Basal ganglia lesions after MPTP administration in rhesus monkeys.

In monkeys, intracarotid infusion of a single low dose of MPTP reliably induces a hemiparkinsonian syndrome that is stable over time. This model has been widely used to assess novel anti-parkinsonian therapies. Here, we report the exceptional finding of severe necrotic lesions that were observed in the basal ganglia (but not in the substantia nigra) of monkeys that received a single intracarotid injection of MPTP followed by gene therapy treatments. Although extensive unilateral dopaminergic nigrostriatal loss was found in all the animals, partial behavioral recovery was observed in the subjects that presented pallidal necrotic lesions. This report discusses possible causes and effects of the necrotic lesions and their locations and the value of the intracarotid MPTP model. Testing novel therapies in monkey models has become an essential step before clinical trials. These results indicate that evaluation of any treatment should consider possible confounding factors that may affect the results.

Unappreciated agenesis of cerebellum in an adult: case report of a 38-year-old man.

An unexpected finding at autopsy of almost complete agenesis of the cerebellum in an apparently functional, mentally subnormal 38-year-old man who died as the result of an accidental electrocution is reported. The posterior fossa was normal in appearance despite nearly complete absence of the cerebellum. A number of syndromes of cerebellar atrophy or dysgenesis have been reported, but congenital agenesis is considered a very rare condition. It does not resemble most common cerebellar malformations or acquired conditions, especially in an adult, who apparently had reasonable motor and coordinative function. The relevant literature is reviewed.

Sudden unexplained death in epilepsy: observations from a large clinical development program.

PURPOSE: The present study was conducted to determine the rate of sudden unexplained death in epilepsy (SUDEP) in a well-defined cohort of patients included in the lamotrigine (LTG) clinical development database. METHODS: A panel of scientists experienced in the area of SUDEP was assembled and provided with case summaries on all deaths (n = 45) reported during the initial clinical development of LTG. The panel developed a set of criteria for classifying cases as SUDEP (definite or highly probable), possible SUDEP, or non-SUDEP. This classification algorithm was then applied to the LTG cases, and SUDEP rates were calculated using patient-years of exposure as the denominator. RESULTS: At the time of the study, 4,700 patients (5,747 patient-years of exposure) were included in the worldwide LTG clinical trials database. In this cohort, 45 deaths were reported. Eighteen were judged by the panel to be SUDEP, 6 were defined as possible SUDEP, 20 were judged to be due to other causes (non-SUDEP), and 1 lacked sufficient data from which to make a classification. The overall SUDEP rate (definite/ highly probable SUDEP and possible SUDEP combined) was calculated to be 3.5 in 1,000 patient-years of exposure to LTG. CONCLUSIONS: The rate of SUDEP in this cohort of patients was comparable to the rate that would be expected in young adults with severe epilepsy (the subgroup of patients believed to be at highest risk of SUDEP). The data suggest that the rate of SUDEP in the LTG clinical development program is a function of the clinical trial population and is unrelated to drug treatment.

Forensic considerations in sudden unexpected death in epilepsy.

Sudden death in epilepsy has recently found its way into both civil and criminal litigation in the United States. Civil cases commonly involve actions or inactions by physicians with respect to antiepileptic drugs (AEDs) alleged to have caused sudden unexpected death in a patient with epilepsy (SUDEP). The context may be discontinuation or change of AEDs or failure to warn of the complication of SUDEP. A common issue in adjudication of such cases is the role of causality of medication type and level in SUDEP. Current knowledge does not permit an accurate assessment of risk for medication discontinuation or poor compliance. Related issues are discussed. In criminal litigation, SUDEP has been accepted by a Federal Court as a cause of death in a crime victim for whom the actions of the accused caused an epileptic state.

The expression of Gal beta 1,4GlcNAc alpha 2,6 sialyltransferase and alpha 2,6-linked sialoglycoconjugates in human brain tumors.

