Citalopram distribution in postmortem cases.

This is a report of the analytical findings in 13 cases investigated by either the Office of the Chief Medical Examiner, State of Maryland or the Bexar County (San Antonio, TX) Medical Examiner's Office in which citalopram, a highly selective serotonin reuptake inhibitor used therapeutically as an antidepressant, was identified. In 8 of the 9 cases in which both blood and urine specimens were received, the urine citalopram concentration exceeded the blood concentration, indicating that urine is an appropriate specimen for screening citalopram use. The average liver to blood citalopram concentration ratio was 6.5 (range 3.1-13, n = 6). Three cases had blood concentrations less than 0.24 mg/L, which is in the reported antemortem therapeutic range of the drug. Eleven cases had blood concentrations less than 1.3 mg/L; in each of these cases, citalopram was determined to be an incidental finding to the ultimate cause of death. Quantitation of citalopram and the metabolite desmethylcitalopram in these cases yielded an average parent-to-metabolite ratio of 6.4.

Decreasing incidence of sudden death due to undiagnosed primary central nervous system tumors.

CONTEXT: Although most fatal brain tumors are diagnosed well before a patient's death, occasionally medical examiners and coroners encounter cases in which the presence of a primary tumor of the central nervous system (CNS) was not suspected prior to death. Analysis of such cases can shed light on specific pitfalls hindering the diagnosis of brain tumors. In addition, by analyzing the incidence of these cases in a large autopsy series, one can draw conclusions about the evolving effectiveness of medical diagnosis. OBJECTIVE: To determine the incidence of deaths due to undiagnosed primary CNS tumors in the era of advanced neuroimaging techniques. DESIGN: Records from forensic autopsies performed during a 20-year period (1980-1999) at the Office of the Chief Medical Examiner of the State of Maryland were reviewed to identify cases in which death was caused by primary CNS tumors undiagnosed prior to the patient's death. RESULTS: We present 11 cases of undiagnosed primary CNS tumors resulting in sudden death that were identified among 54 873 forensic autopsies. Sudden deaths due to undiagnosed CNS neoplasms account for a significantly lower percentage of cases in our study (0.02%) than in similar series reported prior to 1980 (> or =0.16%). CONCLUSIONS: We hypothesize that improvements in imaging techniques, notably the introduction of computed tomography and magnetic resonance imaging, have resulted in increased early detection of CNS neoplasms. However, vague or short-term symptoms and limited health care access can dissuade patients from seeking medical attention and result in failure to diagnose these tumors correctly.

Palliative pain therapy at the end of life and forensic medicine issues.

An 83-year-old woman with a history of Alzheimer's disease and breast cancer died at home while receiving palliative pain therapy with oral morphine from her family for metastatic breast cancer. Allegations of mistreatment were made, and this case was ultimately referred to the Office of the Chief Medical Examiner, State of Maryland. An autopsy failed to identify any injuries or residual cancer, leaving no anatomic explanation for the pain that had been presumed to be metastatic breast carcinoma involving bone. The blood free morphine concentration was 5,200 ng/ml, and the total morphine concentration was 15,000 ng/ml. This case demonstrates the challenges and difficulties in forensic medicine when faced with the interpretation of toxicologic results at the end of life.

A rapid postmortem cardiac troponin T assay: laboratory evidence of sudden cardiac death.

Postmortem examination may be useful in establishing the cause of sudden unexpected death. In many instances, however, limitations of staffing, budget, and time may force the pathologist to triage cases to external examination rather than autopsy. A rapid assay for cardiac troponin T (cTnT) to document suspected cardiac-related deaths may optimize the use of the time and resources of the autopsy pathologist. Peripheral blood was sampled percutaneously before each of 40 autopsies and placed in the well of the Cardiac T Rapid Assay unit in accordance with the included instructions, and the results were read after 15 minutes. The assay result, decedent age, postmortem interval, and evidence of cardiopulmonary resuscitation were tabulated and subsequently correlated with the cause of death. On final sign-out of each of the autopsies, the cause of death was determined to be cardiac-related (n = 20) versus the cause in non-cardiac control subjects (n = 20). This determination was made while the investigators were blinded to the cTnT assay result. Of the 20 cardiac deaths, 17 (85%) showed positive results for cTnT compared with 6 (30%) false-positive results among the 20 control cases; this result was statistically significant according to the chi-square test. In the over-50 age group, the sensitivity of this assay in detecting cardiac-related death was 91%, with a specificity of 86%. Perimortem cardiopulmonary resuscitation did not appear to result in false-positive results. In the appropriate setting, this rapid assay for cTnT can provide valuable data supportive of a cardiac-related death. This inexpensive test may best be used in triaging sudden deaths in persons over 50 to external examination versus complete autopsy.

