cases but further validation is warranted.

Summarizing the multiplicity and heterogeneity of cerebrovascular disease (CVD) features into a single measure has been difficult in both neuropathology and imaging studies. The objective of this work was to evaluate the association between neuroimaging surrogates of CVD and two available neuropathologic CVD scales in those with both antemortem imaging CVD measures and postmortem CVD evaluation. Individuals in the Mayo Clinic Study of Aging with MRI scans within 5 years of death (N = 51) were included. Antemortem CVD measures were computed from diffusion MRI (dMRI), FLAIR, and T2* GRE imaging modalities and compared with postmortem neuropathologic findings using Kalaria and Strozyk Scales. Of all the neuroimaging measures, both regional and global dMRI measures were associated with Kalaria and Strozyk Scales (p

Multi-compartment modelling of white matter microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) can provide information on white matter health through neurite density index and free water measures. We hypothesized that cerebrovascular disease, Alzheimer’s disease, and TDP-43 proteinopathy would be associated with distinct NODDI readouts of white matter damage which would be informative for identifying the substrate for cognitive impairment. We identified two independent cohorts with multi-shell diffusion MRI, amyloid and tau PET, and cognitive assessments: specifically, a population-based cohort of 347 elderly randomly sampled from the Olmsted county, Minnesota, population and a clinical research-based cohort of 61 amyloid positive Alzheimer’s dementia participants. We observed an increase in free water and decrease in neurite density using NODDI measures in the genu of the corpus callosum associated with vascular risk factors, which we refer to as the vascular white matter component. Tau PET signal reflective of 3R/4R tau deposition was associated with worsening neurite density index in the temporal white matter where we measured parahippocampal cingulum and inferior temporal white matter bundles. Worsening temporal white matter neurite density was associated with (antemortem confirmed) FDG TDP-43 signature. Post-mortem neuropathologic data on a small subset of this sample lend support to our findings. In the community-dwelling cohort where vascular disease was more prevalent, the NODDI vascular white matter component explained variability in global cognition (partial R2 of free water and neurite density = 8.3%) and MMSE performance (8.2%) which was comparable to amyloid PET (7.4% for global cognition and 6.6% for memory). In the AD dementia cohort, tau deposition was the greatest contributor to cognitive performance (9.6%), but there was also a non-trivial contribution of the temporal white matter component (8.5%) to cognitive performance. The differences observed between the two cohorts were reflective of their distinct clinical composition. White matter microstructural damage assessed using advanced diffusion models may add significant value for distinguishing the underlying substrate (whether cerebrovascular disease versus neurodegenerative disease caused by tau deposition or TDP-43 pathology) for cognitive impairment in older adults. Graphical abstract

Sudden unexplained death in childhood (SUDC) affects children >1-year-old whose cause of death remains unexplained following comprehensive case investigation and is often associated with hippocampal abnormalities. We prospectively performed systematic neuropathologic investigation in 20 SUDC cases, including (i) autopsy data and comprehensive ancillary testing, including molecular studies, (ii) ex vivo 3T MRI and extensive histologic brain samples, and (iii) blinded neuropathology review by 2 board-certified neuropathologists. There were 12 girls and 8 boys; median age at death was 33.3 months. Twelve had a history of febrile seizures, 85% died during apparent sleep and 80% in prone position. Molecular testing possibly explained 3 deaths and identified genetic mutations in TNNI3, RYR2, and multiple chromosomal aberrations. Hippocampal abnormalities most often affected the dentate gyrus (altered thickness, irregular configuration, and focal lack of granule cells), and had highest concordance between reviewers. Findings were identified with similar frequencies in cases with and without molecular findings. Number of seizures did not correlate with hippocampal findings. Hippocampal alterations were the most common finding on histological review but were also found in possibly explained deaths. The significance and specificity of hippocampal findings is unclear as they may result from seizures, contribute to seizure pathogenesis, or be an unrelated phenomenon.

