The spectrum of disease and tau pathology of nodding syndrome in Uganda.

Nodding syndrome is an enigmatic recurrent epidemic neurologic disease that affects children in East Africa. The illness begins with vertical nodding of the head and can progress to grand mal seizures and death after several years. The most recent outbreak of nodding syndrome occurred in northern Uganda. We now describe the clinicopathologic spectrum of nodding syndrome in northern Uganda. The neuropathologic findings of 16 children or young adults with fatal nodding syndrome were correlated with the onset, duration and progression of their neurological illness. The affected individuals ranged in age from 14 to 25 years at the time of death with a duration of illness ranging from 6-15 years. All 16 cases had chronic seizures. In 10 cases, detailed clinical histories were available and showed that three individuals had a clinical course that was predominantly characterized by epilepsy, whereas the other seven individuals had progressive cognitive, behavioural and motor decline, in addition to epilepsy. The main neuropathologic findings included: tau pathology (16/16 cases), cerebellar degeneration (11/16 cases) and white matter degeneration (7/16 cases). The tau pathology was characterized by filamentous tau-positive deposits in the form of neurofibrillary tangles, pre-tangles and dot-like grains and threads in the neuropil. All cases showed some degree of tau pathology in the neocortex and in the locus coeruleus with frequent involvement of the substantia nigra and tegmental nuclei and lesser involvement of other grey matter sites, but there was a lack of glial tau pathology. The tau pathology in the neocortex showed a multifocal superficial laminar pattern. We conclude that nodding syndrome is a clinicopathological entity associated consistently with tau pathology, but our observations did not establish the cause of the disease, or an explanation for the tau pathology.

Death by fecaloma.

A 59-year-old man with a history of cerebral palsy and dextroscoliosis died in a group home. He required supplemental oxygen and had no bowel movement for weeks prior to death. At autopsy, the abdomen was markedly distended and there were flexion contractures of the legs. Postmortem computed tomography revealed a dilated digestive tract and fecal loading in the sigmoid and rectum, marked upwardly displaced diaphragm and scoliosis. On internal examination, the diaphragm was displaced rostrally and the rectosigmoid colon contained 2.5 kg of fecaloma with two rectal fecaliths. Severe scoliosis with marked reduction in volume of thoracic cavity was present. Microscopic examination revealed chronic aspiration pneumonia and chronic pulmonary hypertension. Overall, four factors led to respiratory failure: fecaloma; cerebral palsy; scoliosis; and chronic aspiration pneumonia. Based on clinicopathological correlation, the cause of death was determined to be a combination of these factors, and the key acute factor was the fecaloma.

Autopsy-reported cause of death in a population-based cohort of sudden unexpected death in epilepsy.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is a diagnosis of exclusion; the definition includes individuals with epilepsy who die suddenly without an identifiable toxicological or anatomical cause of death. Limited data suggest underidentification of SUDEP as the cause of death on death certificates. Here, we evaluate the autopsy-reported cause of death in a population-based cohort of SUDEP cases. METHODS: Case summaries of forensic autopsies conducted in Ontario, Canada between January 2014 and June 2016 were retrospectively screened using a language processing script for decedents with a history of epilepsy or seizures. After manual review for potential SUDEP cases, two neurologists independently examined the autopsy reports and classified deaths by Nashef criteria. Demographic characteristics and consideration by the forensic pathologist of the role of epilepsy, seizure, and SUDEP in death were summarized. RESULTS: One hundred and eight Definite, 34 Definite Plus, and 22 Possible SUDEP cases were identified. Seventy-five percent of Definite/Definite Plus SUDEP cases identified by the neurologists were attributed to SUDEP, epilepsy, or seizure disorder in the autopsy report. There was a significant association between the proportion of cases listed in the autopsy report as SUDEP, epilepsy, or seizure disorder and neurologists' SUDEP classification (86% of Definite, 38% of Definite Plus, 0% of Possible). Age was significantly associated with SUDEP classification; Definite cases were younger than Definite Plus, which were younger than Possible SUDEP cases. SIGNIFICANCE: Most SUDEP cases identified by neurologists were classified concordantly by forensic pathologists in Ontario, Canada; however, concordance decreased with increased case complexity. Although the role of epilepsy/seizures was considered in most Definite/Definite Plus cases, this study highlights the need for autopsy report review of potential SUDEP cases in research studies and assessments of the public health burden of SUDEP. The relationship between age and SUDEP classification has important public health implications; SUDEP incidence may be underappreciated in older adults.

