Clonazolam Intoxication Case Report: Danger of Designer Benzodiazepines.

ABSTRACT: Clonazolam is a derivative of the Xanax active ingredient, alprazolam. Classified as a designer benzodiazepine, clonazolam availability has been rising because of its circulation on illegal internet drug markets and marginal cost in comparison to its parent analogs. Clonazolam's accessibility encourages abuse prevalence and use of designer benzodiazepines. In our case, a 14-year-old male was found unresponsive the morning after ingesting multiple tablets believed to be Xanax. Toxicology testing indicated 140 ng/mL of 8-aminoclonazolam, a clonazolam metabolite, in the decedent's system. Alprazolam was not identified. Pathological analysis determined cerebral and respiratory depression to be the mechanism of death, resulting from acute clonazolam intoxication. This case presents the first death induced by clonazolam alone. Current literature identifies a gap in designer benzodiazepine confirmatory testing and a lack of awareness within the forensic and medical communities. Knowledge of designer benzodiazepines is needed to better understand their potency and to help prevent future intoxications. We present this case to aid in the recognition of novel benzodiazepines by medical examiners and coroners, to encourage their consideration in suspected Xanax and other substance related investigations, and to be aware of the capabilities of toxicological testing to improve novel benzodiazepine identification and subsequent interpretation.

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.

Autopsy Cardiac Troponin I Plasma Levels Can Be Elevated in Myocardial Infarction Type 3: A Proposal to Modify the Definition of Myocardial Infarction Type 3.

AIMS: The definition of myocardial infarction (MI) type 3 does not include the possible elevation of postmortem biomarkers if measured at autopsy. We determined postmortem cardiac troponin I (cTnI) levels in plasma samples obtained at autopsy in patients who died from MI type 3 to determine whether cTnI plasma levels may be elevated. METHODS AND RESULTS: Using a chemiluminescent microparticle immunoassay system, we determined postmortem cTnI plasma levels at autopsy performed within 24 hours of death in every decedent who died from MI type 3, confirmed by an autopsy. Over 2 years, autopsy confirmed 52 decedents who died from MI type 3 due to coronary atherosclerotic disease. The age range and mean age were 40 to 78 and 60.6 years, respectively, 38 (73%) men and 14 (27%) women. Ten percent of the decedents exhibited postmortem cTnI plasma levels that were within the normal reference levels (0.01-0.30 ng/mL). Ninety percent of the decedents exhibited elevated cTnI plasma levels at autopsy, which ranged from 0.31 to greater than 4400 ng/mL. Sixty-nine percent of our decedents showed severe/significant (75%-100%) luminal occlusion in 2 or 3 major coronary arteries. CONCLUSIONS: If cTnI plasma levels are measured in autopsy blood samples after sudden and unexpected death due to MI type 3, highly elevated cTnI plasma levels may be detected. We propose that the current MI type 3 definition be slightly modified to include the possible elevation of cTnI plasma levels if measured at autopsy in the immediate postmortem period.

Postmortem Autopsy-Confirmation of Antemortem [F-18]FDDNP-PET Scans in a Football Player With Chronic Traumatic Encephalopathy.

Currently, only presumptive diagnosis of chronic traumatic encephalopathy (CTE) can be made in living patients. We present a modality that may be instrumental to the definitive diagnosis of CTE in living patients based on brain autopsy confirmation of [F-18]FDDNP-PET findings in an American football player with CTE. [F-18]FDDNP-PET imaging was performed 52 mo before the subject's death. Relative distribution volume parametric images and binding values were determined for cortical and subcortical regions of interest. Upon death, the brain was examined to identify the topographic distribution of neurodegenerative changes. Correlation between neuropathology and [F-18]FDDNP-PET binding patterns was performed using Spearman rank-order correlation. Mood, behavioral, motor, and cognitive changes were consistent with chronic traumatic myeloencephalopathy with a 22-yr lifetime risk exposure to American football. There were tau, amyloid, and TDP-43 neuropathological substrates in the brain with a differential topographically selective distribution. [F-18]FDDNP-PET binding levels correlated with brain tau deposition (rs = 0.59, P = .02), with highest relative distribution volumes in the parasagittal and paraventricular regions of the brain and the brain stem. No correlation with amyloid or TDP-43 deposition was observed. [F-18]FDDNP-PET signals may be consistent with neuropathological patterns of tau deposition in CTE, involving areas that receive the maximal shearing, angular-rotational acceleration-deceleration forces in American football players, consistent with distinctive and differential topographic vulnerability and selectivity of CTE beyond brain cortices, also involving midbrain and limbic areas. Future studies are warranted to determine whether differential and selective [F-18]FDDNP-PET may be useful in establishing a diagnosis of CTE in at-risk patients.