Chronic traumatic encephalopathy is a debilitating neurodegenerative disorder associated with repetitive traumatic brain injuries often sustained through prior contact sport participation. The frequency of this disorder in a diverse population, including amateur athletes, is unknown. Primary historical obituary and yearbook records were queried for 2566 autopsy cases in the Mayo Clinic Tissue Registry resulting in identification of 300 former athletes and 450 non‐athletes. In these cases, neocortical tissue was screened for tau pathology with immunohistochemistry, including pathology consistent with chronic traumatic encephalopathy, blinded to exposure or demographic information. Using research infrastructure of the Rochester Epidemiology Project, a comprehensive and established medical records‐linkage system of care providers in southern Minnesota and western Wisconsin, medical diagnostic billing codes pertaining to head trauma, dementia, movement disorders, substance abuse disorders and psychiatric disorders were recorded for cases and controls in a blinded manner. A total of 42 individuals had pathology consistent with, or features of, chronic traumatic encephalopathy. It was more frequent in athletes compared to non‐athletes (27 cases versus 15 cases) and was largely observed in men (except for one woman). For contact sports, American football had the highest frequency of chronic traumatic encephalopathy pathology (15% of cases) and an odds ratio of 2.62 (P‐value = 0.005). Cases with chronic traumatic encephalopathy pathology had higher frequencies of antemortem clinical features of dementia, psychosis, movement disorders and alcohol abuse compared to cases without chronic traumatic encephalopathy pathology. Understanding the frequency of chronic traumatic encephalopathy pathology in a large autopsy cohort with diverse exposure backgrounds provides a baseline for future prospective studies assessing the epidemiology and public health impact of chronic traumatic encephalopathy and sports‐related repetitive head trauma.

Context.—Preanalytic errors, including specimen labeling errors and specimen loss, occur frequently during specimen collection, transit, and accessioning. Radio-frequency identification tags can decrease specimen identification and tracking errors through continuous and automated tracking of specimens.Objective.—To implement a specimen tracking infrastructure to reduce preanalytic errors (specimen mislabeling or loss) between specimen collection and laboratory accessioning. Specific goals were to decrease preanalytic errors by at least 70% and to simultaneously decrease employee effort dedicated to resolving preanalytic errors or investigating lost specimens.Design.—A radio-frequency identification specimen-tracking system was developed. Major features included integral radio-frequency identification labels (radio-frequency identification tags and traditional bar codes in a single printed label) printed by point-of-care printers in collection suites; dispersed radio-frequency identification readers at major transit points; and systems integration of the electronic health record, laboratory information system, and radio-frequency identification tracking system to allow for computerized physician order entry driven label generation, specimen transit time tracking, interval-based alarms, and automated accessioning.Results.—In the 6-month postimplementation period, 6 mislabeling events occurred in collection areas using the radio-frequency identification system, compared with 24 events in the 6-month preimplementation period (75% decrease; P = .001). In addition, the system led to the timely recovery of 3 lost specimens. Labeling expenses were decreased substantially in the transition from high-frequency to ultrahigh frequency radio-frequency identification tags.Conclusions.—Radio-frequency identification specimen tracking prevented several potential specimen-loss events, decreased specimen recovery time, and decreased specimen labeling errors. Increases in labeling/tracking expenses for the system were more than offset by time savings and loss avoidance through error mitigation.

AIMS: 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 haematoxylin and eosin (H&E) slides (n = 67; 36 SUDC, 31 controls) from clinical and forensic collaborators were evaluated by nine blinded reviewers: three board-certified forensic pathologists, three neuropathologists and three dual-certified neuropathologists/forensic pathologists. RESULTS: Among nine reviewers, about 50% of hippocampal sections were rated as abnormal (52.5% SUDC, 53.0% controls), 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’ κ = 0.014, p = 0.47). Within reviewer groups, there were no findings more frequent in SUDC compared with 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 maldevelopment associated with sudden death (HMASD). These findings underscore a need for larger studies to standardise evaluation of hippocampal findings, identifying 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.