Fatal pneumococcal septicemia in a girl with visceral heterotaxy and polysplenia: a case report.

We report an unusual case of a 15-month old previously healthy girl who died of pneumococcal septicemia in the background of visceral heterotaxy with polysplenia. Heterotaxy can also present with asplenia whereas polysplenia cases usually present with functional asplenia. Of particular note, this girl received the 13-valent pneumococcal conjugate vaccine as recommended by the Centers for Disease Control and Prevention in the routine pediatric immunization schedule used in the USA and Canada. Unfortunately, although the strain causing death (serotype 22F) is not contained in Prevnar 13®, it is in the 23-valent pneumococcal polysaccharide vaccine (e.g. Pneumovax 23®), currently suggested only for immunocompromised children age 2 with either functional or anatomic asplenia. This syndrome has the potential of being diagnosed prenatally. The intent of our case report is to raise awareness of the syndrome, highlight that heterotaxy patients with polysplenia are at danger for infections with encapsulated organism, such as pneumococcus, meningococcus, and Haemophilus influenza amongst others due to functional asplenia, recommend the 23-valent pneumococcal polysaccharide vaccine for these children before age two for the outlined reasons, and illustrate that with early diagnosis of the heterotaxy syndrome, and early diagnosis and treatment of septic complications, the morbidity or death of young children with heterotaxy syndrome can likely be reduced or prevented.

Nodding syndrome in Uganda is a tauopathy.

Nodding syndrome is an epidemic neurologic disorder of unknown cause that affects children in the subsistence-farming communities of East Africa. We report the neuropathologic findings in five fatal cases (13-18 years of age at death) of nodding syndrome from the Acholi people in northern Uganda. Neuropathologic examination revealed tau-immunoreactive neuronal neurofibrillary tangles, pre-tangles, neuropil threads, and dot-like lesions involving the cerebral cortex, subcortical nuclei and brainstem. There was preferential involvement of the frontal and temporal lobes in a patchy distribution, mostly involving the crests of gyri and the superficial cortical lamina. The mesencephalopontine tegmental nuclei, substantia nigra, and locus coeruleus revealed globose neurofibrillary tangles and threads. We conclude that nodding syndrome is a tauopathy and may represent a newly recognized neurodegenerative disease.

Intra-Abdominal Hemorrhage Complicating Electrothermal Arterial Injury During Pelvic Surgery: A Case Report.

Iatrogenic vascular injury is a potentially serious complication of surgical procedures. Here we report a case of delayed fatal intra-abdominal hemorrhage because of electrocautery injury of a right external iliac artery. The decedent, a 31-year-old woman, died suddenly on postoperative day 1 after a laparoscopic staging operation for an ovarian tumor. Her past medical history included a recent diagnosis of a microinvasive carcinoma in the background of a mucinous cystic neoplasm of the right ovary. Postmortem examination revealed a young woman with evidence of emergency intervention, recent laparoscopic pelvic surgery, and pale hypostasis limited to the back surfaces of the body. The internal examination confirmed the postmortem computed tomography findings of a large amount of blood in the pelvic and abdominal cavities and evidence of recent surgical intervention. The soft tissues around the aorta and major pelvic vessels showed electrocautery change and marked perivascular hemorrhage preferentially surrounding the right external iliac artery. Histological examination of the vascular bundle showed an electrocautery injury of the arterial wall: transmural necrosis, acute inflammation, and hemorrhage. In this report, we offer an approach to a postmortem examination in postoperative deaths with emphasis on deaths due to iatrogenic vascular injuries and discuss the rationale for determining the manner of death.

Fatal acute retropharyngeal hemorrhage in neurofibromatosis type 1.