Strong Correlation of Genome-Wide Expression after Traumatic Brain Injury In Vitro and In Vivo Implicates a Role for SORLA.

The utility of in vitro models of traumatic brain injury (TBI) depends on their ability to recapitulate the in vivo TBI cascade. In this study, we used a genome-wide approach to compare changes in gene expression at several time points post-injury in both an in vitro model and an in vivo model of TBI. We found a total of 2073 differentially expressed genes in our in vitro model and 877 differentially expressed genes in our in vivo model when compared to noninjured controls. We found a strong correlation in gene expression changes between the two models (r = 0.69), providing confidence that the in vitro model represented at least part of the in vivo injury cascade. From these data, we searched for genes with significant changes in expression over time (analysis of covariance) and identified sorting protein-related receptor with A-type repeats (SORLA). SORLA directs amyloid precursor protein to the recycling pathway by direct binding and away from amyloid-beta producing enzymes. Mutations of SORLA have been linked to Alzheimer's disease (AD). We confirmed downregulation of SORLA expression in organotypic hippocampal slice cultures by immunohistochemistry and Western blotting and present preliminary data from human tissue that is consistent with these experimental results. Together, these data suggest that the in vitro model of TBI used in this study strongly recapitulates the in vivo TBI pathobiology and is well suited for future mechanistic or therapeutic studies. The data also suggest the possible involvement of SORLA in the post-traumatic cascade linking TBI to AD.

Fatal Pulmonary Thromboembolism in Patients with Diabetic Ketoacidosis: A Seven-Case Series and Review of the Literature.

Diabetes mellitus is a well-recognized risk factor for arterial thrombosis, however its relationship to venous thromboembolism (VTE) in adults is still debated. We report here seven cases of fatal pulmonary thromboembolism in adults with diabetic ketoacidosis as the underlying cause. In four of seven cases, there was no prior diagnosis of diabetes mellitus and patients were newly diagnosed either upon presenting to the hospital in diabetic ketoacidosis (DKA) or at the time of autopsy by the vitreous glucose concentration. None of the patients had family history, recent surgery, recent trauma, long distance travel, or other strong risk factors for VTE. Only two patients had a body mass index greater than 35 kg/m2 and the same two cases had hospital stays that ranged from three to five days. We believe that DKA is a frequently unrecognized and sometimes overlooked risk factor for VTE, particularly in the forensic setting where routine toxicology and vitreous glucose analysis may not be standard practices. We encourage forensic pathologists, medical examiners, and coroners to consider the possibility of diabetic ketoacidosis as a risk factor, and in some cases, the underlying etiology for pulmonary thromboembolism. Additionally, we recommend vitreous glucose testing be performed if there are any signs of DKA or diabetes present, such as acetone in the blood.

Diagnosis of hemorrhagic stroke in an exhumed brain after three years of burial in a deep grave.

We present the forensic neuropathologic analysis of an exhumed decomposed brain following long-term interment in a 50-year-old white woman, who had been buried for 34 months. Next of kin authorized exhumation of the body for an autopsy to determine the cause of death. The embalmed body was anatomically intact and revealed decompositional changes with mold colonies. Internal viscera showed intact histomorphology. The brain revealed diffuse congestive swelling and extracellular edema with dissecting parenchymal hemorrhage and hematoma originating from the left putamen and thalamus and extending to the left lateral ventricle. Excitotoxic neuronal injury as well as penumbric parenchymal changes was noted. Cause of death was determined to be a hypertensive cerebral parenchymal hemorrhage. This case and our previously reported case are sentinel cases, which should encourage and guide the forensic neuropathologic work-up and investigation of causes of death in spite of long-term burial in deep graves.