Use of alcohol as a risk factor for bicycling injury.

CONTEXT: Bicycling is one of the leading causes of recreational injuries. Elevated blood alcohol concentrations (BACs) are found in about one third of fatally injured bicyclists aged 15 years or older. OBJECTIVE: To assess the relative risk of fatal and serious bicycling injury according to BAC. DESIGN: Matched case-control study. SETTING AND SUBJECTS: Bicyclists aged 15 years or older who were fatally or seriously injured while riding a bicycle during the day in Maryland in 1985-1997 (cases, n = 124) and bicyclists aged 15 years or older who were interviewed and given a breath test for estimated BAC during roadside surveys that took place in June 1996 through May 1998 at the same site, time of day, day of week, and month of year in which a case bicyclist was injured (controls, n = 342). MAIN OUTCOME MEASURE: Odds ratio of bicycling injury according to estimated BAC. RESULTS: An estimated positive BAC (>/=0.02 g/dL) was detected in 12.9% of the case bicyclists (23.5% of the 34 fatally injured and 8.9% of the 90 seriously injured) compared with 2.9% of the control bicyclists (P<.001). Relative to an estimated BAC of less than 0.02 g/dL, the adjusted odds ratio of bicycling injury was 5.6 (95% confidence interval [CI], 2.2-14.0) for a BAC of 0.02 g/dL or higher and was 20.2 (95% CI, 4.2-96.3) for a BAC of 0.08 g/dL or higher. Rates of helmet use at the time of injury or interview were 5% and 35%, respectively, for those with and without a positive BAC (P =.007). CONCLUSION: Alcohol use while bicycle riding is associated with a substantially increased risk of fatal or serious injury.

Intraneuronal abeta-amyloid precedes development of amyloid plaques in Down syndrome.

CONTEXT: Down syndrome patients who live to middle age invariably develop the neuropathologic features of Alzheimer disease, providing a unique situation in which to study the early and sequential development of these changes. OBJECTIVE: To study the development of amyloid deposits, senile plaques, astrocytic and microglial reactions, and neurofibrillary tangles in the brains of young individuals (<30 years of age) with Down syndrome. METHODS: Histologic and immunocytochemical study of a series of autopsy brains (n = 14, from subjects aged 11 months to 56 years, with 9 subjects <30 years) examined at the Office of the Chief Medical Examiner of the State of Maryland and The Johns Hopkins Hospital. RESULTS: The principal observations included the presence of intraneuronal Abeta immunostaining in the hippocampus and cerebral cortex of very young Down syndrome patients (preceding the extracellular deposition of Abeta) and the formation of senile plaques and neurofibrillary tangles. CONCLUSIONS: We propose the following sequence of events in the development of neuropathologic changes of Alzheimer disease in Down syndrome: (1) intracellular accumulation of Abeta in neurons and astrocytes, (2) deposition of extracellular Abeta and formation of diffuse plaques, and (3) development of neuritic plaques and neurofibrillary tangles with activation of microglial cells.

Lamotrigine distribution in two postmortem cases.

Lamotrigine (Lamictal) is a new anticonvulsant drug recently approved for use in the United States. Although a therapeutic range for lamotrigine has not been definitively established, a range of between 2 and 14 mg/L has been reported. Two cases are presented in which lamotrigine was identified in cases investigated by the Office of the Chief Medical Examiner, State of Maryland. Lamotrigine was identified by gas chromatography-nitrogen-phosphorus detection following an alkaline extraction. A DB-5 column provided analytical separation; no derivatization was required. Confirmation was achieved by full scan electron ionization gas chromatography-mass spectrometry. In Case 1, primidone (11 mg/L) and phenobarbital (5.5 mg/L) were found in the heart blood in addition to lamotrigine (8.3 mg/L); in Case 2, no drugs other than lamotrigine (52 mg/L) were detected in the heart blood. The peripheral blood concentration in Case 2 was 54 mg/L. The liver lamotrigine concentrations in the two cases were 41 and 220 mg/kg. The medical examiner ruled that the cause of death in Case 1 was seizure disorder and the manner of death was natural. In Case 2, the medical examiner ruled that the cause of death was lamotrigine intoxication and the manner of death was undetermined.