We report the sudden death of a woman with neurofibromatosis type 1 (NF1). The decedent developed acute respiratory distress and died rapidly despite an emergent cricothyroidotomy. An autopsy with postmortem CT scan was performed to determine the cause of the fatal respiratory collapse and to determine if death was related to neurofibromatosis. Postmortem examination revealed the classical external hallmarks of neurofibromatosis, including innumerable cutaneous neurofibromas. In addition, there was a massive retropharyngeal hematoma with fatal extrinsic compression of the airway. On macroscopic examination A localized 3 cm diameter tumor nodule was found in the soft tissues of the neck. Histologic examination of the nodule revealed a neurofibroma. In addition, histologic sections of the hematoma and surrounding soft tissues revealed plexiform neurofibroma with infiltration of the walls of small blood vessels and of the right vertebral artery. The fatal retropharyngeal hemorrhage was caused by diffuse infiltration of the blood vessels of the neck by plexiform neurofibroma. We concluded that the underlying cause of death was NF1. This case underscores the protean nature of neurofibroma, particularly when diffuse interstitial hemorrhage is present. Infiltration of soft tissues by neurofibroma may only be detectable on histologic examination.

A mimic of sexually-motivated homicide: insect stings and heat exhaustion in a forest.

We report the case a woman who was found dead in a forest. The body was nude and the position of the body suggested a sexually motivated homicide. We concluded that death was not related to homicide, but was related to the conjunction of environmental factors, including insect stings, and acute psychosis. A medicolegal death investigation with postmortem examination was undertaken to determine cause of death. At the scene, the body was supine with legs spread apart and the knees flexed, exposing the external genitalia. There were multiple apparent bruises on the body and neck. At autopsy, based on macroscopic and microscopic examination, the apparent bruises were found to be hemorrhagic insect bites. No significant injuries were present and no semen was found. Death appeared to be related to heat exhaustion and innumerable insect stings. Investigation of the medical history revealed longstanding schizoaffective disorder with episodic psychotic decompensations. In the past, during an acute psychotic episode the decedent removed her clothing and ran wildly in a forest, until she was rescued in a state of exhaustion and marked agitation, and taken to hospital for treatment. We concluded that the same circumstances had been repeated but with a fatal outcome. This case is an example of a mimic of sexually-motivated homicide and is a reminder to forensic pathologists to avoid tunnel vision. We need to be skeptical of the allure of common sense based on first impressions of the scene and the body. Forensic pathologists must be unafraid to scientifically explore improbable, but true, alternate explanations.

Sudden Death Due to Acute Epiglottitis in Adults: A Retrospective Review of 11 Postmortem Cases.

We report a retrospective review of fatal acute epiglottitis cases in adults in the province of Ontario, Canada, between 2001 and 2014. Information on demographics, clinical history, gross, microscopic, and laboratory findings were collected and analyzed. Eleven cases, predominantly male (73%), with a mean age of 50 years were identified. Common presenting symptoms included sore throat, dysphagia, and low-grade fever. The predominant postmortem findings included hyperemia and edema of the epiglottis and aryepiglottic folds. Histological features included vascular congestion, stromal edema, and acute inflammation. Five cases (45%) were positive for growth of various bacterial organisms on blood and/or tissue cultures. Acute epiglottitis should be in the differential diagnosis in fatalities presenting with symptoms of upper respiratory tract infection, followed by an episode of acute shortness of breath. History, thorough postmortem examination with close attention to the head and neck structures, histological examination of tissues, and sampling for microbiology will assist in differentiating epiglottitis from other cases of laryngeal swelling leading to death.

Fatal rhabdomyolysis after torture by reverse hanging.