Chronic traumatic encephalopathy in an Iraqi war veteran with posttraumatic stress disorder who committed suicide.

Following his discovery of chronic traumatic encephalopathy (CTE) in football players in 2002, Dr. Bennet Omalu hypothesized that posttraumatic stress disorder (PTSD) in military veterans may belong to the CTE spectrum of diseases. The CTE surveillance at the Brain Injury Research Institute was therefore expanded to include deceased military veterans diagnosed with PTSD. The authors report the case of a 27-year-old United States Marine Corps (USMC) Iraqi war veteran, an amphibious assault vehicle crewman, who committed suicide by hanging after two deployments to Fallujah and Ramadi. He experienced combat and was exposed to mortar blasts and improvised explosive device blasts less than 50 m away. Following his second deployment he developed a progressive history of cognitive impairment, impaired memory, behavioral and mood disorders, and alcohol abuse. Neuropsychiatric assessment revealed a diagnosis of PTSD with hyperarousal (irritability and insomnia) and numbing. He committed suicide approximately 8 months after his honorable discharge from the USMC. His brain at autopsy appeared grossly unremarkable except for congestive brain swelling. There was no atrophy or remote focal traumatic brain injury such as contusional necrosis or hemorrhage. Histochemical and immunohistochemical brain tissue analysis revealed CTE changes comprising multifocal, neocortical, and subcortical neurofibrillary tangles and neuritic threads (ranging from none, to sparse, to frequent) with the skip phenomenon, accentuated in the depths of sulci and in the frontal cortex. The subcortical white matter showed mild rarefaction, sparse perivascular and neuropil infiltration by histiocytes, and mild fibrillary astrogliosis. Apolipoprotein E genotype was 3/4. The authors report this case as a sentinel case of CTE in an Iraqi war veteran diagnosed with PTSD to possibly stimulate new lines of thought and research in the possible pathoetiology and pathogenesis of PTSD in military veterans as part of the CTE spectrum of diseases, and as chronic sequelae and outcomes of repetitive traumatic brain injuries.

Autopsy features of sudden death due to isolated eosinophilic coronary arteritis: report of two cases.

Isolated eosinophilic coronary arteritis (IECA) has been reported as a cause of sudden unexpected death and has recently been recognized as a newly emerging vasculitic disease. We identified eight case reports and two case series of sudden death due to IECA in the medical literature and we present two new cases of sudden death due to IECA. Our cases further support the proposition that IECA may be a newly emerging distinct vasculitis, which can go undiagnosed and present with sudden death. At autopsy IECA presents with isolated non-necrotizing predominantly eosinophilic inflammation of the coronary arteries without vasculitis in any other organ or blood vessel. The mean age of death of our two cases and the previously reported cases of IECA is 47 years, comprising 13 females and 3 males with a range of 34-64 years. All cases died suddenly and unexpectedly. Past medical history of recurrent chest pain was documented in 63% of cases. The patho-etiology of IECA may involve an aberrant immune response or hypersensitivity reaction. Elucidation of the pathology of IECA may be translated into definitive diagnostic, interventional, and preventive modalities, which will further reduce the person years of life lost to heart disease.

Emerging histomorphologic phenotypes of chronic traumatic encephalopathy in American athletes.