We report the neuropathological findings of a patient who died from complications of COVID-19. The decedent was initially hospitalized for surgical management of underlying coronary artery disease. He developed post-operative complications and was evaluated with chest imaging studies. The chest computed tomography (CT) imaging results were indicative of COVID-19 and he was subsequently tested for SARS-CoV-2, which was positive. His condition worsened and he died after more than 2 weeks of hospitalization and aggressive treatment. The autopsy revealed a range of neuropathological lesions, with features resembling both vascular and demyelinating etiologies. Hemorrhagic white matter lesions were present throughout the cerebral hemispheres with surrounding axonal injury and macrophages. The subcortical white matter had scattered clusters of macrophages, a range of associated axonal injury, and a perivascular acute disseminated encephalomyelitis (ADEM)-like appearance. Additional white matter lesions included focal microscopic areas of necrosis with central loss of white matter and marked axonal injury. Rare neocortical organizing microscopic infarcts were also identified. Imaging and clinical reports have demonstrated central nervous system complications in patients’ with COVID-19, but there is a gap in our understanding of the neuropathology. The lesions described in this case provide insight into the potential parainfectious processes affecting COVID-19 patients, which may direct clinical management and ongoing research into the disease. The clinical course of the patient also illustrates that during prolonged hospitalizations neurological complications of COVID may develop, which are particularly difficult to evaluate and appreciate in the critically ill.

Context.—Autopsy rates have decreased dramatically despite providing important clinical information to medical practices and social benefits to decedents' families.Objective.—To assess the impact of an institutional Office of Decedent Affairs (ODA), a direct communication link between pathology and decedents' families, on hospital autopsy consent rates, autopsy-related communication, practitioner views, and next-of-kin experiences.Design.—A before and after study involving all hospital decedents whose deaths did not fall within the jurisdiction of the medical examiner's office from 2013 to 2018. A pathology-run ODA launched in May 2016 to guide next-of-kin through the hospital death process (including autopsy-related decisions) and serve as the next-of-kin's contact for any subsequent autopsy-related communication. Critical care and hematology/oncology practitioners were assessed for their autopsy-related views and decedents' next-of-kin were assessed for their autopsy-related experiences. Autopsy consent rates for non–medical examiner hospital deaths, autopsy-related communication rates, practitioner views on the role and value of autopsy, and next-of-kin autopsy experiences and decisions factors were compared prior to and after ODA launch.Results.—Autopsy consent rates significantly increased from 13.2% to 17.3% (480 of 3647 deaths versus 544 of 3148 deaths; P < .001). There were significant increases in the rate of autopsy-related discussions and bereavement counseling provided to decedents' families. Practitioner views on the positive role of autopsy for any hospital death and those with advanced stage cancer also significantly increased. Next-of-kin indicated more consistent autopsy-related discussions with the potential benefits of autopsy discussed becoming key decision factors.Conclusions.—An ODA improves hospital autopsy consent rates, autopsy-related communication, providers' autopsy-related views, and next-of-kins autopsy experiences.

The legal system of the United States is complex, with nuances that are particular to its many jurisdictions. The neuropathologist may professionally interact with the legal system in both criminal and civil proceedings as either a fact or expert witness, and in rare instances as a defendant. The nature of the legal issue at hand will define the pathologist's role and determine what actions are required or requested. The intersection of neuropathology and the laws governing quality assurance may be less defined as legal statutes vary by state; although, the general principles of privilege, peer review, and confidentiality remain similar. Aside from a forensic pathology fellowship, there is often little in the way of our training to prepare us for our potential roles in the courtroom. This article serves as a review for the neuropathologist's role as a witness, the legal proceedings that you may participate in, and the intersection between quality assurance and law.

