Jan E. Leestma

Sudden Unexplained Death in Epilepsy: Observations from a Large Clinical Development Program

Summary: 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.

Sudden Unexpected Death Associated with Seizures: Analysis of 66 Cases

Summary: 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 SUE) 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.

Cohort Study of Incidence of Sudden Unexplained Death in Persons with Seizure Disorder Treated with Antiepileptic Drugs in Saskatchewan, Canada

Summary: 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 prescription 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.

Case analysis of brain-injured admittedly shaken infants: 54 cases, 1969-2001.

The English-language medical case literature was searched for cases of apparent or alleged child abuse between the years 1969 and 2001. Three-hundred and twenty-four cases that contained detailed individual case information were analyzed yielding 54 cases in which someone was recorded as having admitted, in some fashion, to have shaken the injured baby. Individual case findings were tabulated and analyzed with respect to shaking as being the cause for the injuries reported. For all 54 admittedly-shaken-infant cases, the provided details regarding the shaking incidents and other events are reported. Data in the case reports varied widely with respect to important details. Only 11 cases of admittedly shaken babies showed no sign of cranial impact (apparently free-shaken). This small number of cases does not permit valid statistical analysis or support for many of the commonly stated aspects of the so-called shaken baby syndrome.

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/coroners 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.

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<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.

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.

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.

Forensic considerations in sudden unexpected death in epilepsy.

Summary: 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.