CMP-NeuAc: Gal beta 1,4GlcNAc alpha 2,6 sialyltransferase (alpha 2,6-ST) [EC 2.4.99.1] is developmentally regulated, shows a high degree of tissue specificity, and appears to play a role in oncogenic transformation and metastasis. In the present study, we have performed the first detailed analysis of the expression of alpha 2,6-ST and alpha 2,6-linked sialoglycoconjugates in human brain tumors. We used a polyclonal, monospecific anti-rat alpha 2,6-ST antibody and the alpha 2,6-linked sialic acid-specific lectin, Sambucus nigra agglutinin (SNA) for histochemical studies, and a human alpha 2,6-ST-specific cDNA probe for Northern analysis. Meningiomas, chordomas and craniopharyngiomas frequently expressed alpha 2,6-ST and alpha 2,6-linked sialoglycoconjugates. Among the different meningioma subtypes, meningothelial meningiomas stained more strongly with both anti-alpha 2,6-ST antibody and SNA than the fibroblastic and anaplastic meningiomas. On the other hand, all tumors of glial origin and medulloblastomas were virtually devoid of either alpha 2,6-ST or alpha 2,6-linked sialoglycoconjugate expression. Moreover, very weak to negligible expression of both alpha 2,6-ST and alpha 2,6-linked sialoglycoconjugates was observed in brain metastases. In conclusion, alpha 2,6-ST and alpha 2,6-linked sialoglycoconjugate expression is associated with non-neuroectodermal epithelial-like tumors.

Cohort study of incidence of sudden unexplained death in persons with seizure disorder treated with antiepileptic drugs in Saskatchewan, Canada.

To measure the incidence of sudden unexplained death in treated persons with epilepsy (SUDEP) and to identify risk factors for SUDEP, a cohort of 6,044 persons aged 15-49 years with more than four prescriptions for antiepileptic drugs (AEDs) was identified from the Saskatchewan Health prscription drug file. To exclude subjects whose sudden deaths (SUDs) might be misattributed to another chronic underlying disease, subjects with hospitalizations for cancer or heart problems were excluded. To exclude subjects without epilepsy, subjects with > 2-year AED treatment followed by AED-free time and subjects receiving < 1 U/day were excluded. The final cohort consisted of 3,688 subjects. Follow-up was started at the first AED prescription listed in the prescription drug file and ended at the earliest of the following: age 50 years, death, or last registration in the Saskatchewan Health. For 153 of 163 deaths occurring in the cohort, copies of anonymized death certificates were obtained and copies of anonymized autopsy reports of potential SUDEP cases were examined. There were 18 definite/probable SUDs and 21 possible SUDEPs, yielding a minimum incidence of 0.54 SUDEP per 1,000 person-years and a maximum of 1.35 SUDEP per 1,000 person-years. SUDEP incidence increased with male sex, number of AEDs ever prescribed, and prescription of psychotropic drugs and was highest in males with a history of treatment with three or more AEDs and four or more psychotropic drug prescriptions. Poisson regression showed a 1.7-fold increase in risk of SUDEP for each increment in maximum number of AEDs administered, a likely surrogate for severity and persistence of seizures.

A prospective study on sudden unexpected death in epilepsy.

Sudden unexpected death accounts for a substantial portion of deaths among epileptics. The incidence of this phenomenon is probably 1 in 370 to 1 in 1,110 in the general epileptic population but may be even higher in the 20- to 40-year age group, and still higher if epileptics with symptomatic epilepsy are selected. Sudden unexpected death in epileptics has been observed at least once weekly by the Office of the Medical Examiner of Cook County (Chicago), Illinois, for many years. A year-long prospective study revealed that victims of this complication of epilepsy are most commonly black males averaging 35 years of age who have infrequent generalized seizures and usually have some structural lesion in the brain responsible for their seizures. They tend to abuse alcohol and have poor compliance with anticonvulsant medication. The electroencephalograms display considerable variability from record to record. At autopsy the heart, lung, and liver weights were heavier and the brain weights were lighter than expected. The mechanisms involved in sudden unexpected death in epileptics may include autonomically mediated cardiac arrhythmia alone or in combination with sudden "neurogenic" pulmonary edema and "backward" cardiac failure.

Castleman's disease manifesting in the central nervous system: case report with immunological studies.