Exploding targets are marketed for their ability to indicate long-range marksmanship by detonating upon high velocity impact. The Internet has popularized recreational use of these targets outside of the scope of their intended design. We present a case of a 47-year-old man who was a bystander during recreational use of exploding targets. A .300 Winchester Magnum rifle was used to detonate an exploding target, on top of which was placed a fire extinguisher inside an aluminum pipe. The decedent was struck in the abdomen by a fragment of aluminum and collapsed. Despite emergency efforts at the scene, he was pronounced dead. Scene investigation revealed aluminum fragments throughout the blast radius. External examination and postmortem radiograph showed an entry wound of the left mid-abdomen without evidence of retained shrapnel. The autopsy findings included a hemoperitoneum due to transection of the right common iliac artery and inferior vena cava. A 10.6 g fragment of aluminum was recovered from within the abdomen. This case illustrates a dangerous misuse of exploding targets that has been popularized in the media. It also exemplifies a potential pitfall of a negative radiograph, despite the presence of metal shrapnel, because of the radiolucency of aluminum.

Epilepsy is commonly encountered in forensic pathology and is ultimately determined to be the cause of death in 1–2% of medicolegal death investigations. Epilepsy is a risk factor for death from external causes, including accidents and drowning. More commonly, deaths result from the underlying epilepsy pathology, including intracranial neoplasms, cerebrovascular disease, status epilepticus, and sudden unexpected death in epilepsy (SUDEP). SUDEP refers to the sudden death in an epilepsy patient that lacks an alternative anatomic or toxicological cause of death. At autopsy, intracranial pathology is present in the majority of epilepsy-related deaths and is more likely to be identified following brain fixation. Common findings include brain tumors, mesial temporal sclerosis, and malformations of cortical development. Death investigators should pay particular attention to clinical history to establish a clear history of epilepsy and to determine seizure type, frequency, underlying etiology, and prior medical and surgical treatments as well as other comorbid medical conditions. A complete autopsy with toxicology is necessary to identify other causes of death, particularly in cases of suspected SUDEP. While toxicology may be helpful in some cases, caution must be taken in interpreting postmortem antiepileptic drug concentrations as levels decrease postmortem.

The National Association of Medical Examiners convened a panel to create a position paper for recommendations for the investigation of infant deaths due to inflicted head trauma. The correct certification of both the cause and manner of death is dependent upon an evaluation of all available data including information derived from the investigation, scene, postmortem examination, and ancillary studies. This paper provides recommendations for the forensic pathologist on what constitutes the dataset to be produced during the postmortem examination of infants who have died of, or have apparently died of, inflicted head trauma. Specifically, this paper describes 1) procedures, 2) ancillary laboratory tests, and 3) forms of documentation that are important in the investigation of these deaths. The evaluation and documentation of such infant deaths involves the production of a detail oriented and thoroughly documented examination that is independently reviewable to support the multitude of inquiries that may follow from the public and the criminal justice system.

Background Myoglobin-related renal injury (MRRI) is a significant cause of acute renal injury and may result in death. Common etiologies in forensic pathology include trauma and drug abuse. This study sought to determine the prevalence and causes of MRRI at autopsy and discuss diagnostic challenges. Methods The institutional autopsy archives were queried for cases in which a myoglobin (MG) immunohistochemical stain was performed or MRRI was diagnosed or considered. The clinicopathological characteristics of this population were described. Results Of 9996 cases over a period of 19.5 years, 17 cases (0.2%) fulfilled the criteria. Patient age ranged from 15 to 74 years; 11 were men. The MG stain was performed in 13 cases. In 11 (65%) cases, MRRI was diagnosed with or without immunohistochemistry. The clinical backgrounds were varied; sepsis and liver injury predominated. Time between original insult and death ranged from seven hours to four months. Patterns of MRRI included cast formation or fine brush border staining in the proximal tubules. Discussion MRRI is infrequently considered in the autopsy setting. Many causes of MRRI identified in this series involved circumstances placing the death into medical examiner jurisdiction; the MG stain contributed to understanding the mechanism of death. Acute tubular injury with cast formation was observed in the majority of cases. Conclusion MRRI is common in a select group of autopsies but may be underappreciated. The MG stain is a useful and inexpensive tool to aid in the diagnosis of MRRI in autopsy pathology.

