Forensic antiepileptic drug levels in autopsy cases of epilepsy.

A 1-year retrospective coroner-based forensic examination of causes of death among persons with a history of epilepsy was conducted at the Allegheny County Coroner's Office to evaluate the phenomenon of sudden unexplained/unexpected death in epilepsy (SUDEP), a diagnosis of exclusion. All cases at the Coroner's Office from January 1, 2001 through December 31, 2001, were examined. Review of a total of 1200 autopsied deaths revealed 12 cases with a past medical history of seizure disorder on the death certificate, which listed seizure disorder as the immediate cause of death or contributory cause of the death. Of the 7 men with seizure disorders, 5 were categorized as definite SUDEP and 2 as possible SUDEP. Of the 5 women with seizure disorders, 2 were listed as definite SUDEP, 2 as possible, and 1 as non-SUDEP because the convulsive seizures developed from a grade II glial tumor. Postmortem findings were evaluated for 11 cases; 1 body was decomposed. Toxicological screens were carried out on blood, bile, urine, and eye fluid for all 12. Antiepileptic drug (AED) levels detected in postmortem toxicological analysis were examined. AED levels were determined in 7 cases. Four of 7 had subtherapeutic AED levels, 2 had therapeutic levels, and only 1 victim of SUDEP had levels above the therapeutic range. Five cases had no detectable AED levels. AED levels at autopsy were either absent or subtherapeutic in 9 of 10 SUDEP cases, findings consistent with the likelihood of poor AED compliance. Subtherapeutic levels of AEDs may be a risk factor for SUDEP that could contribute to increased interictal and/or ictal epileptiform activity with associated autonomic dysfunction leading to disturbance of heart rate, heart rhythm, and/or blood pressure.

New perspectives on community-acquired pneumonia in 388 406 patients. Results from a nationwide mandatory performance measurement programme in healthcare quality.

BACKGROUND: The database of the German programme for quality in healthcare including data of every hospitalised patient with community-acquired pneumonia (CAP) during a 2-year period (n = 388 406 patients in 2005 and 2006) was analysed. METHODS: End points of the analysis were: (1) incidence; (2) outcome; (3) performance of the CRB-65 (C, mental confusion; R, respiratory rate >or=30/min; B, systolic blood pressure <90 mm Hg or diastolic blood pressure or=65 years) score in predicting death; and (4) lack of ventilatory support as a possible indicator of treatment restrictions. The CRB-65 score was calculated, resulting in three risk classes (RCs). RESULTS: The incidence of hospitalised CAP was 2.75 and 2.96 per 1000 inhabitants/year in 2005 and 2006, respectively, higher for males (3.21 vs 2.52), and strongly age related, with an incidence of 7.65 per 1000 inhabitants/year in patients aged >or=60 years over 2 years. Mortality (13.72% and 14.44%) was higher than reported in previous studies. The CRB-65 RCs accurately predicted death in a three-class pattern (mortality 2.40% in CRB-65 RC 1, 13.43% in CRB-65 RC 2 and 34.39% in CRB-65 RC 3). The first days after admission were consistently associated with the highest risk of death throughout all risk classes. Only a minority of patients who died had received mechanical ventilation during hospitalisation (15.74%). CONCLUSIONS: Hospitalised CAP basically is a condition of the elderly associated with a higher mortality than previously reported. It bears a considerable risk of early mortality, even in low risk patients. CRB-65 is a simple and powerful tool for the assessment of CAP severity. Hospitalised CAP is a frequent terminal event in chronic debilitated patients, and a limitation of treatment escalation is frequently applied.

A new goldfish model to evaluate pharmacokinetic and pharmacodynamic effects of drugs used for motion sickness in different gravity loads.

This paper proposes a new goldfish model to predict pharmacodynamic/pharmacokinetic effects of drugs used to treat motion sickness administered in differing gravity loads. The assumption of these experiments is that the vestibular system is dominant in producing motion sickness and that the visual system is secondary or of small import in the production of motion sickness. Studies will evaluate the parameter of gravity and the contribution of vision to the role of the neurovestibular system in the initiation of motion sickness with and without pharmacologic agents. Promethazine will be studied first. A comparison of data obtained in different groups of goldfish will be done (normal vs. acutely and chronically bilaterally blinded vs. sham operated). Some fish will be bilaterally blinded 10 months prior to initiation of the experiment (designated the chronically bilaterally blinded group of goldfish) to evaluate the neuroplasticity of the nervous system and the associated return of neurovestibular function. Data will be obtained under differing gravity loads with and without a pharmacological agent for motion sickness. Experiments will differentiate pharmacological effects on vision vs. neurovestibular input to motion sickness. Comparison of data obtained in the normal fish and in acutely and chronically bilaterally blinded fish with those obtained in fish with intact and denervated otoliths will differentiate if the visual or neurovestibular system is dominant in response to altered gravity and/or drugs. Experiments will contribute to validation of the goldfish as a model for humans since plasticity of the central nervous system allows astronauts to adapt to the altered visual stimulus conditions of 0-g. Space motion sickness may occur until such an adaptation is achieved.

