R. Ross Reichard

National Association of Medical Examiners Position Paper: Retaining Postmortem Samples for Genetic Testing

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.

Association between microinfarcts and blood pressure trajectories

Importance Cerebral microinfarcts are associated with increased risk of cognitive impairment and may have different risk factors than macroinfarcts. Subcortical microinfarcts are associated with declining blood pressure (BP) in elderly individuals. Objective To investigate BP slopes as a risk factor for microinfarcts. Design, Setting, and Participants From the population-based Mayo Clinic Study of Aging, 303 of 1158 individuals (26.2%) in this cohort study agreed to have an autopsy between November 1, 2004, and March 31, 2016. Cerebral microinfarcts were identified and classified as cortical or subcortical. Baseline and BP trajectories were compared for groups with no microinfarcts, subcortical microinfarcts, and cortical microinfarcts. A secondary logistic regression analysis was performed to assess associations of subcortical microinfarcts with midlife hypertension, as well as systolic and diastolic BP slopes. Main Outcomes and Measures The presence of cerebral microinfarcts using BP slopes. Results Of the 303 participants who underwent autopsy, 297 had antemortem BP measurements. Of these, 177 (59.6%) were men; mean (SD) age at death was 87.2 (5.3) years. The autopsied individuals and the group who died but were not autopsied were similar for all demographics except educational level with autopsied participants having a mean of 1 more year of education (1.06; 95% CI, 0.66-1.47 years; P < .01). Among 297 autopsied individuals with antemortem BP measurements, 47 (15.8%) had chronic microinfarcts; 30 (63.8%) of these participants were men. Thirty (63.8%) had cortical microinfarcts, 19 (40.4%) had subcortical microinfarcts, and 4 (8.5%) had only infratentorial microinfarcts. Participants with microinfarcts did not differ significantly on baseline systolic (mean difference, −1.48; 95% CI, −7.30 to 4.34; P = .62) and diastolic (mean difference of slope, −0.90; 95% CI, −3.93 to 2.13; P = .56) BP compared with those with no microinfarcts. However, participants with subcortical microinfarcts had a greater annual decline (negative slope) of systolic (mean difference of slope, 4.66; 95% CI, 0.13 to 9.19; P = .04) and diastolic (mean difference, 3.33; 95% CI, 0.61 to 6.06; P = .02) BP. Conclusions and Relevance Subcortical microinfarcts were associated with declining BP. Future studies should investigate whether declining BP leads to subcortical microinfarcts or whether subcortical microinfarcts are a factor leading to declining BP.

An Association of Hippocampal Malformations and Sudden Death? We Need More Data

Two recent studies from the San Diego SUDC Research Project describe a case series of 151 children, age 1–7 years, who died suddenly and unexpectedly [1, 2]. Cases were not population based and accrued retrospectively from offices across the US and abroad, with varied and unstandardized investigations. Limitations of this retrospective study are reflected in deficiencies of available data (56 % lacked radiology, 31 % lacked microbiology, 51 % lacked vitreous electrolytes, and 97 % lacked genetic testing). In addition, neuropathology sections were incomplete: 57 % hippocampus, 50 % medulla, and 72 % cortex. Thus, most investigations were limited in scope. These children died at a mean age of 1.7 years, were predominantly male, nearly always died during sleep, and half were associated with a personal or family history of febrile seizures. Hippocampal anomalies, including a combination the authors term hippocampal maldevelopment associated with sudden death (HMASD) were found in almost half of cases with available hippocampal sections; i.e., a quarter of the overall SUDC cohort. The authors described HMASD as a frequent finding in sudden unexplained death in childhood (SUDC), but did not suggest that this represents an entity distinct from SUDC without hippocampal abnormalities. Notably, there were no differences in SUDC children with and without HMASD with respect to a wide range of clinical and circumstances of death parameters [2]. Nevertheless, the question arises whether HMASD children should be removed from the SUDC group and considered a separate cause of death.

Investigation of Deaths in Seizure Patients

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.

A Quality Assurance Strategy for Forensic Pathology

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.

Microinfarcts and blood pressure trajectories: response to Dr Niu et al.

We appreciate the comments expressed by Dr. Niu on our recent publication on microinfarcts and blood pressure trajectories. We agree with Dr. Niu that more research is needed to understand the relationship between the blood pressure trajectories and microinfarcts [1], and prospective studies using high field MRI imaging will improve our understanding of this relationship. The possibility of the microinfarcts occurring in “early old age” or “ young” adulthood seems unlikely since microinfarcts are relatively uncommon in autopsied individuals ages 65–74 but increase steeply with age [2]. Dr. Niu suggests that it is possible that a positive blood pressure slope earlier in life may be associated with the development of subcortical microinfarcts. One of the strengths of our population based study is that we were able to determine whether midlife hypertension was associated with microinfarcts. As reported in our results, midlife hypertension alone was not associated with the development of microinfarcts. Certainly it is possible that the combination of midlife increasing blood pressure slopes in combination with declining blood pressure trajectories late in life would make individuals susceptible to microinfarcts, which we did not investigate in the current study. In the ARIC study, the pattern of a prior history of hypertension (approximately 15 years) with subsequent hypotension concurrent with neuroimaging was associated with smaller brain volumes [3]. Other key lines of evidence that microinfarcts may be associated with declining blood pressures include the fact that individuals who have microinfarcts at autopsy have atrophy in a watershed distribution [4]. Similarly, others have shown that greater numbers of microinfarcts occur in watershed zones than in other brain regions suggesting a contribution of hypoperfusion in their development [5]. While the association between declining blood pressure late in life and subcortical microinfarcts does not prove causation, dismissing the possibility altogether would seem unwise.

Clinicopathological and 123I-FP-CIT SPECT correlations in patients with dementia

The relationship between clinicopathologic diagnosis and 123I‐FP‐CIT SPECT in 18 patients with dementia (12 with Lewy body disease) from one center in the United States was assessed. The sensitivity and specificity of abnormal 123I‐FP‐CIT SPECT with reduced striatal uptake on visual inspection for predicting Lewy body disease were 91.7% and 83.3%, respectively. The mean calculated putamen to occipital ratio (mPOR) based on regions of interest was significantly reduced in Lewy body disease compared to non‐Lewy body disease cases (P = 0.002). In this study, abnormal 123I‐FP‐CIT SPECT was strongly associated with underlying Lewy body disease pathology, supporting the utility of 123I‐FP‐CIT SPECT in the clinical diagnosis of dementia with Lewy bodies.

Exploding Targets in Recreational Use

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.

Critical Diagnoses in Forensic Pathology: Ethics of Disclosure

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.

A Pragmatic Approach to the Postmortem Neuropathological Diagnosis of Dementia

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.