A complex set of systems exists in the United States to manage and regulate the practice of medicine, and forensic pathologists (FPs) are bound by the associated ethical guidelines and associated statutory obligations. Individual FPs, for example, are required to have and maintain a state medical license that requires continuing medical education and provides oversight of many aspects of the practice of medicine. The laboratories in which forensic pathology is practiced, however, generally do not have to be accredited. In contrast, the College of American Pathologists (CAP) is the recognized accrediting body that “regulates” the majority of anatomic pathology and laboratory medicine, including hospital (consented) autopsies. Unlike hospital-based pathology practices, few incentives are present that encourage or require forensic pathology practices to pursue accreditation. Since the preponderance of forensic pathology practices do not fall under the purview of CAP, this relatively small subset of pathologists are left to determine their own set of professional and ethical standards. The National Association of Medical Examiners (NAME) laboratory accreditation and published autopsy guidelines provides a foundation for development of a quality management program, but does not specifically address disclosure of test results. Defining “critical diagnoses” in forensic pathology is challenging, and communicating these important findings to the proper individual(s) or organizations may not fall under statutory or accrediting requirements, and thus may become an ethical issue for the medical examiner/coroner.

Sudden unexpected death is typically diagnosed in infants, children, teenagers, and young adults following completion of an autopsy that fails to identify a cause of death or when autopsy suggests a potentially genetic cause of death in an individual less than 40, such as cardiomyopathy or aneurysm. Such deaths may be a result of genetic abnormalities that are unable to be diagnosed by gross or microscopic inspection, but may be detectable by molecular studies. Unfortunately, the ability to perform postmortem genetic testing is frequently hindered by lack of an appropriate specimen following completion of an autopsy. This paper provides recommendations developed by the National Association of Medical Examiners with the assistance of genetic counselors. The recommendations establish procedures to facilitate postmortem genetic testing and DNA banking by health care professionals assisting families who have experienced sudden death in young relatives by clarifying proper sample acquisition and storage. Additionally, recommendations for discussion with surviving family members and test planning are provided. The objective of these recommendations is to ensure that postmortem samples suitable for DNA banking are retained, allowing at risk family members improved detection of potentially treatable genetic diseases.

The report begins with the case of an 18-year-old male who presented to a community hospital with difficulty walking and speaking. His illicit drug use history included smoking heroin. After admission to the hospital, a thorough workup was consistent with toxic heroin related leukoencephalopathy. The young man continued to decline and died approximately 2 months after his initial presentation and diagnosis. An autopsy and a thorough neuropathology examination were completed. Sections through the cerebral hemispheres and the cerebellum revealed diffuse and profound softening and discoloration of the white matter, most prominently in the occipital lobes. Microscopically, there was vacuolization and spongiosis of the white matter. The pathologic findings were consistent with the diagnosis of toxic or heroin related leukoencephalopathy. Toxic leukoencephalopathy is a rare disorder of unknown etiology linked to the smoking of heroin, known as “chasing the dragon.” The exact mechanism of the disorder is unknown, but it is thought that impurities cut into the heroin may become toxic substances upon sublimation, as the disorder is not seen with injected heroin. Currently, therapy is supportive with no effective cures available. The natural history of the disorder is variable, with an approximately 25% mortality rate. The popularity of smoking heroin is growing in the United States, and it is particularly seen with increasing frequency in new heroin users. Thus, this is an important, and likely increasingly common, effect of illicit drug use that should be recognized by forensic pathologists.

Increased age is a significant risk factor for the development of dementia, predominately Alzheimer disease (AD). Since the fastest growing population sector in the United States is individuals over the age of 85 years, a surge in cases of dementia is expected. The inherent features of dementia mean those affected will eventually be incapacitated and require a high level of medical care. The majority of individuals dying from the complications of dementia will be under the care of a physician. However, dementia is a significant morbidity and demented patients are at risk from dying of non-natural causes (e.g., neglect/abuse or accidental injury) that necessitates the medical examiner/coroner (ME/C) to determine if the individual was incapacitated by a neurodegenerative process. The definitive diagnosis of a specific type of dementia requires a postmortem neuropathological examination. This paper provides a concise description of and a practical neuropathological algorithmic approach to the diagnosis of the most common neurodegenerative diseases.