An unusual drug death involving maggots.

Toxicologic analysis of decomposed specimens provides greater analytical challenges than those encountered with fresh postmortem specimens. Despite the difficulties involved, in cases in which the cause of death is not determined at autopsy or when there is a strong indication of drug intoxication, all reasonable steps must be undertaken to perform as comprehensive a drug screen as possible. An unidentified white male was found in a field near a river. The body was decomposed and skeletonized, and 3- to 4-mm maggots were present on the body. Near the body was an empty bottle of secobarbital that had been prescribed to a female. There was no evidence of injury. Calf muscle and maggots were sent for toxicologic analysis. No volatile substances or drugs were detected in the calf muscle. Because intoxication due to secobarbital was strongly suggested from the scene investigation, the only other specimen available, the maggots, were tested for acid-neutral drugs. Secobarbital was identified by retention time and was confirmed by full-scan electron ionization gas chromatography/mass spectrometry. Based on the available information, the medical examiner ruled that the cause of death was secobarbital intoxication and the manner of death was suicide.

Lethal combination of tramadol and multiple drugs affecting serotonin.

The death of a 36-year-old alcoholic man who died after developing seizure activity while being treated with tramadol, as well as with venlafaxine, trazodone, and quetiapine, all of which interact with the neurotransmitter serotonin, is reported. The decedent, who had a history of chronic back pain, alcoholism, depression, mild hypertensive cardiovascular disease, and gastritis, had just been discharged from the hospital after 4 days of alcohol detoxification treatment. During the admission, no withdrawal seizures were noted. The morning after discharge, a witness observed the decedent exhibiting seizure activity and then collapsing. An autopsy was performed approximately 6 hours after death, and the anatomic findings were consistent with seizure activity and collapse, which included biting injuries of the tongue and soft-tissue injuries of the face. Toxicologic analysis identified tramadol, venlafaxine, promethazine, and acetaminophen in the urine; tramadol (0.70 mg/L) and venlafaxine (0.30 mg/L) in the heart blood, and 0.10 mg of tramadol in 40 ml of submitted stomach contents. No metabolites, such as acetate, acetone, lactate, and pyruvate, were found in the specimens that would be characteristically found in a person with alcohol withdrawal syndrome. The threshold for seizures is lowered by tramadol. In addition, the risk for seizure is enhanced by the concomitant use of tramadol with selective serotonin reuptake inhibitors or neuroleptics, and its use in patients with a recognized risk for seizures, i.e., alcohol withdrawal. The cause of death in this individual was seizure activity complicating therapy for back pain, depression, and alcohol withdrawal syndrome. The data in Adverse Event Reporting System of the Food and Drug Administration from November 1, 1997 to September 8, 1999 was reviewed along with a MEDLINE search from 1966 to the present. This case appears to be the first reported death caused by seizure activity in a patient taking tramadol in combination with drugs that affect serotonin.

Status of alcohol absorption in drinking drivers killed in traffic accidents.