PURPOSE: Reverse hanging (also known as Palestinian hanging) is a form of positional torture where the victim is suspended for a prolonged period of time by the wrists, after the wrists are bound at the back. We report the first autopsy case of reverse hanging. We have discovered that fatal myoglobinuric renal failure due to rhabdomyolysis can be a complication of Palestinian hanging. METHOD: An adult detainee, who underwent interrogation by authorities, was admitted to hospital from a prison and died in hospital after a few days. Death was due to myoglobinuric renal failure. An autopsy was performed. RESULTS: At autopsy, the body showed anasarca due to renal failure. There were healing ligature marks on the wrist and forearm, but no blunt impact injury to the shoulders or arms. There was extensive necrosis of the pectoralis major, biceps, and deltoid muscles, organizing hemoarthrosis of the right glenohumeral joint and hemorrhage into the joint capsule of the both glenohumeral joints. The kidneys showed evidence of myoglobin deposition grossly. The overstretching of the major muscles of the shoulder, in response to the prolonged Palestinian hanging, gave rise to the muscle necrosis. CONCLUSION: This case underscores the importance of conducting autopsies on people who die in custody, particularly if detained at times of political instability when torture may be practiced by state actors and others. This case also reveals that fatal rhabdomyolysis can occur by positional torture in a stress position, despite the absence of direct trauma due to blunt impacts.

Sudden death during struggle in the setting of heterozygosity for a mutation in calsequesterin 2.

Instances of sudden and unexpected death while in police custody remain complex and controversial cases in forensic pathology, and provide unique diagnostic challenges. In general, the circumstances of these cases have resulted in two major theories to account for these deaths: "excited delirium syndrome", and positional (restraint) asphyxia. However, some cases that are not easily explained by one of these theories may be best explained by a theory from another emergent area in forensic pathology, non-structural genetic heart disease. We present one such case, a sudden arrhythmic death during struggle/restraint. A 45 year old man with developmental delay was walking outdoors as part of his daily routine. He was misidentified as a criminal suspect by police officers, who attempted to take him into custody. He resisted this arrest violently. He was taken to the ground, and restrained in a face-down position. Both police and civilian witness state that he was pushing his chest off the ground with his arms, when he suddenly collapsed and died. The interaction with police lasted approximately 3 min. There was no prior excited delirium. At autopsy, minor external blunt force injuries were observed. The heart showed mild cardiomegaly with concentric left ventricular hypertrophy, and sub-occlusive coronary atherosclerosis. Toxicological testing was negative for common drugs, including cocaine and its metabolites. Post-mortem molecular testing demonstrated this man to be heterozygous for a catecholaminergic polymorphic ventricular tachycardia (CPVT) associated mutation (Phe189Leu) in the calsequestrin 2 (CASQ2) gene. This mutation was classified as a class I mutation (deleterious), that may cause disease in a heterozygous state. The cause of death was given as cardiac arrhythmia precipitated by struggle/restraint in a man with CPVT. This case illustrates the difficulty assigning a scientific cause of death in rare and controversial cases, and the value of the molecular autopsy in identifying disease causing mutations.

Rickets or abuse? A histologic comparison of rickets and child abuse-related fractures.

PURPOSE: The bone changes of vitamin D deficiency rickets have been invoked as an alternate explanation for child-abuse related fractures identified through medical imaging. The lack of modern histopathologic comparisons between these two entities limits the abilities of the forensic pathologist to address this differential diagnosis, both in their autopsy reports and on the witness stand. METHODS: We report a comparison of the histologic appearance of the bones in a two year old child with vitamin D deficiency rickets with fractures occurring in three young children with child abuse. RESULTS: In the case of rickets, there was marked architectural disorganization of endochondral ossification at the costochondral junctions and growth plates of long bones. The child abuse-related fractures showed osteochondral callus at different stages of healing, either centered on a discrete fracture line or at metaphyses (e.g. classical metaphyseal lesions). In many instances, the healing fractures disrupted the line of endochondral ossification. In none of the child abuse-related fractures was there any similarity to the histologic appearance of rickets. CONCLUSION: The maturation disturbance in the growth plate that occurs in rickets is a distinctive entity that cannot be confused histologically with healing fractures, including the classical metaphyseal lesion.

Acute hemorrhagic leukoencephalomyelitis in a man with viral myocarditis.

