A case of paracetamol retard poisoning with fatal outcome

A case of fatal paracetamol (acetaminophen) poisoning in a 26-year-old woman who developed liver necrosis is described. The patient reported having ingested 11 g of a slow-release paracetamol preparation and a certain amount of alcohol and benzodiazepine. An unknown dose of phenobarbital (phenemal) had been ingested 24 hours previously, leading to a serum phenobarbital concentration of 0.195 mmol/l at the time of admission. The patient was initially treated with N-acetylcysteine intravenously. This treatment was discontinued after five hours due to a serum paracetamol concentration of 0.49 mmol/l, well below the "treatment line" paracetamol concentration of 0.8 mmol/l six hours after ingestion. Possible aggravating factors are discussed, including sustained high serum concentration of paracetamol due to the slow-release preparation and enzyme induction caused from concomitant phenobarbital and alcohol intake, as well as benzodiazepines displacing paracetamol from liver enzymes. These factors make serum paracetamol concentrations undependable; the importance of continuing N-acetylcysteine treatment in spite of "safe" serum concentrations in the above cases is stressed.     

Paracetamol poisoning

Administration of paracetamol (acetaminophen) has analgetic and antipyretic effect. After trauma paracetamol has an anti-inflammatory activity. It was presumed that paracetamol in therapeutic doses had fewer and more acceptable side-effects than other analgetic drugs such as acetylsalicylic acid and NSAID-drugs. However, in toxic concentrations, paracetamol is more life-threatening. The toxic effects of paracetamol most often occur in the liver and kidneys. Phosphate and lactate turn-over can also be impaired. Paracetamol poisoning can induce temporary liver disfunction or even irreversible liver failure with liver transplantation as the only therapeutic possibility. Chronic alcoholics are especially at risk, as liver damage may occur following paracetamol even in recommended doses. When intoxication with paracetamol is presumed, administration of N-acetylcysteine is vital. N-acetylcysteine therapy should be initiated not later than 15 hours after paracetamol intake. Moreover, the antitoxic effect has been observed even when N-acetylcysteine therapy is initiated 24-36 hours after presumed paracetamol intake. Measures of preventing further absorption of paracetamol from the gastrointestinal tract should be taken. Activated charcoal should be given if less than two hours have passed since paracetamol intake. Between two and four hours following paracetamol intake gastric lavage should be performed. During the last 10 years the incidence of paracetamol self-poisoning has increased, but death following paracetamol poisoning is relatively constant at around nine per year in Denmark. It is suggested that the incidence of serious cases of paracetamol poisoning could be reduced by simple measures. Special attention should be paid to the risk-group of chronic alcoholics.     

Relative bioavailability of paracetamol in suppositories preparations in comparison to tablets

Relative Bioavailability of Paracetamol as Suppositories Compared to Tablets. The relative bioavailability of paracetamol (CAS 103-90-2) in ben-u-ron 500 mg and ben-u-ron 1000 mg suppositories (test formulations) was compared with that of Benuron tablets 500 mg (reference product) in an open, intraindividual, 3-period-changeover-study in 18 healthy subjects. Plasma concentrations of paracetamol were determined using a specific and sensitive HPLC method with UV detection. For the assessment of bioavailability AUC, Cmax, tmax and HVD were used as pharmacokinetic characteristics. Bioequivalence of the rectal formulations was tested by calculating 90% confidence intervals using the Two-one-sided-t-tests-procedure and log-transformed data of AUC and Cmax. For AUC the confidence intervals were required to be in the 80 and 125% range, for Cmax between 70 and 143% (inclusion rule). Data from 17 subjects could be evaluated. Bioavailability of paracetamol was 89 and 90% for the 500 and 1000 mg suppositories, respectively compared with that of the 500 mg reference tablets. Mean maximum paracetamol plasma concentrations (Cmax) were 3.55 and 6.02 or 7.16 mg/l after administration of the 500 and 1000 mg suppositories or the 500 mg tablets, respectively. These maximum concentrations were achieved 2.0, 2.7 and 0.6 h (tmax) after administration of the respective preparations. The corresponding HVD values were 4.3, 5.2 and 2.0 h, respectively. After dose adjustment of the results for the 1000 mg suppositories relative bioavailabilities of paracetamol from both rectal formulations exceeded 80% of that from the tablets.(ABSTRACT TRUNCATED AT 250 WORDS)     