Treatment of chronic plaque-stage psoriasis and psoriatic arthritis with mycophenolate mofetil.

Mycophenolate mofetil (MMF), a widely used immunosuppressant in organ transplantation, is a recent addition to the therapeutic armamentarium of autoimmune and inflammatory skin disorders in dermatology. We describe 5 patients with moderate to severe chronic plaque psoriasis and 6 patients with psoriatic arthritis that was refractory to conventional systemic and/or topical antipsoriatic treatment who were treated with MMF monotherapy (2 g/d) in a 10-week study. Although MMF was tolerated well in all patients, only patients with moderate psoriasis and psoriatic arthritis improved with therapy, whereas patients with severe psoriasis did not respond to MMF. Although MMF seems to be effective and safe for blistering autoimmune diseases and pyoderma gangrenosum, our data do not allow optimistic statements on the use of MMF in severe plaque-stage psoriasis. However, MMF may develop into an interesting therapeutic alternative for patients with psoriatic arthritis.

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.

Clinical pharmacology of antiepileptic drug use: "clinical pearls about the perils of patty".

This Clinical Pharmacology Problem Solving (CPPS) Unit is for use with fourth- or fifth-year pharmacy students and third- or fourth-year medical students during conferences held when they are taking either a rotation in Neurology or Clinical Pharmacology. It may also be used for house staff teaching of residents in Neurology, Pediatrics, Internal Medicine, and Family Practice and fellows in Clinical Pharmacology. This material was prepared for a Teaching Clinic in Clinical Pharmacology taught by Claire M. Lathers, PhD, FCP, Hugh J. Burford, PhD, FCP, and Cedric M. Smith, MD, FCP, and sponsored by the American College of Clinical Pharmacology, September 19-20, 1992, Washington, DC. This workbook includes: (1) an introduction to the Clinical Pharmacology Problem Solving (CPPS) Unit; (2) the learning objectives of the clinical simulation; (3) a pretest; (4) four clinical episodes occurring over many years in the life of a patient; (5) answers to the pretest; (6) a posttest; (7) answers to the posttest.

Experience-based teaching of therapeutics and clinical pharmacology of antiepileptic drugs. Sudden unexplained death in epilepsy: do antiepileptic drugs have a role?

The contents of this paper have been written to be used in a teaching program specifically designed for medical postgraduate education of resident physicians and fellows in training interested in the clinical pharmacology of antiepileptic drugs and their role in the treatment of epilepsy and/or in the prevention of sudden unexpected death associated with this disease. With some modifications, such as a specific lecture to provide an overview of the numerous concepts presented in the text, the article could be used when teaching fourth-year medical students. The format of the paper is a combination of didactic review and eight case reports in a self-learning format. A quiz for self-assessment is included at the end of the article (see Appendix). This material was covered in part in the 1992 Board Review Course for Clinical Pharmacology sponsored by the American College of Clinical Pharmacology. The format or setting of instruction for this material could include small learning groups composed of 10 to 15 students. When used in combination with other topics prepared in similar formats, this could become a take home course for those preparing to take the Boards in Clinical Pharmacology. Each instructor could select specific publications from the reference list for assigned readings depending upon the material emphasized by the instructor. The questions included at the end of the text could be used as either a closed or an open book quiz to assess student learning.

The spectrum of syncope.