One issue which constantly confronts the forensic toxicologist in drinking driver cases is the relationship between the breath or blood alcohol concentration (AC) of the driver at the time of an event such as a traffic stop or an accident and the AC measured at a time subsequent to the event. In theory, the AC can be rising, on a plateau or declining at the time of the event. Several studies have indicated that the overwhelming majority of drinking drivers are on a plateau or are post-absorptive at the time of the event. In this study, driver fatality cases investigated by the Office of the Chief Medical Examiner, State of Maryland during a three-year period were reviewed. Included in this study were cases positive for alcohol in the blood at a cutoff of 0.01 g/dL and death occurring within 15 min of the accident. In fact, many of these deaths were instantaneous or near instantaneous based on the injuries documented by the medical examiner at autopsy. The blood and urine were analyzed for alcohol by head-space gas chromatography and urine AC to blood AC ratios were calculated. A total of 129 cases were included in this study. Eleven of the 129 cases (8.5%) had urine to blood AC ratio less than 1.0. It is likely that these individuals were in the absorptive phase at the time that the accident occurred. Thirty-two cases had a urine to blood AC ratio between 1.0 and 1.2 inclusive. In these cases, the subject could be viewed as in the plateau phase of the blood AC versus time curve. The remaining 86 cases had a urine to blood AC ratio greater than 1.2. This suggests that these individuals were in the post-absorptive state at the time of the accident. The information acquired from this study provides additional evidence to support the notion that the vast majority of individuals are not in the absorptive phase at the time of a traffic stop or an accident.

Fatal methadone poisoning in children: Maryland 1992-1996.

The prevention of accidental poisoning by prescribed an over-the-counter medication has been successfully addressed by the use of child-resistant containers. Nevertheless. accidental methadone poisoning in children remains a problem. The Office of the Chief Medical Examiner for the State of Maryland has investigated four deaths in children due to methadone poisoning over a 4-year period. Three of the cases occurred within a 3-month period. Two victims accidentally ingested methadone within 3 days of each other. The authors address the continuing danger of methadone poisoning to children and identify factors contributing to this problem.

Quantitation of latent varicella-zoster virus and herpes simplex virus genomes in human trigeminal ganglia.

Using real-time fluorescence PCR, we quantitated the numbers of copies of latent varicella-zoster virus (VZV) and herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) genomes in 15 human trigeminal ganglia. Eight (53%) and 1 (7%) of 15 ganglia were PCR positive for HSV-1 or -2 glycoprotein G genes, with means of 2,902 +/- 1,082 (standard error of the mean) or 109 genomes/10(5) cells, respectively. Eleven of 14 (79%) to 13 of 15 (87%) of the ganglia were PCR positive for VZV gene 29, 31, or 62. Pooling of the results for the three VZV genes yielded a mean of 258 +/- 38 genomes/10(5) ganglion cells. These levels of latent viral genome loads have implications for virus distribution in and reactivation from human sensory ganglia.

A case of familial angiolipomatosis with Lisch nodules.

Familial angiolipomatosis is a rare syndrome that may be confused clinically with neurofibromatosis type 1. This condition is most often inherited in an autosomal recessive manner; however, several reports have been published suggesting an autosomal dominant mode of inheritance. Angiolipomatosis, although somewhat disfiguring, is a benign condition with no known association with malignant neoplasms. This is in contradistinction to neurofibromatosis, an autosomal dominant syndrome associated with a myriad of benign and malignant neoplasms. It is, therefore, important to discriminate this entity from neurofibromatosis when a patient presents with multiple subcutaneous tumors and a family history of similar lesions. Described is a case of a prison inmate with a history of seizures and "neurofibromatosis" without clinical documentation. Lisch nodules were noted on the irides. Postmortem examination showed multiple subcutaneous yellow tumors on the chest and arms. Fine-needle aspiration of 1 mass yielded adipose tissue with prominent vessels; histologic sections of another mass showed angiolipoma. The remainder of the autopsy showed significant coronary artery disease and a remote cerebral infarction of the temporal lobe but no signs of neurofibromatosis. We feel that the presence of multiple angiolipomas in combination with Lisch nodules lends credence to the proposed relationship between fatty tumors and neurofibromatosis suggested by other authors.

Tissue distribution of mirtazapine (Remeron) in postmortem cases.