Henneguya malabarica sp. nov. (Myxozoa, Myxobolidae) in the Amazonian fish Hoplias malabaricus

The mainstay of treatment for acetaminophen-induced hepatotoxicity, produced by the accumulation of the toxic metabolite N-acetylbenzoquinoneimine, is an enteral 18-dose course of N-acetylcysteine (NAC). However, absence of characteristic symptomatology is a frequent reason for premature cessation of NAC and early discharge of the toxic acetaminophen poisoned patient. We report a series of confirmed acetaminophen poisonings who were discharged early with NAC and instructions to self-administer. All cases of acute acetaminophen poisoning without concomitant drugs, reported to a certified Regional Poison Information Center for a 3-mo period of time, were reviewed. Inclusion criteria included patients who were discharged with orders to complete the course of NAC outside of a hospital, despite toxic serum acetaminophen concentrations. Data parameters evaluated included age, amount taken, symptoms, laboratory results, treatment, and medical outcome. 131 cases of confirmed toxic acetaminophen poisoning yielded 6 patients who received 4 to 6 doses of NAC during hospitalization, but were discharged to home with the remaining 11-13 doses. Patients' ages ranged from 16-28 y (mean 20.0 y). Serum acetaminophen concentrations measured at 4 h post-ingestion ranged from 171-198 mcg/ml (mean 182 mcg/ml). Follow-up by the certified Regional Poison Information Center at 1-3 w post-discharge determined dosing compliance to be 83%. All 6 patients remained asymptomatic with normal liver function testing. Since health care reform encourages practitioners to reconsider established approaches to the delivery of health care, perhaps home delivery of NAC would not only be clinically preferred to premature cessation of the antidote, but also offer cost savings. Self-administration of NAC in the home setting may be representative of a new era in America's health care delivery system.     

Adenosine triphosphate (ATP) levels in paracetamol-induced cell injury in the rat in vivo and in vitro

We have investigated the relationship between ATP levels and the onset and progression of cell injury induced by paracetamol overdose both in vivo and in vitro. Liver slices obtained from phenobarbitone-induced and non-induced rats were used in a model in vitro system. Slices were exposed to paracetamol (2-10 mM), for 120 min and then incubated without paracetamol for a further 240 min. ATP levels are reduced upon exposure to paracetamol in liver slices from both phenobarbitone-induced and non-induced rats. Cell injury, as quantified by measuring leakage of lactate dehydrogenase (LDH) and potassium (K+), does not become apparent until 240 min, some 120 min after exposure to paracetamol had ended. This irreversible cell injury is not observed in liver slices from non-induced rats. For in vivo studies rats were phenobarbitone-induced and received i.p. injections of 800 mg/kg body weight paracetamol. Hepatic ATP levels were measured and are found to drop sharply by 3 h post-injection. Development of irreversible hepatic cell injury was assessed by measuring serum enzyme (ALT) activity. ALT levels do not rise until 12 h have elapsed. Paracetamol in overdose gives rise to ATP depletion in liver cells, that is early, independent of paracetamol metabolism and probably spread throughout the lobule. In contrast cell injury is found late and only in our phenobarbitone-induced rats. No cell injury is observed in liver slices from non-induced rats. This suggests that while the level of ATP depletion which is observed may be a necessary part of cell injury by paracetamol, it is not a sufficient cause.     

Haemoperfusion treatment in pigs experimentally intoxicated by paraquat

1. Because of their similarity in renal morphology and physiology to humans, domestic pigs (gilts, 70 kg) were bolus treated by intramuscular injection of 74, 17, and 6 mg kg-1 and by oral loading (70 mg kg-1 n = 4) of paraquat. The concentration peak of plasma paraquat was reached at 1.5 - 2.5 h. Renal clearance of paraquat rose to its maximum at 5-6 h after intoxication and then sharply decreased indicating renal failure. All the intoxicated pigs died. 2. An additional 10 gilts were also orally treated with 70 mg kg-1 paraquat but received haemoperfusion from 2 h post intoxication for either 2 h (n = 6) or 6 h (n = 4). The 2 h haemoperfusion resulted in a 5.1% toxin removal but failed to save any of six poisoned pigs. Prolonged 6 h haemoperfusion successfully rescued three out of four intoxicated pigs. 3. The plasma paraquat concentrations of the three surviving pigs were above 2 mg l-1 at 10 h post intoxication. This level is not only similar to those of untreated animals that died later, but also well beyond the suggested limit for survival of poisoned patients. 4. Pigs proved to be a good animal model for studies in paraquat poisoning and/or haemoperfusion. It is also suggested that early haemoperfusion is effective in treating paraquat poisoning even in very severe cases due to its possible detoxicating effect in addition to toxin removal.     