Castleman's disease is an uncommon lymphoproliferative disorder that manifests itself as a local or generalized tumor-like condition affecting both lymph nodes and nonnodal tissues, usually in the chest or abdomen. Only two prior examples involving the central nervous system had been reported when this patient was encountered. Very recently, three additional cases have been reported by Severson et al. We report the sixth case of Castleman's disease affecting the central nervous system, which occurred in a 63-year-old woman in whom the diagnosis was made after craniotomy for a mass lesion involving the dura over the frontal regions. Neuroradiological, clinical, and immunopathological characteristics of the case are presented. The lesion was treated with cranial irradiation and the patient is alive and symptom free three years after initial treatment.

Embolization of cotton pledgets following insertion of porcine cardiac valve bioprostheses.

A variety of complications involving heart valve implants have been documented. Embolism originating from thrombosis of the valve has been a recurrent problem in mechanical and to a lesser extent porcine implants. We report two accidental deaths as a result of embolization of cotton pledgets from porcine valves. Hospital personnel failed to remove this cotton material from the valves before surgical placement. In the first case, when portions of the pledgets embolized to both carotid arteries, fatal cerebral infarction occurred. In the second case, portions of the pledgets embolized to a coronary artery producing severe left ventricular failure.

Medulloblastomas in childhood: histological factors influencing patients' outcome.

Sixty-five medulloblastomas in infancy and childhood treated from 1965 through 1981 were reviewed, and the correlation between histological findings of medulloblastomas and clinical course of the patients was studied. Thirty-five patients died but the remaining 30 are alive and without clinical evidence of recurrence 5 years or more after surgery. Certain histological features on light microscopic examinations (e.g., pleomorphism of tumor cells, nuclear-cytoplasmic ratio, mitotic index, degree of vascularity and endothelial proliferation) do influence patient outcome with statistical significance (P less than 0.05). Thirty out of 65 medulloblastomas were examined further, using immunohistochemical methods with glial fibrillary acidic protein (GFAP), neuron specific enolase (NSE), and factor VIII/vW factor (F VIII/vWF). GFAP stain was negative in 20%, NSE stain in 13.3% and F VIII/vWF stain in 16.7% of the medulloblastomas studied. "Desmoplastic" medulloblastomas showed a strong tendency toward positive NSE and GFAP staining in the glomerular portion. There was no correlation between patient outcome and the results of applied immunohistochemical studies. Our data indicate that certain histological features may influence patient outcome, but the degree and pattern of cellular differentiation do not predict outcome.

Cerebral astroblastoma: immunohistochemical and ultrastructural features. Case report.

Astroblastoma is a rare glial tumor occurring predominantly in the cerebral hemispheres of young adults. Foci of astroblastoma-like patterns are commonly found in glioblastomas and other malignant glial tumors and cause confusion over the classification of the tumor as an individual entity. However, the existence of astroblastoma in histologically pure form and its typically long history, as compared with the more aggressive gliomas in which it may occur as a pattern, distinguish it as a separate and distinct tumor. A case of pure astroblastoma of the cerebral hemisphere is reported in a 3-year-old child with a 5-year course. The tumor has been resected five times, and its pattern has remained the same in all recurrences. The child is presently alive with some neurological deficit. The immunohistochemical and electron microscopical findings of this tumor are presented, and the historical development of the entity is discussed.

Sudden epilepsy deaths and the forensic pathologist.

Sudden unexpected deaths in epileptic persons are not rare events, most commonly encountered by the forensic pathologist rather than the clinician. Such deaths may represent 1-1.5% of all "natural" deaths certified by the medical examiner or coroner. The typical victim is a black male about 30 years of age who tends to abuse alcohol, with a history of generalized epilepsy for more than 1 year and likely for more than 10 years. There are a lack of obvious anatomic causes for the death at autopsy, but 60-70% of cases will have a lesion in the brain (most commonly old trauma) to explain the epilepsy. Most victims have no blood levels of anticonvulsant medications at the time of death. We have evolved a form for use by medical examiner/coroner's investigators at the scene to collect relevant information which will be of assistance to the pathologist in interpreting the case. Estimated prevalence of sudden epilepsy death, mechanisms, and other features of such cases are reviewed briefly.