Syncope is a loss of consciousness and postural tone. Although arising suddenly from prolonged recumbency or returning from weightlessness to Earth's gravity can result in syncope from orthostatic or vasovagal effects, there are many other possible causes. These causes can be divided into several groups. Causes listed in the cardiovascular category, especially cardiac causes, are more likely to occur in the elderly; noncardiac causes are more common in the younger population. The cases described herein illustrate the often unexpected mechanisms of syncope in otherwise healthy individuals. Two of the cases emphasize the usefulness of prolonged combined EEG/EKG monitoring. The categories of loss of consciousness experienced by air crew members are reviewed. The most important screening tool in identifying the mechanism(s) of syncope is a detailed history emphasizing a search for underlying disease, the specific associated circumstances, and pre- and post-event symptoms. The type of diagnostic studies, i.e., cardiac or neurologic, undertaken should be based on the historical data. Seizures must be considered as a possible mechanism of otherwise unexplained loss of consciousness in nonelderly persons, including air crew members.

Reflex sympathetic dystrophy associated with antiepileptic drugs.

Reflex sympathetic dystrophy syndrome (RSDS) complicating antiepileptic drug (AED) therapy is not well acknowledged in the neurologic literature. We report 4 patients with reflex sympathetic dystrophy that occurred while they were receiving AEDs. All patients had shoulder and hand involvement, which in 2 was bilateral, and 1 had ipsilateral foot involvement. Two patients did not respond to a change in AEDs, but all improved with a course of prednisone. One patient with phenobarbital (PB)-associated RSDS relapsed on inadvertent rechallenge with secobarbital. A review of the literature showed that several other fibrosing disorders are associated with AED administration, including Dupuytren's contractures, frozen shoulder, plantar and hand nodules, and Peyronie's disease. RSD associated with AEDs is important to recognize because it may result in permanent disability if treatment is delayed.

Evaluation of the mechanisms of antiepileptic drug-related chronic leukopenia.

Antiepileptic drug (AED)-related chronic leukopenia [white blood cell (WBC) count < 4,000/microliters] is a dilemma, especially when the AED is effective in controlling seizures. We evaluated the possible mechanisms of leukopenia in 7 patients. Mean WBC count was 3,000/microliters with a mean of 42% polymorphonuclear leukocytes (PMN). The AEDs were carbamazepine (CBZ) alone in 1 patient or CBZ combined with phenytoin (PHT), primidone (PRM), phenobarbital (PB) and/or valproate (VPA) in 5 patients; one patient was receiving PHT only. Bone marrow (BM) aspirates and PMN antibody studies using chemiluminescence were normal. Two liver-spleen scans showed mild relative splenomegaly. After exercise, WBC count (n = 7) increased by 54% (SEM 12%), while the WBC counts in controls (n = 5) increased by 52 +/- 16%. Antinuclear antibodies (Hep-2) were absent in 6 patients and positive (1:160) in 1. PMN adhesion to nylon wool was decreased (54 +/- 10% in patients vs. 80 +/- 5% in controls: n = 13, p < 0.005). Our data, particularly the appropriate WBC response to the stress of exercise, and normal BM examinations suggest that continuation of AED therapy when leukopenia is stable and the percentage of PMN is normal is probably safe. Caution should be used if the absolute PMN count is consistently < 1,000/microliters. BM examinations need not be performed routinely for every patient with neutropenia due to AEDs, especially if the leukopenia fluctuates in the range of 2,000-4,000 cells/microliters.

The effect of phenobarbital on autonomic function and epileptogenic activity induced by the hippocampal injection of penicillin in cats.

This study addressed whether penicillin-induced epileptiform discharges in the right hippocampus produced associated autonomic dysfunction. The study also examined the effect of phenobarbital on the heart rate and blood pressure changes that were induced by the epileptiform discharges. The delay in onset of epileptiform activity at the site of injection ranged from 1 second to 16 minutes, and consisted of interictal discharges or ictal discharges. With the onset of epileptiform activity, blood pressure and heart rate increased significantly from control (P < .05). Electrocardiogram alterations included: P-R interval changes; increased P-wave amplitude; QRS complex changes; T-wave inversion; and ST elevation. Phenobarbital 20 mg/kg intravenously suppressed the epileptogenic activity and depressed the blood pressure and heart rate below control (P < .05). In an additional series of experiments, penicillin G injected into the right hippocampus in five cats produced epileptiform activity and increased the blood pressure and the heart rate significantly from the control (P < .05). Phenobarbital (20 mg/kg, intravenously, and 40 mg/kg, intravenously) also prevented the penicillin-induced epileptiform activity. Phenobarbital (40 mg/kg, intravenously) reversed the effect of penicillin on the blood pressure and heart rate, to levels significantly below that of control (P < .05). Phenobarbital diminished both epileptiform activity and autonomic dysfunction. The autonomic dysfunction related to epileptiform activity induced by focal hippocampal administration of penicillin was similar to that induced by the intravenous administration of pentylenetetrazol.