The influence of epidural administration of fentanyl infusion on gastric emptying in labour

The effect of epidural infusions containing fentanyl on maternal gastric emptying in labour was examined using the rate of paracetamol absorption. Women were randomly allocated to receive one of two epidural infusions, bupivacaine 0.125% alone or bupivacaine 0.0625% with fentanyl 2.5 micrograms.ml-1 at a rate of 10-12 ml.h-1. Paracetamol 1.5 g was given orally to women after either 30 ml of the infusion solution had been given (mean time 2.5 h, study A) or 40-50 ml (mean time 4.5 h. study B). Six venous blood samples were taken over the next 90 min for measurement of plasma paracetamol concentration. There were no significant differences in maximum plasma paracetamol concentration, time to maximum paracetamol concentration and area under the concentration-time curve between the two groups for study A. In study B the time to maximum plasma paracetamol concentration was significantly delayed in women receiving > 100 micrograms fentanyl compared with controls (p < 0.05). We conclude that the dose of fentanyl that may delay gastric emptying when given by epidural infusion is greater than 100 micrograms.     

Five-year administration of fenretinide: pharmacokinetics and effects on plasma retinol concentrations

PURPOSE: Monitoring of fenretinide (4HPR) levels, kinetics, and effects on retinal was performed in patients who participated in a phase I trial and who continued to be treated for 5 years as phase III trial patients. Accumulation of 4HPR in the breast was also assessed. PATIENTS AND METHODS: Plasma concentrations of 4HPR, of its main metabolite N-(4-methoxyphenyl)retinamide (4MPR), and of retinol were assayed by high-performance liquid chromatography (HPLC) in breast cancer patients treated orally with 4HPR 200 mg/d for 5 years with a 3-day drug interruption at the end of each month. RESULTS: 4HPR, at 200 mg/d, resulted in average 4HPR plasma levels of approximately 1 mumol/L, which remained steady and caused steady retinol level reduction; 4MPR levels, similar to those of 4HPR, slightly but significantly increased during the first 35 months, but at 5 years they were similar to those at 5 months. During daily treatment, baseline retinol concentrations were reduced by 71%; after a 3-day drug interruption, all patients recovered and the mean reduction was 38%. After discontinuation of 5-year treatment, 4HPR and 4MPR half-lives (t1/2 beta) were 27 and 54 hours, respectively, similar to those reported after 28 daily treatments. After 6 and 12 months, the concentrations of 4HPR were at the limit of detectability (0.01 mumol/L), whereas those of 4MPR were five times higher. Baseline retinol concentrations were already recovered after 1 month. Accumulation of this retinoid in the breast was evidenced by concentrations of 4HPR and 4MPR in nipple discharge and in breast biopsies that were 10 and 20 times higher, respectively, than those found in plasma. CONCLUSION: 4HPR, at 200 mg/d for 5 years, resulted in constant drug plasma levels and constant retinol level reduction. After treatment interruption, 4HPR plasma concentrations decreased at the limit of detectability at 6 months and baseline retinol plasma concentrations were recovered after 1 month.     

Retrospective multicenter study of the efficacy of interferon alpha in chronic hepatitis C

