Forensic Neuropathologic Phenotypes of Fungal Central Nervous System Infections: A Case Series.

ABSTRACT: Fungal infections of the central nervous system (FI-CNS) are life-threatening infections that most commonly affect immunocompromised individuals, but immunocompetent individuals may also be infected. Although FI-CNS are relatively rare, the prevalence of FI-CNS is on the rise because of the increasing number of transplant recipients, human immunodeficiency virus-infected individuals, and use of immunosuppressive therapies. Most cases of FI-CNS originate from outside the central nervous system. The etiologic fungi can be classified into 3 fungal groups: molds, dimorphic fungi, and yeasts. The clinical presentation of FI-CNS is highly variable and may be difficult to diagnose premortem. We present a case series of 3 patients, each infected by 1 representative species from each of the 3 fungal groups (Aspergillus species, Blastomyces species, Candida species) to illustrate different neuropathologic phenotypes of FI-CNS. All 3 patients had no history of immunodeficiency and were not suspected to have FI-CNS until they were diagnosed at autopsy. Fungal infections of the central nervous system are often fatal due to delayed diagnosis and diagnostic testing. Awareness of such poly-phenotypic manifestations of FI-CNS will be helpful in reducing delayed diagnosis. It is important for clinicians to include FI-CNS on the differential diagnosis when radiographic findings are nonspecific.

Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy.

OBJECTIVE: Chronic traumatic encephalopathy is a progressive neurodegenerative disease characterized by neurofibrillary tau tangles following repetitive neurotrauma. The underlying mechanism linking traumatic brain injury to chronic traumatic encephalopathy has not been elucidated. The authors investigate the role of endoplasmic reticulum stress as a link between acute neurotrauma and chronic neurodegeneration. METHODS: The authors used pharmacological, biochemical, and behavioral tools to assess the role of endoplasmic reticulum stress in linking acute repetitive traumatic brain injury to the development of chronic neurodegeneration. Data from the authors' clinically relevant and validated rodent blast model were compared with those obtained from postmortem human chronic traumatic encephalopathy specimens from a National Football League player and World Wrestling Entertainment wrestler. RESULTS: The results demonstrated strong correlation of endoplasmic reticulum stress activation with subsequent tau hyperphosphorylation. Various endoplasmic reticulum stress markers were increased in human chronic traumatic encephalopathy specimens, and the endoplasmic reticulum stress response was associated with an increase in the tau kinase, glycogen synthase kinase-3ß. Docosahexaenoic acid, an endoplasmic reticulum stress inhibitor, improved cognitive performance in the rat model 3 weeks after repetitive blast exposure. The data showed that docosahexaenoic acid administration substantially reduced tau hyperphosphorylation (t = 4.111, p < 0.05), improved cognition (t = 6.532, p < 0.001), and inhibited C/EBP homology protein activation (t = 5.631, p < 0.01). Additionally the data showed, for the first time, that endoplasmic reticulum stress is involved in the pathophysiology of chronic traumatic encephalopathy. CONCLUSIONS: Docosahexaenoic acid therefore warrants further investigation as a potential therapeutic agent for the prevention of chronic traumatic encephalopathy.

Role of subconcussion in repetitive mild traumatic brain injury.

Research now suggests that head impacts commonly occur during contact sports in which visible signs or symptoms of neurological dysfunction may not develop despite those impacts having the potential for neurological injury. Recent biophysics studies utilizing helmet accelerometers have indicated that athletes at the collegiate and high school levels sustain a surprisingly high number of head impacts ranging from several hundred to well over 1000 during the course of a season. The associated cumulative impact burdens over the course of a career are equally important. Clinical studies have also identified athletes with no readily observable symptoms but who exhibit functional impairment as measured by neuropsychological testing and functional MRI. Such findings have been corroborated by diffusion tensor imaging studies demonstrating axonal injury in asymptomatic athletes at the end of a season. Recent autopsy data have shown that there are subsets of athletes in contact sports who do not have a history of known or identified concussions but nonetheless have neurodegenerative pathology consistent with chronic traumatic encephalopathy. Finally, emerging laboratory data have demonstrated significant axonal injury, blood-brain barrier permeability, and evidence of neuroinflammation, all in the absence of behavioral changes. Such data suggest that subconcussive level impacts can lead to significant neurological alterations, especially if the blows are repetitive. The authors propose "subconcussion" as a significant emerging concept requiring thorough consideration of the potential role it plays in accruing sufficient anatomical and/or physiological damage in athletes and military personnel, such that the effects of these injuries are clinically expressed either contemporaneously or later in life.