The medicolegal autopsy is part of a death investigation that determines the cause and manner of death and the extent of the testing performed is variable and is directed by the specifics of a particular case. Published studies disagree on the value of routine examination of microscopic sections of internal organs in forensic cases and no studies have specifically reviewed the utility of routine neuropathology microscopic sections. We reviewed the Miami-Dade County Medical Examiner Department and Mayo Clinic computer databases to determine whether routine brain histology is of value in medicolegal autopsies and the impact on the cause and manner of death. Consecutive cases from each institution were analyzed to determine whether the microscopic neuropathological findings revealed a previously unrecognized disease, changed the cause or manner of death, or significantly impacted the death investigation. In the cases in which the immediate cause of death was attributable to central nervous system (CNS) pathology, the cause of death was readily apparent from the gross brain examination. If CNS pathology was the proximate cause of death, contributed significantly to the death, or was a significant part of the death investigation, full appreciation of the neuropathology required microscopic examination and often additional special/immunostains. We conclude that microscopic brain examination is needed in selected medicolegal autopsies to exclude and/or diagnose underlying disease processes, particularly if the gross examination doesn't reveal an obvious explanation of the CNS pathology or the clinical history suggests underlying neuropathology.

Adult polyglucosan body disease (APBD) is a rare neurodegenerative condition characterized by typical onset in middle age, progressive neurological impairment that is heterogeneous between cases, and death within 1-14 years of diagnosis. The histopathologic hallmark of the disease is massive deposition of corpora amylacea (designated polyglucosan bodies in this context) in the central nervous system, and variable deposition of similar material in other sites. While the cause of the disease is as yet unknown, recent research has identified mutations in proteins involved in glycogen metabolism in a subset of cases. In this paper, we present a case of unexpected death wherein APBD was diagnosed at forensic autopsy. This represents the first report of an unexpected death due to this disease reported in the medical and forensic literature.

Postmortem examinations have taken place over the past several thousand years. Despite this, the definition of a “complete” autopsy remains nebulus and the subject of controversy. Although ‘minimal autopsy practice standards’ have been published by professional bodies globally, recognition of, and adherence to those standards remains sporadic. An underlying refutation that ‘autopsies can never be complete’ – the reductio ad absurdum fallacy – has influenced many forensic pathologists’ opinions about autopsy. More pragmatic pathologists attempt to balance the financial and workload burdens of autopsies with the principles of adequacy and accuracy. Some medical examiners cite “statutory duty” as the force guiding the nature and completeness of their work, and as such, external examinations, partial autopsies and other limited variants are substituted for complete autopsies. Although it is impossible to perform every conceivable test in any one autopsy, an evidence-based approach guided by three forensic autopsy goals – statutory duty, the creation of a minimal dataset for societal and governmental inquiry, and maintenance of practitioner competency – ensure the completeness of any one postmortem examination.

This article will present an overview of, and a strategy for, designing a comprehensive quality assurance and improvement program for forensic pathology. Quality forensic pathology, as in anatomic pathology in general, depends on creating accurate, timely, complete, and usable reports. A successful quality assurance program requires a well-developed plan to accurately monitor and evaluate the myriad of processes (performance metrics) required to practice quality forensic pathology. A quality assurance program should address all three phases (preanalytic, analytic, and postanalytic) of the forensic autopsy “test cycle” as well as laboratory accreditation and monitoring requirements. A flourishing quality assurance program combined with the appropriate organizational culture is the cornerstone of continuous quality improvement. Many of the components (e.g. quality assurance of the toxicology laboratory) that fold into the practice of forensic pathology should be evaluated using the same quality assurance principles, but will not be addressed specifically in this article.