BACKGROUND: Until very recently, interferon (INF) in Spain was authorized in chronic hepatitis C (C-HCV) at a dosis of 3 megaunits (mu) for 6 months. Nonetheless, the rate of maintained complete response is lower than that obtained with more prolonged treatments. The first aim of this study was to retrospectively know the effectiveness of alpha INF in patients treated for 6 or 12 months with a dosis of 3 or 5-6 MU. The second was to analyze the characteristics of the patients who achieved a maintained complete response. PATIENTS AND METHODS: Patients with C-HCV treated in 9 hospitals in Andalucía, Spain who fulfilled the following conditions were retrospectively analyzed: liver biopsy prior to treatment, positive test for anti HCV and a follow up of at least 6 months after alpha INF treatment. A total of 344 patients were studied: 267 treated with alpha INF-2b, 51 with alpha INF-2a and 26 with lymphoblastoid INF. One hundred ninety-five patients were treated for 6 months and 149 for 12 months. RESULTS: Seventy-seven (22%) of the patients presented maintained complete response, 170 (50%) did not respond and 97 (28%) relapsed. On comparing the three types of interferon used over 6 months, no significant differences were observed. Neither were differences found on comparing the dosis of 3 mu versus 5 or 6 mu. On analyzing the treatments of 6 and 12 months, the following was observed, respectively: maintained complete response 15% vs 32%, relapse 29% vs 30% and non responders 57% vs 38% (p < 0.001). Multivariate analysis demonstrated that the patients who responded the best to INF were those who presented the following characteristics: female sex, age under 40 years last, history of transfusion or IVDA, basal GPT level higher than 145 IU/I, GGT less than 55 IU/I, less evolved histologic lesions and duration of treatment over 12 months. CONCLUSIONS: Of the different treatments analyzed with alpha interferon in chronic hepatitis C, the best was found to be that with 3 mu during 12 months.     

Treatment of mild hyperhomocysteinemia in vascular disease patients

Mild hyperhomocysteinemia is recognized as a risk factor for premature arteriosclerotic disease. A few vitamins and other substances have been reported to reduce blood homocysteine levels, but normalization of elevated blood homocysteine concentrations with any of these substances has not been reported. Therefore, we screened 421 patients suffering from premature peripheral or cerebral occlusive arterial disease by oral methionine loading tests for the presence of mild hyperhomocysteinemia. Thirty-three percent of patients with peripheral and 20% of patients with cerebral occlusive arterial disease were identified with mild hyperhomocysteinemia (14% of the men, 34% of the premenopausal women, and 26% of the postmenopausal women). Mildly hyperhomocysteinemic patients were administered vitamin B6 250 mg daily. After 6 weeks methionine loading tests were again assessed to evaluate the effect of treatment. Patients with nonnormalized homocysteine concentrations were further treated with vitamin B6 250 mg daily and/or folic acid 5 mg daily and/or betaine 6 g daily, solely or in any combination. Vitamin B6 treatment normalized the afterload homocysteine concentration in 56% of the treated patients (71% of the men, 45% of the premenopausal women, and 88% of the postmenopausal women). Further treatment resulted in a normalization of homocysteine levels in 95% of the remaining cases. Thus, mild hyperhomocysteinemia, which is frequently encountered in patients with premature arteriosclerotic disease, can be reduced to normal in virtually all cases by safe and simple treatment with vitamin B6, folic acid, and betaine, each of which is involved in methionine metabolism.     

Engaging the unmotivated in treatment for alcohol problems: A comparison of three strategies for intervention through family members.

In a randomized clinical trial, 130 concerned significant others (CSOs) were offered 1 of 3 different counseling approaches: (a) an Al-Anon facilitation therapy designed to encourage involvement in the 12-step program, (b) a Johnson Institute intervention to prepare for a confrontational family meeting, or (c) a community reinforcement and family training (CRAFT) approach teaching behavior change skills to use at home. All were manual-guided, with 12 hr of contact. Follow-up interviews continued for 12 months, with 94% completed. The CRAFT approach was more effective in engaging initially unmotivated problem drinkers in treatment (64%) as compared with the more commonly practiced Al-Anon (13%) and Johnson interventions (30%). Two previously reported aspects of the Johnson intervention were replicated: that most CSOs decide not to go through with the family confrontation (70% in this study) and that among those who do, most (75%) succeed in getting the drinker into treatment. All approaches were associated with similar improvement in CSO functioning and relationship quality. Overall treatment engagement rates were higher for CSOs who were parents than for spouses. On average, treatment engagement occurred after 4 to 6 sessions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Serum iron concentrations and symptoms of acute iron poisoning in children