Repetitive traumatic brain injury and development of chronic traumatic encephalopathy: a potential role for biomarkers in diagnosis, prognosis, and treatment?

The diagnosis of chronic traumatic encephalopathy (CTE) upon autopsy in a growing number of athletes and soldiers alike has resulted in increased awareness, by both the scientific/medical and lay communities, of the potential for lasting effects of repetitive traumatic brain injury. While the scientific community has come to better understand the clinical presentation and underlying pathophysiology of CTE, the diagnosis of CTE remains autopsy-based, which prevents adequate monitoring and tracking of the disease. The lack of established biomarkers or imaging modalities for diagnostic and prognostic purposes also prevents the development and implementation of therapeutic protocols. In this work the clinical history and pathologic findings associated with CTE are reviewed, as well as imaging modalities that have demonstrated some promise for future use in the diagnosis and/or tracking of CTE or repetitive brain injury. Biomarkers under investigation are also discussed with particular attention to the timing of release and potential utility in situations of repetitive traumatic brain injury. Further investigation into imaging modalities and biomarker elucidation for the diagnosis of CTE is clearly both needed and warranted.

Chronic traumatic encephalopathy in a professional American wrestler.

We present in this case report the tissue substrates and forensic evidence for chronic traumatic encephalopathy (CTE) in a professional American wrestler with Apolipoprotein E (apoE) genotyping. Professional wrestling is a contact-sport, with an integral risk for players to sustain repeated concussions over their careers. This case provides the first autopsy evidence of neuropathological abnormalities that accompany CTE in professional American wrestlers. A complete autopsy was performed on a 40-year-old Caucasian male, after he died unexpectedly by suicidal hanging after he had killed his wife and son. The brain showed no atrophy and no recent or remote contusions or necrosis. There was a mild to moderate neocortical neuronal dropout without any amyloid plaques. There were diffuse, sparse to frequent tau-immunoreactive Neurofibrillary Tangles and Neuropil Threads in the neocortex, subcortical ganglia, and brainstem nuclei including the substantia nigra consistent with CTE. The apoE genotype was determined to be E3/E3. Other autopsy findings included cardiomegaly, left ventricular hypertrophy, and bilateral atrioventricular dilatation; toxicologic analyses showed alprazolam and hydrocodone in the blood, and evidence of exogenous testosterone in the urine. Longitudinal studies of professional contact-sport athletes are needed to identify the differentiating characteristics of athletes who develop CTE and devise strategies for intervention.

Chronic traumatic encephalopathy (CTE) in a National Football League Player: Case report and emerging medicolegal practice questions.

UNLABELLED: We present a case of chronic traumatic encephalopathy (CTE) in a retired National Football League (NFL) Player with autopsy findings, apolipoprotein E genotype, and brain tissue evidence of chronic brain damage. This 44-year-old retired NFL player manifested a premortem history of cognitive and neuropsychiatric impairment, which included in part, chronic depression, suicide attempts, insomnia, paranoia, and impaired memory before he finally committed suicide. A full autopsy was performed with Polymerase Chain Reaction-based analyses of his blood to determine the apolipoprotein genotype. Histochemical and immunohistochemical analyses were performed on topographical gross sections of the brain. Autopsy confirmed a fatal gunshot wound of the head. The apolipoprotein E genotype was E3/E3 and the brain tissue revealed diffuse cerebral taupathy (Neurofibrillary Tangles and Neuritic Threads). This will be the third case of CTE in a national football player, which has been reported in the medical literature. Omalu et al., reported the first two cases in 2005 and 2006. This case series manifested similar premortem history of neuropsychiatric impairment with autopsy evidence of cerebral taupathy without any neuritic amyloidopathy. For a definitive diagnosis of CTE to be made, and for medicolegal purposes, a full autopsy must be performed with histochemical and immunohistochemical analyses of the brain to identify the presence of Neurofibrillary Tangles (NFTs) and Neuritic Threads (NTs). IMPLICATIONS: Further longitudinal prospective studies are required to confirm the common denominators and epidemiology of CTE in professional American football players, which have been identified by this case series.