Computed tomography of primary intrathecal Wilms tumor with diastematomyelia.

A 2-year-old girl evaluated for diastematomyelia proved to have nearly complete block from an associated primary intraarachnoid Wilms tumor (nephroblastoma) situated immediately caudal to the bone spur and dorsal to the reunited hemicords and conus medullaris. No second focus of Wilms tumor could be detected. The computed tomographic appearance of the tumor and a possible embryological explanation for its relationship to the spinal cord are presented.

Sudden unexpected death associated with seizures: analysis of 66 cases.

We have analyzed 66 cases of sudden unexpected death (SUD) in persons with seizure disorders, which were examined by the Office of the Medical Examiner, Cook County (Chicago), Illinois. The individuals ranged in age from 10 months to 60 years (mean age, 28 years). Autopsy findings were insufficient to explain death, and there was no evidence of major systemic pathology. Approximately 40% of victims were found dead in bed, and the remainder in some other room at home, apparently having been engaged in normal activity. Several died in an emergency room following a seizure at home. Cardiopulmonary resuscitation was attempted but was ineffective. Neuropathological examination revealed brain lesions, which probably caused the seizures, in 60% of the cases. In 68% the anticonvulsant blood level was subtherapeutic or below detectable levels. The prevalence of seizure-associated SUD may be between 1:525 and 1:2,100 among epileptics. The mechanism of death in these cases probably involves cardiac arrhythmias mediated by sympathetic autonomic events occurring during the seizure.

Temporal correlates in brain death. EEG and clinical relationships to the respirator brain.

In a prospective study of 32 cases of brain death, gross and microscopic pathological appearances of the CNS were statistically analyzed and correlated with EEG and clinical findings. The diagnosis of a "respirator brain" is best made grossly after fixation, using commonly known gross pathological criteria. The microscopic changes are more unpredictable and variable than the gross findings. Respirator brain changes that can be relied on to confirm the clinical-EEG diagnosis of brain death generally take about 12 hours to become manifest after electrocerebral silence (ECS) and/or cerebral circulatory arrest, and are unaffected by the time interval between termination of respiratory support and refrigeration of the body or by delays in performance of the autopsy. Loss of brain-stem reflexes, evidence of herniation, and deterioration of the EEG to ECS correlate significantly with the development of a respirator brain in the respirator-dependent, comatose patient.

Ponto-medullary avulsion associated with cervical hyperextension.

19 cases of partial or complete ponto-medullary avulsion are reported. This type of damage seems to be produced by severe hyperextension of the head on the neck with or without an additional rotational component.

Multiple mycotic aneurysms and transverse myelopathy complicating repair of aortic coarctation.

The case of an 18-year-old man with coarctation of the aorta discovered on routine physical examination and subsequently surgically repaired is reported. Four months postoperatively, aneurysms developed at the repair site and thrombosis of both femoral arteries was noted. Following an attempt to repair the aneurysm and remove the thrombi, the patient became paraplegic; Aspergillus fumigatus was found infecting the aorta and femoral vessels. After additional operations and a course of amphotericin B to control the fungal infection, the patient died of intrathoracic bleeding originating from infected, aneurysmally dilated intercostal vessels in the area of the original coarctation repair. The complicating fungal infection of the operative site and the paraplegia are discussed. This report is among the first to present a patient with fungal endarteritis complicating operation for coarctation of the aorta.

Sudden unexpected death caused by neuroepithelial (colloid) cyst of the third ventricle.

Sudden unexpected death caused by a colloid cyst of the third ventricle in young apparently healthy persons is an uncommon phenomenon that nevertheless occurs regularly in medical examiner's cases and may occur in general hospital pathology practice. This entity has not received proper attention in the general or forensic pathology literature in spite of the fact that sudden death has been appreciated in the clinical literature for many years. We report four cases of sudden unexpected death in young persons whose only major previous complaint was that the chronic relapsing headaches. Because of the sudden and unexpected nature of their deaths, these cases came to the attention of the medical examiner and the colloid cysts were discovered at autopsy. The history of the lesion, its histogenesis, its pathological physiology, and the experiences of others are reviewed.