Neuropathology of substance use disorders.

Addictions to licit and illicit drugs are chronic relapsing brain disorders that affect circuits that regulate reward, motivation, memory, and decision-making. Drug-induced pathological changes in these brain regions are associated with characteristic enduring behaviors that continue despite adverse biopsychosocial consequences. Repeated exposure to these substances leads to egocentric behaviors that focus on obtaining the drug by any means and on taking the drug under adverse psychosocial and medical conditions. Addiction also includes craving for the substances and, in some cases, involvement in risky behaviors that can cause death. These patterns of behaviors are associated with specific cognitive disturbances and neuroimaging evidence for brain dysfunctions in a diverse population of drug addicts. Postmortem studies have also revealed significant biochemical and/or structural abnormalities in some addicted individuals. The present review provides a summary of the evidence that has accumulated over the past few years to implicate brain dysfunctions in the varied manifestations of drug addiction. We thus review data on cerebrovascular alterations, brain structural abnormalities, and postmortem studies of patients who abuse cannabis, cocaine, amphetamines, heroin, and "bath salts". We also discuss potential molecular, biochemical, and cellular bases for the varied clinical presentations of these patients. Elucidation of the biological bases of addiction will help to develop better therapeutic approaches to these patient populations.

Establishing vitreous glucose and beta-hydroxybutyrate thresholds to assist in the diagnosis of hypothermia.

The post-mortem diagnosis of hypothermia is challenging to establish due to the lack of pathognomonic findings and the confounding problem that any comorbidity may account for death. A 4-year retrospective case-control study was performed to compare the vitreous glucose and beta-hydroxybutyrate (BHB) concentrations between hypothermia deaths and controls. Over the study period 34 cases of hypothermia and 39 controls were analyzed. Hypothermia deaths versus controls had higher mean vitreous glucose (2.93 mmol/L vs. 1.14 mmol/L; p < 0.0001), BHB (1.89 mmol/L vs. 1.35 mmol/L; p = 0.01), and combined glucose+BHB (4.83 mmol/L vs. 2.46 mmol/L; p < 0.0001). Receiver operating characteristic (ROC) curves showed that the best model for predicting hypothermia in all cases was a combined vitreous glucose+BHB threshold of 2.03 mmol/L (sensitivity 88.2 %; specificity 56.4 %). A sub-group analysis broken down by detectable levels of blood ethanol showed that cases of hypothermia with and without ethanol maintained higher median vitreous glucose relative to the controls (2.05 vs. 0.35 mmol/L and 2.70 vs. 0.65 mmol/L; p = 0.02), however median BHB was only significantly elevated when ethanol was absent (1.88 vs. 1.42 mmol/L; p < 0.0001). Subsequent ROC curve analysis demonstrated that a better model for predicting hypothermia was in cases when blood ethanol was absent. In those deaths vitreous BHB alone had the best area under the curve, with an optimum threshold of 1.83 mmol/L (sensitivity 83.3 %; specificity 96.3 %). This study shows that post-mortem vitreous glucose and BHB are useful ancillary studies to assist in the diagnosis of hypothermia. Ethanol however is a confounder and can alter the utility of vitreous BHB when diagnosing hypothermia in those who have consumed alcohol prior to death.

Postmortem survey of haemoglobin A1c, non-alcoholic steatohepatitis and liver fibrosis within a general population.