Chronic traumatic encephalopathy, suicides and parasuicides in professional American athletes: the role of the forensic pathologist.

We present 5 cases of professional American contact sport athletes who committed parasuicides and suicides aged 50, 45, 44, 36, and 40 years old. Full forensic autopsies and immunohistochemical analyses of the brains revealed chronic traumatic encephalopathy (CTE). The brains appeared grossly normal at autopsy without gross evidence of remote traumatic injuries or neurodegenerative disease. Brain immunohistochemical analyses revealed widespread cerebral taupathy in the form of neurofibrillary tangles and neuritic threads without neuritic amyloid plaques. CTE refers to chronic cognitive and neuropsychiatric symptoms of chronic neurodegeneration following a single episode of severe traumatic brain injury or repeated episodes of mild traumatic brain injury. CTE can only be definitively diagnosed by direct tissue examination. Without full autopsies and immunohistochemical brain analyses these cases would never have been identified. Forensic pathologists will play a vital and central role in the emerging disease surveillance of CTE in professional American athletes, in the identification of CTE cases, and in the establishment of the epidemiology of CTE, with the goal of eventually developing preventive and interventional therapeutic protocols for CTE outcomes.

Nursing home deaths which fall under the jurisdiction of the coroner: an 11-year retrospective study.

Twenty percent of deaths in the United States occur in nursing homes, yet less than 1% come to autopsy. The current study analyzed causes and manners of death in all nursing homes between 1993 and 2003, investigated by the coroner of Allegheny County, PA, which has the second highest elderly population in the United States. Two hundred eight decedents were identified, aged 19 to 91 years, 58% women and 42% men, 88% Caucasian and 22% African-American. Fifty-eight percent were accidental and 38.5% were natural manners of death, with 2 homicides, 2 suicides, and 3 undetermined cases. The manner of death was significantly different between Caucasians and African-Americans, with 92.6% of accidental deaths occurring in Caucasians and 6.6% in African-Americans (P < 0.1). Most common natural deaths were arteriosclerotic cardiovascular disease, nonarteriosclerotic cardiovascular disease, pneumonia, pulmonary thromboembolism, chronic obstructive pulmonary disease (COPD), seizure disorder, and atraumatic intracranial hemorrhage. Blunt force trauma was the single most commonly identified traumatic accidental death. Accidental deaths were more common in Caucasians than African-Americans. Homicides and suicides were rare events (<2%). Blunt force trauma is a major autopsy finding in accidental nursing home deaths, and a root-cause analysis may be helpful in developing policies and procedures to decrease the incidence of blunt force trauma.

Death rates and causes of death after bariatric surgery for Pennsylvania residents, 1995 to 2004.

BACKGROUND: Bariatric surgery has emerged as the most effective treatment for class III obesity (body mass index, >or=40). The number of operations continues to increase. We measured case fatality and death rates by time since operation, sex, age, specific causes of death, and mortality rates. DESIGN AND SETTING: Data on all bariatric operations performed on Pennsylvania residents between January 1, 1995, and December 31, 2004, were obtained from the Pennsylvania Health Care Cost and Containment Council. Matching mortality data were obtained from the Division of Vital Records, Pennsylvania State Department of Health. OUTCOME MEASURES: Age- and sex-specific death rates after bariatric surgery. RESULTS: There were 440 deaths after 16 683 operations (2.6%). Age-specific death rates were much higher in men than in women and increased with age. Age- and sex-specific death rates after bariatric surgery were substantially higher than comparable rates for the age- and sex-matched Pennsylvania population. The 1-year case fatality rate was approximately 1% and nearly 6% at 5 years. Less than 1% of deaths occurred within the first 30 days. Fatality increased substantially with age (especially among those > 65 years), with little evidence of change over time. Coronary heart disease was the leading cause of death overall, being cited as the cause of death in 76 patients (19.2%). Therapeutic complications accounted for 38 of 150 natural deaths within the first 30 days, including pulmonary embolism in 31 (20.7%), coronary heart disease in 26 (17.3%), and sepsis in 17 (11.3%). CONCLUSIONS: There was a substantial excess of deaths owing to suicide and coronary heart disease. Careful monitoring of bariatric surgical procedures and more intense follow-up could likely reduce the long-term case fatality rate in this patient population.