Combined ambulatory electroencephalographic and electrocardiographic recordings for evaluation of syncope.

Evaluation of patients with syncope often includes a battery of noninvasive tests. In this study, 45 patients (26 with suspected neurologic and 19 with suspected cardiac syncope) were evaluated with simultaneous 24-hour electroencephalographic (EEG) and 2-channel electrocardiographic (ECG) recordings. Isolated cardiac rhythm abnormalities were noted in 21 patients, but none of these was symptomatic and no definitive arrhythmias occurred. Isolated EEG abnormalities were noted in 11 patients, 5 of whom had EEG abnormalities consistent with seizure disorders. Simultaneous EEG and ECG abnormalities were seen in 4 patients. In 2 cases, a previously unsuspected etiology for syncope was found: seizures in 1 patient with heart disease, and sinus pauses in another thought to have a seizure disorder. Thus, combined ambulatory EEG/ECG monitoring may prove useful in the evaluation of some patients with syncope.

Paroxysmal autonomic dysfunction, epileptogenic activity and sudden death.

Transient abnormalities of autonomic nervous system function are observed during almost every generalized tonic-clonic seizure and include disruptions in blood pressure, cardiac arrhythmias and apnea. An increasing body of literature indicates that epileptogenic discharges, even without accompanying clinical seizure activity, can produce a spectrum of autonomic abnormalities. Marked changes in blood pressure and cardiac rhythm occur in patients paralyzed with neuromuscular blocking agents and subjected to electrical shock or intravenous pentylenetetrazol. Similar changes are observed in patients with focal temporal lobe discharges. There is also experimental evidence suggesting that in addition to the well known effects of generalized seizure discharges, interictal discharges can produce effects upon the cardiovascular system. Neurogenic pulmonary edema may be another autonomic dysfunction associated with seizures. The phenomenon of unexplained sudden death in persons with epilepsy, which accounts for up to 15% of mortality in this group, may be a result of some unexplained irreversible disruption of autonomic homeostasis in the face of all these forces of electrical disorganization. Paradoxically, some persons manifest cardiovascular autonomic dysfunction with consequent seizures which are phenomenologically very similar to those of cerebral origin. It is important to consider performing Holter monitoring in patients with epilepsy of unknown cause and 24 h ambulatory electroencephalograms in patients with unexplained cardiac arrhythmias.

Synchronization of cardiac autonomic neural discharge with epileptogenic activity: the lockstep phenomenon.

Autonomic dysfunction has been implicated in the sudden, unexplained deaths which account for 5-17% of mortality in persons with epilepsy. This study was designed to determine if epileptogenic activity is associated with changes in the pattern of autonomic cardiac neural discharge and the development of arrhythmias. Nine cats, anesthetized with alpha-chloralose, received pentylenetetrazol (PTZ) 10, 20, 50, 100, 200 and 2000 mg/kg, i.v. at 10 min intervals. Cardiac postganglionic sympathetic and vagal nerve discharges were correlated with the interictal spikes, brief ictal discharges (bilateral polyspikes less than 10 sec duration), and prolonged ictal discharges (polyspikes lasting greater than 10 sec). Cardiac sympathetic and vagal neural discharges were intermittently synchronized 1:1 with all 3 types of epileptogenic discharge, i.e., the lockstep phenomenon (LSP); at other times the relationship was almost 1:1 LSP was not present during control and did not always persist for the entire interval after each PTZ dose. Five of 8 cats showed LSP in the cardiac sympathetic neural discharge associated with interictal spikes induced by 10 mg/kg PTZ; 3 others exhibited LSP with interictal spikes seen subsequent to ictal discharges. The incidence of LSP was less often associated with cardiac vagal neural discharge (2 of 7 cats). Premature ventricular contractions were sometimes associated with LSP. Abnormal cardiac sympathetic and vagal neural discharge and cardiac arrhythmias were thus associated with subconvulsant (interictal) activity. Therefore, the LSP may be a factor in the mechanism of unexplained death in persons with epilepsy who exhibited no overt seizure activity at the time of demise.

Review of autonomic dysfunction, cardiac arrhythmias, and epileptogenic activity.