In the United States approximately 250,000 persons have a traumatic spinal cord injury (TSCI) and most will die from complications related to their injury. Interpretation of TSCI deaths by medical examiners is evolving as understanding of SCI pathophysiology increases. We queried our electronic database for deaths meeting inclusion criteria from 1989 to 2008 and identified 305 cases, of which 81% were males and 19% were females. A full autopsy was performed in 38.7% of cases and an external exam was performed in the remaining cases (61.3%). The manner of death distribution was accident (80%), homicide (7%), natural (7%), suicide (4%) or undetermined (2%). The most common mechanisms of spinal cord injury were motor vehicle accidents (42.6%), fall from a standing height (12.8%), fall from above a standing height (9.2%) and gunshot wounds (8.8%). The mechanism of spinal cord injury significantly impacted survival (p=0.0001) with decedents injured from motor vehicle accidents having a mean survival time of 14.4 years compared to 0.7 year from falling from a standing height. Analyzing patterns of deaths due to TSCI in a medical examiner office provides excellent epidemiological data for injury tracking and prevention as well as a context for medical examiners evaluating TSCI.

Birth injury of the scalp, skull and central nervous system (CNS) is a well-recognized complication of a difficult delivery. The rate of birth trauma has dropped precipitously and now accounts for less than 2% of neonatal deaths. Despite this dramatic decrease in birth-trauma mortality significant injuries still occur. A variety of risk factors clearly predispose certain infants to birth-related injury. Recent neuroradiology studies indicate that intracranial hemorrhage, even in asymptomatic infants, is not rare. Pathologists' (neuropathologists and forensic pathologists) appreciation of the spectrum of birth injuries and their sequelae is critical in order to be able to distinguish these from inflicted injuries and post-mortem changes.

Context.—Inflicted traumatic brain injury of infants and young children results in a complex array of autopsy findings. In many cases, immunostains for β-amyloid precursor protein are used to detect axonal injury. Interpretation of the gross, microscopic, and immunostaining results requires the integration of the many facets of the individual case. Objective.—In this article we review the gross and microscopic findings associated with inflicted traumatic brain injury. The application and interpretation of β-amyloid precursor protein immunostains are discussed and photomicrographs are used to illustrate immunostaining patterns. Data Sources.—The pertinent literature is integrated into a review of the subject. Conclusions.—Inflicted traumatic brain injury often results in subdural, subarachnoid, retinal, and optic nerve sheath hemorrhage. These findings must be interpreted within the entire context of the case. β-Amyloid precursor protein immunostains may be helpful in illustrating the traumatic nature of the injuries in some cases.

We present the case of a 7-month-old female infant who was found crying and limp. She was transported to a hospital where a possible subarachnoid hemorrhage was diagnosed radiologically. Before further studies could be pursued, her condition worsened and she died. The autopsy demonstrated diffuse subarachnoid hemorrhage of the brain and along the spinal cord. The brain, spinal cord, and eyes were retained and examined postfixation. An aneurysm of the middle cerebral artery was identified. Examination of the eyes demonstrated bilateral optic nerve sheath hemorrhage and extensive retinal hemorrhages extending to the ora serrata. A rapid increase in intracranial pressure secondary to subarachnoid hemorrhage following rupture of an aneurysm can result in sequelae similar to those found in inflicted traumatic brain injury. In this case, the rise in intracranial pressure resulted in marked hemorrhage within the optic nerve sheaths as well as intra- and preretinal hemorrhages. Patients with subarachnoid hemorrhage, or other causes of rapidly increased intracranial pressure, may develop ocular hemorrhage (Terson syndrome). This case illustrates the importance of ruling out natural disease before attributing the autopsy findings to trauma, as well as the importance of postmortem fixation of pediatric brains and eyes prior to examination.