The role of environmental factors in the causation of sudden death in infants: two cases of sudden unexpected death in two unrelated infants who were cared for by the same babysitter.

We report two cases of sudden unexpected death in two unrelated African American female infants, 2 months and 4 months old. Both infants were attended to by the same babysitter in the same apartment and died 39 days apart in the same bed and in the same bedroom. The autopsy of the first infant revealed sudden unexplained death in an infant. Toxicologic analysis for carbon monoxide (CO) was not performed because it was not suspected. When the second infant died, investigation into the ambient air quality within the apartment revealed high levels of CO emanating from a poorly ventilated and defective hot water heater, which was located across a hallway from the bedroom where the two babies died. CO saturation levels in the postmortem blood samples of the two babies were elevated and were similar (13% and 14%). Nicotine and cotinine were not detected in the blood sample of the two infants. Cherry-red livor mortis was absent. Acute CO intoxication was determined to be the underlying cause of these two unexpected deaths. These two cases underscore the need to integrate ambient air analysis and postmortem CO analysis as routine components of the comprehensive death investigation of infants who die suddenly and unexpectedly.

Systemic distribution of West Nile virus infection: postmortem immunohistochemical study of six cases.

Rare cases of West Nile virus (WNV)-associated inflammation outside the central nervous system (CNS) have been reported. We evaluated the systemic distribution of WNV in postmortem tissues during encephalitis in six patients using immunohistochemistry. WNV antigens were detected in neurons of CNS (all 6 cases), kidney (4 cases), lungs (2 cases), pancreas (2 cases), thyroid (2 cases), intestine (2 cases), stomach (1 case), esophagus (1 case), bile duct (1 case), skin (1 case), prostate (1 case) and testis (1 case). In systemic organs epithelial cells were infected. In none of the six cases were viral antigens identified in hepatocytes, heart, adrenal gland, nerves, skeletal muscles, bone, vessels and fat. All cases in which viral antigens were identified in systemic organs in addition to CNS were severely immunocompromised transplant recipients. With the exception of testis and brain, most foci of infection were not associated with inflammation. While the absence of inflammation may in part be due to patient immunosuppression or to possible transient nature of any host response, compartmentalization of viral antigen to the luminal region of epithelial cells may sequester WNV from immune recognition. Comparison of our findings with previous reports suggests that patients with WNV encephalitis can have widespread systemic infection.

Chronic traumatic encephalopathy in a national football league player: part II.