We report a case of acute hemorrhagic leukoencephalomyelitis in a man with viral myocarditis. A 48-year-old previously healthy male was found dead in his locked apartment. At autopsy he was found to be malnourished, and his lungs showed gross evidence of bilateral pneumonia with abscess formation and bullous emphysema. Multiple petechial hemorrhages were observed in the brain and mainly involved white matter in the cerebral hemispheres including the corpus callosum and internal capsule, as well as the cerebellum, brainstem, and spinal cord. Microscopy of the brain and spinal cord revealed perivenular hemorrhages, central microthrombi in venules with fibrin exudation into the subcortical white matter, and early perivenular demyelination associated with scanty mixed cellular infiltrates. Other microscopic features included widespread diffuse viral myocarditis, extensive suppurative bronchopneumonia, and chronic bronchitis. This case illustrates the death of a man with a rare fatal disease associated with two other potentially lethal diseases. The case also illustrates the importance of a holistic approach when determining the cause of death, especially when there are competing causes of death.

Fatal laryngeal angioedema: a case report and a workup of angioedema in a forensic setting.

Angioedema is an episodic swelling of the deep dermis, subcutis, and/or submucosal tissue due to an increase in local vascular permeability. Swelling may involve skin, respiratory, and gastrointestinal tracts. The most commonly involved areas are the periorbital region and the lips. Here we report a case of a fatal laryngeal obstruction due to angioedema likely caused by an angiotensin-converting-enzyme inhibitor. The decedent, a 58-year-old man, was witnessed developing sudden facial swelling and acute respiratory difficulties quickly followed by unresponsiveness. His past medical history suggested that this was his second episode of angioedema without urticaria. Postmortem examination revealed a complete laryngeal obstruction in the absence of infection, neoplasm, or autoimmune disease. Postmortem computed tomography of the head and neck showed a complete obstruction of the upper airway. Based on the current understanding of the pathophysiology of different types of angioedema, we will suggest a workup of angioedema without urticaria in the forensic setting and offer readers resources they can use in their practice.

Giant cell myocarditis associated with amoxicillin hypersensitivity reaction.

We report a case of sudden unexpected death in an adult woman from florid myocarditis with necrosis, replacement fibrosis, and diffuse infiltration of the myocardium by eosinophils and conspicuous giant cells. Clinical history revealed that 3 weeks prior to death, shortly after commencing antibiotic therapy for the treatment of traumatic wound of a finger, she presented to the emergency room with a hypersensitivity reaction characterized by facial rash with edema and generalized pruritus. She was treated with antihistamines and discharged. The clinico-pathological correlation suggests a link between drug hypersensitivity and the giant cell myocarditis.

Nodding syndrome is unlikely to be an autoimmune reaction to leiomodin-1 after infection by Onchocerca volvulus.

Nodding syndrome is a neurological disease of children in northern Uganda. Infection with the nematode parasite Onchocerca volvulus has been epidemiologically implicated as the cause of the disease. It has been proposed that an autoantibody directed against the human protein leiomodin-1 cross reacts with a tropomyosin-like nematode protein, thus suggesting that nodding syndrome is an autoimmune brain disease due to extra-cerebral parasitism. This hypothesis is dependent on constitutive neuronal expression of leiomodin-1. We tested this hypothesis by studying the distribution of leiomodin-1 in the normal human brain and other human tissues using immunohistochemistry. We found that immunostaining for leiomodin-1 follows a smooth muscle cell specific pattern. In the brain, it is confined to the smooth muscle cells of cerebral blood vessels and is not generally present in neurons or glia. However, immunoreactivity was identified in human Purkinje cell membrane and the body wall of C. elegans (as a proxy for Onchocerca volvulus) but only when immunostained with an antibody recognizing the N-terminal of leiomodin-1. Homology between leiomodin-1 and tropomodulin, specifically at the N-terminus, could explain why leiomodin-1 antibody cross reactivity between human Purkinje cells and C. elegans. However, we cannot provide proof confirming that the immunoreactivity in the membranes of Purkinje cells is specifically caused by the expression of tropomodulin. To overcome this limitation, further investigations using additional immunohistochemical and biochemical studies are required to corroborate our findings and provide more comprehensive evidence. Nevertheless, our findings do not support to the autoimmunity hypothesis involving Onchocerca volvulus and leiomodin-1. To gain a more comprehensive understanding of the cause and pathogenesis of NS, it is essential to explore alternative hypotheses.