AIMS: Non-alcoholic steatohepatitis (NASH), fatty liver disease and fibrosis are associated with diabetes mellitus and obesity. Previous autopsy series have reported prevalence of fatty liver disease to be 11%-24%. Recent studies, using imaging and serology, suggest a prevalence of 20%-35%, NASH of 5% and advanced fibrosis of 2%-3%. We examined the prevalence of NASH and liver fibrosis in a general autopsy population. METHODS: A cross-sectional study of consecutive, adult, medicolegal autopsies over a 1-year period was conducted. Liver sections were scored for fibrosis, inflammation and steatosis using a modified NASH scoring system. Stepwise logistic regression was used to identify associations between NASH or moderate/severe fibrosis and several clinicopathological parameters, including postmortem haemoglobin A1c (HbA1c). RESULTS: Of 376 cases, 86 (22.9%) were classified as NASH. Prevalence of diabetes mellitus, body mass index (BMI) and postmortem HbA1c were significantly higher in NASH cases (39.5%, 32.3 kg/m2 and 6.88%) than non-NASH cases (12.1%, 27.0 kg/m2 and 5.73%). Decedents with moderate/severe fibrosis (6.9%) had higher prevalence of diabetes, BMI and HbA1c (50%, 31.4 kg/m2 and 6.7%) compared with those with no/mild fibrosis (16%, 28 kg/m2 and 5.9%). HbA1c ≥7% was found to be an independent predictor of NASH (OR 5.11, 95% CI 2.61 to 9.98) and advanced fibrosis (OR 3.94, 95% CI 1.63 to 9.53). CONCLUSIONS: NASH and advanced fibrosis were higher in our general adult autopsy population compared with previously published estimates. This is a large series with histological evaluation showing that HbA1c >7.0% is independently associated with NASH and advanced fibrosis.

The histopathology of drugs of abuse.

The use of drugs for recreational purposes is widespread. The drugs used can be divided into groups including stimulants (cocaine, amphetamines, etc.), opiates and opioids (heroin, oxycodone, methadone, fentanyl, etc.), sedatives (benzodiazepines and related substances) and miscellaneous drugs, including ketamine and cannabis (marijuana). These drugs can have profound effects on all organ systems in the body. The method of administration, whether by injection or inhalation, can cause localized and systemic effects, including the transmission of infection and granulomata at the site of injection and in the lungs. Suppurative abscesses from injection can result in systemic amyloidosis. Stimulants have profound effects on the cardiovascular and cerebrovascular systems, with enlarged hearts with fibrosis seen microscopically and cerebral infarction and haemorrhage. Crack cocaine use is also associated with changes in the pulmonary system, including carbon pigmented intra-alveolar macrophages, emphysema and pulmonary arterial changes. Cannabis use is associated with brown pigmented macrophages in the lung as well as changes in the respiratory tract epithelium. Opiates/opioids are associated with inhalational pneumonitis and hypoxic brain damage due to their respiratory depressant effects. Heroin use has been associated with focal segmental glomerulonephritis (heroin-associated nephropathy: HAN). 3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) use is associated with changes in the cardiovascular system. Its use can lead to hyperpyrexia, which results in systemic changes. Ketamine abuse has been associated with cystitis. Drugs of abuse may affect testicular function. In analysing the effects of drugs at autopsy a systematic approach to sampling of histology is required.

Fatal traumatic aneurysm of the posterior inferior cerebellar artery with delayed rupture.

Traumatic aneurysms of intracranial arteries are rare, forming less than 1% of all intracranial arteries. They may be associated with penetrating and non-penetrating trauma. Most cases are associated with fracturing of the skull. Rupture of traumatic aneurysms occur in up to 50% of cases and are typically delayed from days to weeks following the initiating trauma. We report a case of a 22-year-old man who was punched to the head. He was rendered unconscious but recovered and had a GCS of 14 on admission. CT scans showed subarachnoid hemorrhage. An initial angiogram was negative but on day 7 following the incident he was noted to have a 1 mm aneurysm of the posterior inferior cerebellar artery on CT angiogram. On day 9 he collapsed and was found to have new subarachnoid hemorrhage and to have a 4.0 mm × 3.7 mm. He did not recover and was declared brain dead on day 12. At autopsy, there was a 4.0 mm aneurysm of the left PICA just after the origin of the artery. Histological examination confirmed the presence of a traumatic false aneurysm in the left PICA. This case study shows sequential radiological imaging with pathologiocal correlation.