OBJECTIVE: We present the second reported case of autopsy-confirmed chronic traumatic encephalopathy in a retired professional football player, with neuropathological features that differ from those of the first reported case. These differing pathological features underscore the need for further empirical elucidation of the pathoetiology and pathological cascades of long-term neurodegenerative sequelae of professional football. METHODS: A psychological autopsy was performed with the next-of-kin and wife. Medical and hospital records were reviewed. A complete autopsy was accompanied by a comprehensive forensic neuropathological examination. Restriction fragment length polymorphism analysis was performed to determine apolipoprotein-E genotype. RESULTS: Pertinent premortem history included a 14-year span of play in organized football starting from the age of 18 years. The subject was diagnosed with severe major depressive disorder without psychotic features after retirement, attempted suicide multiple times and finally committed suicide 12 years after retirement by ingestion of ethylene glycol. Autopsy revealed cardiomegaly, mild to moderate coronary artery disease, and evidence of acute ethylene glycol overdose. The brain showed no atrophy, a cavum septi pellucidi was present, and the substantia nigra showed mild pallor. The hippocampus and cerebellum were not atrophic. Amyloid plaques, cerebral amyloid angiopathy, and Lewy bodies were completely absent. Sparse to frequent tau-positive neurofibrillary tangles and neuropil threads were present in all regions of the brain. Tufted and thorn astrocytes, as well as astrocytic plaques, were absent. The apolipoprotein-E genotype was E3/E4. CONCLUSION: Our first and second cases both had long careers without multiple recorded concussions. Both manifested Major Depressive Disorder after retirement. Amyloid plaques were present in the first case and completely absent in the second case. Both cases exhibited neurofibrillary tangles, neuropil threads, and coronary atherosclerotic disease. Apolipoprotein-E4 genotypes were different. Reasons for the contrasting features in these two cases are not clear. Further studies are needed to identify and define the neuropathological cascades of chronic traumatic encephalopathy in football players, which may form the basis for prophylaxis and therapeutics.

Cause of death among elder homicide victims: a 10-year medical examiner review.

A study of elderly homicide victims brought to a Pennsylvania medical examiner's office reveals interesting findings about cause of death.

Diagnosis of Alzheimer's disease in an exhumed decomposed brain after twenty months of burial in a deep grave.

After 20 months of interment in a deep grave, the decomposed body of the 81-year old testator of a will was exhumed to sustain the burden of proof that he lacked testamentary capacity when the will was rewritten two days prior to his death. The brain was mushy and pulverized with complete disappearance of the brainstem, cerebellum and subcortical ganglia. Small foci of relatively intact dorsal frontal neocortex were identified. Sections from these foci were stained with hematoxylin and eosin, bielchowsky silver stain and immunostains for beta amyloid peptide (betaA4), tau and alpha-synuclein. Despite severe autolysis and decomposition, the bielchowsky stain and the betaA4 immunostains showed preserved frequent neuritic amyloid plaques with very few residual neurofibrillary tangles. Cerebral Amyloid Angiopathy was present. At the present time this case represents the first documented and reported case of direct tissue diagnosis of Alzheimer's Disease pathology in a decomposed brain following long term burial in a deep grave.

Chronic traumatic encephalopathy in a National Football League player.

OBJECTIVE: We present the results of the autopsy of a retired professional football player that revealed neuropathological changes consistent with long-term repetitive concussive brain injury. This case draws attention to the need for further studies in the cohort of retired National Football League players to elucidate the neuropathological sequelae of repeated mild traumatic brain injury in professional football. METHODS: The patient's premortem medical history included symptoms of cognitive impairment, a mood disorder, and parkinsonian symptoms. There was no family history of Alzheimer's disease or any other head trauma outside football. A complete autopsy with a comprehensive neuropathological examination was performed on the retired National Football League player approximately 12 years after retirement. He died suddenly as a result of coronary atherosclerotic disease. Studies included determination of apolipoprotein E genotype. RESULTS: Autopsy confirmed the presence of coronary atherosclerotic disease with dilated cardiomyopathy. The brain demonstrated no cortical atrophy, cortical contusion, hemorrhage, or infarcts. The substantia nigra revealed mild pallor with mild dropout of pigmented neurons. There was mild neuronal dropout in the frontal, parietal, and temporal neocortex. Chronic traumatic encephalopathy was evident with many diffuse amyloid plaques as well as sparse neurofibrillary tangles and tau-positive neuritic threads in neocortical areas. There were no neurofibrillary tangles or neuropil threads in the hippocampus or entorhinal cortex. Lewy bodies were absent. The apolipoprotein E genotype was E3/E3. CONCLUSION: This case highlights potential long-term neurodegenerative outcomes in retired professional National Football League players subjected to repeated mild traumatic brain injury. The prevalence and pathoetiological mechanisms of these possible adverse long-term outcomes and their relation to duration of years of playing football have not been sufficiently studied. We recommend comprehensive clinical and forensic approaches to understand and further elucidate this emergent professional sport hazard.