SARS-CoV-2 infection dysregulates the expression of clinically relevant drug metabolizing enzymes in Vero E6 cells and membrane transporters in human lung tissues.

SARS-CoV-2-mediated interactions with drug metabolizing enzymes and membrane transporters (DMETs) in different tissues, especially lung, the main affected organ may limit the clinical efficacy and safety profile of promising COVID-19 drugs. Herein, we investigated whether SARS-CoV-2 infection could dysregulate the expression of 25 clinically relevant DMETs in Vero E6 cells and postmortem lung tissues from COVID-19 patients. Also, we assessed the role of 2 inflammatory and 4 regulatory proteins in modulating the dysregulation of DMETs in human lung tissues. We showed for the first time that SARS-CoV-2 infection dysregulates CYP3A4 and UGT1A1 at the mRNA level, as well as P-gp and MRP1 at the protein level, in Vero E6 cells and postmortem human lung tissues, respectively. We observed that at the cellular level, DMETs could potentially be dysregulated by SARS-CoV-2-associated inflammatory response and lung injury. We uncovered the pulmonary cellular localization of CYP1A2, CYP2C8, CYP2C9, and CYP2D6, as well as ENT1 and ENT2 in human lung tissues, and observed that the presence of inflammatory cells is the major driving force for the discrepancy in the localization of DMETs between COVID-19 and control human lung tissues. Because alveolar epithelial cells and lymphocytes are both sites of SARS-CoV-2 infection and localization of DMETs, we recommend further investigation of the pulmonary pharmacokinetic profile of current COVID-19 drug dosing regimen to improve clinical outcomes.

Forensic pathology and the miscarriage of justice.

A case of conviction for rape-murder that was eventually overturned based on a post-conviction re-evaluation of the findings at autopsy is described. The main issue elucidated on post-conviction review was that postmortem anal dilation and postmortem hypostatic hemorrhages of the neck were misinterpreted as injuries. After review of the autopsy findings, the prosecution agreed with the appellant that a miscarriage of justice had occurred and the conviction was quashed by an appellate court. This case underscores the need for an awareness of key pitfalls that can be encountered at autopsy, such as the proper interpretation of postmortem artefacts. The evolving role of the evidence-based framework for forensic pathology is explored as a systemic solution to enhance the administration of justice.

Sudden unexpected death in epilepsy: a retrospective analysis of 24 adult cases.

Sudden unexpected death in epilepsy is a common form of seizure-related death but is poorly appreciated by the medical profession. A number of risk factors have been identified in this context including male gender, young adult age group (20-40 years), poor compliance with antiepileptic drugs, polytherapy, and presence of neuropathological lesions. In addition it has been noted that most of the victims sustained an unwitnessed collapse at home. In this paper, we describe a retrospective review of 24 adult cases of sudden unexpected death in epilepsy. The study recognizes two risk factors; poor compliance with anti-epileptic monotherapy and an age between 20 and 29 years. All the victims were found dead at home and only one had a witnessed collapse. Our study shows a variety of neuropathological findings as the etiology. The completeness of the autopsy findings for all the cases is a strength compared to some of the other studies.

Alcoholism and the Armanni-Ebstein lesion.

The Armanni-Ebstein lesion is a histological change in the kidney consisting of sub-nuclear vacuolation of the proximal tubules. It has been most associated with diabetic ketoacidosis. The vacuoles have been reported to contain glycogen. More recent studies show them to contain fat. Recent papers have associated the Armanni-Ebstein lesion with non-diabetic ketoacidosis. We present 11 cases of alcoholic ketoacidosis where the Armanni-Ebstein lesion was identified. None had a history of diabetes mellitus and none showed any changes of diabetic nephropathy. All 11 cases had raised acetone levels (3-67 mg/100 mL (mean 17.9 mg/100 mL and median value of 16 mg/100 mL). In addition a case of isopropanol poisoning was found to have the Armanni-Ebstein lesion. Isopropanol is converted to acetone but is not associated with acidosis. These results indicate that the Armanni-Ebstein lesion is not specific to diabetes mellitus.