BACKGROUND: We define chronic traumatic encephalopathy (CTE) as a progressive neurodegenerative syndrome caused by single, episodic, or repetitive blunt force impacts to the head and transfer of acceleration-deceleration forces to the brain. OBJECTIVE: We present emerging histomorphologic phenotypes of CTE that we identified in our cohort of CTE cases with apolipoprotein E genotyping and causes and manners of death. METHODS: Autopsy brain tissue of 14 professional athletes and 3 high school football players was examined after unexpected deaths. Histochemical and immunohistochemical tissue staining was performed with apolipoprotein E genotyping. RESULTS: Ten of 14 professional athletes (71%) were positive for CTE: 7 of 8 football players, 2 of 4 wrestlers, and 1 boxer. One of 3 high school players manifested incipient CTE. The age range of those with CTE was 18 to 52 years; they were all male athletes. In all cases of CTE, Alzheimer-type cerebral cortical atrophy was absent; negligible to mild neocortical neuronal dropout was present. The fundamental neuropathologic feature of CTE was the topographic distribution of sparse, moderate, and frequent band-shaped, flame-shaped, small and large globose neurofibrillary tangles and neuritic threads in the cerebral cortex, subcortical nuclei/basal ganglia, hippocampus, and brainstem nuclei. Sparse to frequent diffuse amyloid plaques may accompany tauopathy and was seen in only 2 CTE cases. No α-synucleinopathy was present. All 7 CTE-positive professional athletes with known apolipoprotein E genotypes had at least 1 E3 allele comprising 5 E3/E3 (71%) and 2 E3/E4 (29%). Alcohol- and drug-related deaths, suicides, and accidental deaths were overrepresented in our CTE cohort. CONCLUSION: The emerging histomorphologic features of our CTE cohort may specify histologic criteria for CTE diagnosis, may identify emerging histologic variants of CTE and may facilitate more objective surveillance and accurate identification of sentinel CTE cases.

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.

Risk of suicide after long-term follow-up from bariatric surgery.

PURPOSE: Bariatric surgery is recognized as the treatment of choice for class III obesity (body mass index ≥40) and has been increasingly recommended for obese patients. Prior research has suggested an excess of deaths due to suicide following bariatric surgery, but few large long-term follow-up studies exist. We examined postbariatric surgery suicides by time since operation, sex, age, and suicide death rates as compared with US suicide rates. METHODS: Medical data following 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 from suicides between September 1, 1996 and December 28, 2006 were obtained from the Division of Vital Records, Pennsylvania State Department of Health. RESULTS: There were 31 suicides (16,683 operations), for an overall rate of 6.6/10,000; 13.7 per 10,000 among men and 5.2 per 10,000 among women. About 30% of suicides occurred within the first 2 years following surgery, with almost 70% occurring within 3 years. For every age category except the youngest, suicide rates were higher among men than women. Age- and sex-matched suicide rates in the US population (ages 35-64 years) were 2.4/10,000 (men) and 0.7/10,000 (women). CONCLUSIONS: Compared with age and sex-matched suicide rates in the US, there was a substantial excess of suicides among all patients who had bariatric surgery in Pennsylvania during a 10-year period. These data document a need to develop more comprehensive longer-term surveillance and follow-up methods in order to evaluate factors associated with postbariatric surgery suicide.

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.

Poor prognostic significance of unamplified chromosome 17 polysomy in invasive breast carcinoma.

The human epidermal growth factor receptor 2 (HER2) oncoprotein is overexpressed in about 20% of breast cancers, with HER2 gene amplification responsible for protein overexpression in the vast majority of patients. A subset of breast cancers have chromosome 17 aneusomy, due to either 17 monosomy (a single copy of chromosome 17) or polysomy (increased copy numbers of chromosome 17). Although HER2 overexpression is an established adverse prognostic factor in breast cancer, the role of unamplified chromosome 17 polysomy is uncertain and there is a paucity of literature on the correlation of chromosome 17 aneusomy with important prognostic and predictive pathologic factors in invasive breast carcinoma. Furthermore, while patients showing HER2 amplification with or without polysomy 17 are treated with trastuzumab with or without other chemotherapy, treatment of patients with unamplified chromosome 17 polysomy is not well defined. Currently most of these patients are treated similar to patients with neither amplification nor 17 polysomy. The aim of this study was to compare some prognostic and predictive factors in invasive breast carcinoma in patients with unamplified chromosome 17 polysomy with that seen in cases with HER2 gene amplification and those with neither amplification or polysomy. We found that invasive breast carcinomas with unamplified chromosome 17 polysomy are associated with several adverse prognostic indicators such as a higher nuclear grade, mitotic activity, Nottingham score, histologic grade, tumor stage, and greater estrogen receptor negativity with a trend towards the amplified group, in contrast to patients with neither amplification or polysomy. Although most patients with unamplified 17 polysomy have a 2+ equivocal score on immunohistochemistry, a minority has a 3+ positive score. An increased adverse role for unamplified polysomy along with 3+ protein expression in some patients supports the idea that these patients should be considered for therapy with trastuzumab and/or anthracyclines.