Suicides following bariatric surgery for the treatment of obesity.

The proportion of the United States population living with bariatric surgery has increased exponentially since the mid 1990s. It is pertinent to study and understand the mortality patterns of this emergent population cohort and determine the role bariatric surgery may play in these mortality patterns. We present the forensic and clinical characteristics of three cases of suicide following bariatric surgery for the treatment of morbid obesity. The clinical history in each case included recurrent major depressive disorder before and after surgery. Surgery-suicide intervals were 12 months, 27 months and 26 months, respectively. Pre-surgery and pre-mortem body mass indices were 37.7 and 22.2 kg/m(2); 42.0 and 25.0 kg/m(2); 39.5 and 29.4 kg/m(2). Depressive disorder may persist in the bariatric surgery patient despite successful surgical control of obesity.

Postmortem grading of cerebral contusions : A proposed modification of the adams' contusion index with re-definition of anatomic markers.

In the 1970s, J. H. Adams and other researchers at the Institute of Neurological Sciences, Glasgow, Scotland introduced a grading system for the quantification and analysis of contusions of the brain. They derived a brain contusion index based on regional surface distribution and parenchymal depth of contusions of the brain. Following a subsequent modification of this scheme in the 1980s, they recommended evolving modifications that will fit a variety of possible applications. Having tested the applicability of this grading system for the forensic/medico-legal autopsy, we have encountered some applied anatomic limitations and have derived a modification that addresses these limitations in reference to the forensic/medico-legal autopsy.We recommend a two-tier system based on the Adams' system, which quantifies contusions of the brain by the gyral spread of contusions and by the parenchymal depth of penetration of contusions with a re-definition of the lobar distinctions and classifications of the brain. Gyral spread is assigned a grading scheme of 0-3 and the parenchymal depth of contusions is assigned a grading scheme of 0-4. A lobar contusion score is derived by multiplying the two assigned grades. A total brain contusion index is derived by summating all the lobar contusion scores. This reproducible grading system can be applied to routine bench forensic neuropathology reporting, court room illustrations and in comparative research analysis of brain trauma subjects.

Forensic pathology and forensic epidemiology of suicides in allegheny county, pennsylvania : A 10-year retrospective review (1990-1999).

Suicide has assumed epidemic proportions and constitutes a major public health issue throughout the United States. Suicide remains one of the top eight leading causes of death, accounting for approximately 30,000 deaths annually. The understanding and prevention of suicide requires a multidisciplinary approach that involves psychosocial and medical specialties starting with a forensic analysis of the characteristics of suicide. The aim of this 10-year (1990-1999) retrospective study was threefold: first, to examine the forensic epidemiological characteristics of suicides examined by the Allegheny County Coroner's Office; second, to describe emerging epidemiological patterns of suicide; and finally, to make recommendations for preventive measures. A total of 1447 suicides were identified, with 1164 males (80%) and 283 females (20%) resulting in a male to female ratio of 4:1. The race distribution comprised 90% whites, 9% blacks, and 1% other races. The age of suicide victims ranged from 13 to 96 years old with a peak within the 31- to 40-year-old age group, which represented 24.5% of all suicides. Overall, 40% of the victims were single and more blacks than whites were single. The greatest number of suicides occurred in July, with the least in December. Suicides most frequently occurred between 9:01 AM and 3:00 PM. Suicide notes were present in 29% of all suicides. Firearm injuries, hanging, and drug overdose were the leading methods of suicide. Use of firearms was the leading method of suicide among both sexes. Female drug overdose deaths outnumbered male drug overdose deaths. The 10 most common overdose drugs were all central nervous system depressants, with amitriptyline being the most common prescription overdose drug. Based on reported antecedent trends in suicides, we make two recommendations regarding suicide prevention: (1) physicians should be educated to replace the prescription of older and more toxic antidepressants such as amitriptyline with newer and less toxic antidepressants such as serotonin reuptake inhibitors; and (2) firearms should be made inaccessible to individuals with risk factors for suicide, especially in the home.