Similarities in autonomic dysfunction associated with arrhythmias and death in animal models for digitalis toxicity, myocardial infarction, psychotropic toxicity, and epileptogenic activity are reviewed. When intravenous (IV) pentylenetetrazol was given to anesthetized cats, autonomic dysfunction was associated with both interictal and ictal epileptogenic activity. The autonomic dysfunction was manifested by the fact that autonomic cardiac nerves did not always respond in a predictable manner to changes in blood pressure, the development of a marked increase in variability in mean autonomic cardiac nerve discharge, and the appearance of a very large increase in the variability of the discharge rate of parasympathetic nerves first and then secondly in sympathetic discharge. The altered autonomic cardiac nerve discharge was associated with interictal epileptogenic activity and arrhythmia, which may contribute to sudden unexplained death in patients with epilepsy. Since phenobarbital (20 mg/kg, IV 60 min prior to pentylenetetrazol) exhibited anticonvulsant, but not antiarrhythmic and neural depressant activity, phenobarbital does not appear to be the ideal agent to prevent the autonomic dysfunction associated with epileptogenic activity in this animal model.

Ictal catatonia as a manifestation of nonconvulsive status epilepticus.

Three patients with EEG documented ictal catatonia, a nonconvulsive status epilepticus, who responded dramatically to intravenous phenytoin are described. The EEG showed continuous bilateral pseudoperiodic sharp waves and spike discharges in one patient, spike and wave complexes were seen prominently in the right fronto-central region in another, and the EEG of the third patient showed periodic lateralising epileptiform discharges during the catatonic state. We postulate that such catatonia was due to involvement of the limbic system by seizure activity.

Effect of phenobarbital pretreatment on cardiac neural discharge and pentylenetetrazol-induced epileptogenic activity in the cat.

The effect of phenobarbital on autonomic function associated with ictal discharges and interictal spikes (IS) was examined. Phenobarbital (20 mg/kg, i.v.) was infused over 10 min; 1 h later, pentylenetetrazol (PTZ) 10, 20, 50, 100, 200, and 2,000 mg/kg was given intravenously at 10-min intervals. 10 mg/kg PTZ produced IS in only 3 of 9 phenobarbital-pretreated cats; when used alone, 10 mg/kg of PTZ produced IS in 8 of 9 cats. Ictal discharges first appeared at 20 mg/kg PTZ in 6 of 9 phenobarbital-pretreated cats; all 9 cats receiving only PTZ exhibited ictal discharges after 20 mg/kg. Phenobarbital pretreatment depressed heart rate, blood pressure and postganglionic cardiac sympathetic neural discharge. Maximal ictal discharges in the cats pretreated with phenobarbital occurred with 100 mg/kg PTZ. This discharge was associated with a 10 mm Hg increase in blood pressure and a slight decrease in heart rate, followed by a subsequent return to baseline. The concurrent sympathetic neural discharge increased. When maximal ictal discharges occurred in the cats receiving PTZ alone, blood pressure, heart rate, and sympathetic neural discharge increased significantly. Cardiac vagal neural discharge was not altered after PTZ even in phenobarbital-pretreated cats. Although phenobarbital suppressed PTZ-induced epileptogenic activity and the associated changes in blood pressure and heart rate, a X2 test indicated no significant difference in the incidence of arrhythmias between the two groups. Since phenobarbital did not prevent the changes in cardiac neural discharge and the arrhythmias associated with epileptogenic activity, its effectiveness in decreasing autonomic dysfunction is questionable.

Neural mechanisms in cardiac arrhythmias associated with epileptogenic activity: the effect of phenobarbital in the cat.

Sudden unexplained death accounts for 5-17% of mortality in epileptic persons; autonomic dysfunction is thought to be a contributing factor. This paper describes the effect of phenobarbital (PB) pretreatment (20 mg/kg, i.v.) one hour prior to pentylenetetrazol (PTZ) 10, 20, 50, 100, 200, and 2000 mg/kg, i.v. given at ten minute intervals on autonomic parameters in the cat. PB depressed heart rate, blood pressure, and postganglionic cardiac sympathetic neural discharge, but did not significantly alter vagal discharge. PB shifted the peak duration of interictal activity from a lower to a higher dose of PTZ without affecting the average duration across doses. PB also significantly diminished the increases in heart rate and blood pressure induced by PTZ but altered neither the occurrence of arrhythmias nor the changes in cardiac autonomic neural discharge. Thus, PB appears to prevent only some forms of autonomic dysfunction associated with epileptogenic activity in this model.