Mirtazapine (Remeron) is a member of the relatively new class of tetracyclic antidepressants. There are published cases of mirtazapine's detection as an incidental finding in postmortem cases; however, case reports with associated tissue concentrations and interpretations are not available. This report documents the tissue distribution of mirtazapine in eight postmortem cases in which it was identified but did not contribute to the cause or manner of death. The following mean mirtazapine concentrations (milligrams per liter or milligrams per kilogram) were found: heart blood 0.12 (range, < 0.01-0.33, n = 7); peripheral blood 0.09 (< 0.01-0.14, n = 4); urine 0.61 (0.01-3.2, n = 7); liver 0.88 (0.04-3.6, n = 6), kidney 0.21 (0.02-0.48, n = 5); and bile 0.62 (0.11-1.6, n = 6). In each case, the mirtazapine concentration in heart blood was approximately equal to that of peripheral blood, indicating that postmortem redistribution was not a factor in evaluating postmortem blood concentrations in these cases. However, because the liver mirtazapine concentrations were 5-30 times the blood concentrations, the potential for postmortem redistribution cannot be excluded. Additionally, because urine concentrations of the parent compound were consistently greater than the blood concentrations, urine is an adequate screening specimen for mirtazapine.

Schizophrenia and sudden death: a medical examiner case study.

This study reviews the causes of sudden death of 66 schizophrenic patients who presented to the Office of the Chief Medical Examiner (OCME) for the State of Maryland over a 3-year period from 1994 through 1996. We identified an increased incidence of suicide compared with the general population of OCME cases. This observation is consistent with reports by other investigators. The majority of the deaths were the result of natural diseases, mostly atherosclerotic cardiovascular disease. Accidents, suicides, and 1 homicide were also present in this group.

Postmortem percutaneous core biopsy of the liver.

Unexpected deaths related to significant hepatopathology are encountered daily by forensic pathologists. After investigation, a decision will be made regarding whether or not to perform an autopsy. In considering the options available to assess the degree of hepatopathology, a study was undertaken to evaluate the potential role of percutaneous core biopsy of the liver at the time of postmortem examination. Postmortem percutaneous hepatic core biopsy was attempted at the time of external examination in 28 nonconsecutive cases examined at the Office of the Chief Medical Examiner, State of Maryland; hepatic tissue was obtained in 26 cases. In 21 of these cases, hepatic tissue was obtained during subsequent partial or complete autopsy and submitted for histologic correlation. There was complete histologic correlation of tissue obtained via percutaneous biopsy with hepatic tissue obtained by open biopsy in 18 of 20 cases (86%). Significant hepatopathology was identified by core biopsy in 5 of 9 cases (56%) with a history of ethanol abuse and in 8 of 19 cases (42%) with a negative ethanol history. The sensitivity of this technique was 82% and the specificity was 100%. This study has shown that core biopsy of the liver can provide information related to the cause of death in cases with and without a history of alcohol consumption. In cases in which a complete autopsy is deferred because of familial religious objections, infectious disease, or time/budgetary constraints, this modality can be used to obtain diagnostic tissue.

The interpretation of cocaine and benzoylecgonine concentrations in postmortem cases.

This study examined cocaine and benzoylecgonine concentrations in 100 consecutive deaths where either compound was identified in blood or urine specimens to determine whether any relationship between these concentrations and cause of death can be found. Forty-seven of the 100 cases were deaths attributed to cocaine, narcotic or combined cocaine and narcotic intoxication. There were 13 cases of cocaine intoxication where no psychoactive substance other than ethanol was detected. The mean cocaine concentration in these deaths was 908 ng/ml; three cases had cocaine concentrations greater than 2000 ng/ml, while the other ten cases had cocaine concentrations less than or equal to 700 ng/ml. The mean cocaine concentration in non-cocaine deaths where no psychoactive substance other than ethanol was detected was 146 ng/ml. This difference was not statistically significant. However, the average blood benzoylecgonine concentration in the 13 cocaine deaths was significantly higher than in the 19 non-cocaine deaths. A review of combined cocaine and narcotic deaths suggest that the narcotic is the main causative agent in these deaths.

Perphenazine distribution in a postmortem case.

The case of a 34-year-old, mentally challenged, Caucasian female found dead in a group home is presented. Empty containers of perphenazine and valproic acid were found next to her bed. The perphenazine had been prescribed to another patient. No anatomic cause of death was determined at autopsy. Comprehensive testing of the heart blood for ethanol and drugs identified perphenazine at a concentration of 4.4 mg/L and valproic acid at a concentration of 950 mg/L. The distribution of perphenazine in other specimens was consistent with previously reported phenothiazine cases. The medical examiner ruled that the cause of death in this case was multiple drug intoxication and the manner of death was suicide.