The histologic characteristics of grossly unremarkable pediatric dura mater obtained at autopsy are not well defined. The microscopic examination of pediatric dura mater is often undertaken to look for evidence of recent, resolving, or remote craniocerebral trauma. Pathologic processes cannot be defined without knowledge of expected histology, however. In this study, we examined grossly unremarkable dura mater from 11 children, utilizing hematoxylin and eosin, iron, CD-34, CD-68, and epithelial membrane antigen stains. Pediatric dura mater is a relatively vascular tissue, particularly on its internal and external surfaces. Several sections contained iron deposits. Almost all of the para-sagittal and many of the lateral dura mater sections contained intradural blood, whereas dura mater attached to bone did not. Intradural blood could arise by several mechanisms, including the act of removing the dura mater from the calvarium during the autopsy. CD-34 staining showed potential as a means to differentiate the internal from the external dural surfaces. Familiarity with the histologic features of pediatric dura mater is crucial for the correct interpretation true dura mater pathology.

Subacute combined degeneration (SCD) of the spinal cord is the most common neurologic manifestation of vitamin B12 (cobalamin) deficiency and is usually secondary to autoimmune gastritis, but may also be seen in malnutrition syndromes such as chronic alcoholism, strict vegetarianism, gastrectomy, and also in nitrous oxide abuse. Although traumatic spinal cord injury is routinely encountered in the medical examiner's office, medical causes of spinal cord abnormalities such as SCD should be considered in the appropriate clinical setting. We report a case of alcohol-associated SCD mimicking traumatic spinal cord injury.

We created a model surveillance system (Med-X) designed to enable medical examiners and coroners to recognize fatal infections of public health importance and deaths due to bioterrorism. All individuals who died in New Mexico and fell under medical examiner jurisdiction between November 23, 2000, and November 22, 2002, were prospectively evaluated using sets of surveillance symptoms and autopsy-based pathologic syndromes. All infectious disease deaths were evaluated to identify the specific causative agent. Of 6104 jurisdictional cases, 250 (4.1%) met Med-X criteria, of which 141 (56.4%) had a target pathologic syndrome. Ultimately, 127 (51%) of the 250 cases were due to infections. The causative organism was identified for 103 (81%) of the infectious disease deaths, of which 60 (58.3%) were notifiable conditions in New Mexico. Flu-like symptoms, fever and respiratory symptoms, and encephalopathy or new-onset seizures had predictive values positive for fatal infections of 65%, 72%, and 50%, respectively, and are useful as autopsy performance criteria. Before the development of surveillance criteria, 37 (14.8%) of the cases ordinarily would not have been autopsied resulting in a 1% increase in autopsy workload. Med-X is an effective method of detecting infectious disease deaths among medical examiner cases. Uniform criteria for performing medical examiner autopsies and reporting cases to public health authorities enhance surveillance for notifiable infectious diseases and increase the likelihood of recognizing deaths related to bioterrorism.

Immunohistochemical staining for beta-amyloid precursor protein (betaAPP) has been validated as a marker for axonal injury in adults surviving > or = 2 hours after white matter damage. The significance of betaAPP staining in pediatric brains and spinal cords is not as well established. We evaluated the white matter immunoreactivity for betaAPP from a variety of pediatric medicolegal autopsies: natural disease (non-Sudden Infant Death Syndrome [SIDS]), SIDS, motor vehicle accidents, drowning, near-drowning, overlay, carbon monoxide toxicity, miscellaneous trauma, and mechanical asphyxia. The cases of carbon monoxide toxicity, motor vehicle accidents (death at scene), drowning (with resuscitation), and a natural (non-SIDS) death had no significant white matter staining. The traumatic deaths with a significant survival interval, a variety of natural deaths, the near-drowning case, and surprisingly, all SIDS had detectable betaAPP white matter immunostaining. These results demonstrate that features other than traumatic axonal injury, such as metabolic insults and hypoxic-ischemic injury secondary to vascular compromise, must contribute to betaAPP immunostaining. In addition, we describe a variety of betaAPP-immunoreactive structures not previously reported in the pediatric population. This study illustrates that betaAPP immunostaining enhances detection of a variety of white matter changes, and provides a basis for interpretation of these results.