STUDY OBJECTIVE: To determine whether serum iron concentrations correlate with the development of symptoms of iron poisoning in children. DESIGN: A retrospective study of medical records from January 1976 through June 1992. SETTING: A tertiary care children's medical center. PATIENTS: Criteria for patient selection included an acute ingestion of iron-containing drugs, measurement of serum iron prior to deferoxamine administration, and a serum iron concentration (obtained within 2-9 hours of exposure) that was greater than 150 micrograms/dl (27 mumol/L). Of the 128 children who were hospitalized for acute iron poisoning, 92 patients (mean age 2.3 +/- 2.2 years) met the selection criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The mean (+/-SD) serum iron concentrations (microgram/dl) of patients who exhibited cardiovascular instability (725 +/- 555, n = 6; p < 0.001) differed from those categorized with central nervous system changes (373 +/- 77, n = 30), gastrointestinal symptoms (334 +/- 83, n = 44), and no symptoms (368 +/- 102, n = 12). Serum iron concentrations in patients with cardiovascular instability ranged from 205-500 micrograms/dl (37-269 mumol/L), whereas those with no symptoms ranged from 170-513 micrograms/dl (30 to 92 mumol/L) demonstrating considerable overlap of ranges. CONCLUSIONS: Serum iron concentrations do not necessarily relate to acute toxicity, and further study is needed to demonstrate the value of serum iron concentrations and to identify alternative strategies in the emergency assessment of the acutely poisoned child.     

Delayed neuropsychologic sequelae after carbon monoxide poisoning: prevention by treatment with hyperbaric oxygen

STUDY OBJECTIVE: Carbon monoxide (CO) poisoning is a major clinical problem. The risk of morbidity and the most effective treatment have not been clearly established. We measured the incidence of delayed neurologic sequelae (DNS) in a group of patients acutely poisoned with CO and tested the null hypothesis that the incidence would not be affected by treatment with hyperbaric oxygen (HBO). DESIGN: We conducted a prospective, randomized study in patients with mild to moderate CO poisoning who presented within 6 hours. Patients had no history of loss of consciousness or cardiac instability. INTERVENTIONS: The incidence of DNS was compared between groups treated with ambient pressure 100% oxygen or HBO (2.8 ATA for 30 minutes followed by 2.0 ATA oxygen for 90 minutes). DNS were defined as development of new symptoms after oxygen treatment plus deterioration on one or more subtests of a standardized neuropsychologic screening battery. RESULTS: In 7 of 30 patients (23%), DNS developed after treatment with ambient-pressure oxygen, whereas no sequelae developed in 30 patients after HBO treatment (P < .05). DNS occurred 6 +/- 1 (mean +/- SE) days after poisoning and persisted 41 +/- 8 days. At follow-up 4 weeks after poisoning, patients who had been treated with ambient pressure oxygen and had not sustained DNS exhibited a worse mean score on one subtest, Trail Making, compared with the group treated with HBO and with a control group matched according to age and education level. There were no differences in scores between the control group and the hyperbaric oxygen group. CONCLUSION: DNS after CO poisoning cannot be predicted on the basis of a patient's clinical history or CO level. HBO treatment decreased the incidence of DNS after CO poisoning.     

Factors associated with improved outcome of Pseudomonas aeruginosa bacteremia in a Finnish university hospital

All 134 episodes of bacteremia caused solely by Pseudomonas aeruginosa in a university hospital in the periods 1976-1982 and 1992-1996 were reviewed retrospectively to determine the clinical manifestations, outcome and prognostic factors. The mortality for the 30-day interval after drawing the first positive blood culture was 41%, but dropped from 53% in the first period to 29% in the second period (P=0.006). Mortality was highest in patients treated with an aminoglycoside only, as against those treated with other appropriate antibiotics (55% versus 25%, P=0.001). Over the two decades studied, use of an aminoglycoside only decreased, use of paracetamol (=acetaminophen) increased, and removal of both urinary and blood vessel catheters became more common. The mortality was 18% in patients with catheter removal (46% in the other patients, P=0.017) and 27% in patients who received paracetamol around the time of drawing the first positive blood culture (50% for the other patients, P=0.010). Logistic regression analysis showed that shock, central nervous system involvement, preceding thromboembolism and rapidly fatal underlying disease were associated with a fatal outcome, whereas catheter removal, appropriate antibiotic therapy and paracetamol therapy were associated with survival. The improved prognosis of Pseudomonas aeruginosa bacteremia over the two decades is thus due mainly to three changes in management of the infection: the more frequent use of new anti-pseudomonal beta-lactams and ciprofloxacin instead of aminoglycosides as monotherapy; the more frequent practice of removing catheters; and the increased use of paracetamol around the time of drawing the first positive blood sample.     

Comparison of multiple immunization schedules for Haemophilus influenzae type b-conjugate and tetanus toxoid vaccines following bone marrow transplantation

Antibody concentrations to vaccine-preventable diseases decline following BMT and an optimal schedule for vaccination after transplant has not been established. We examined antibody responses to tetanus toxoid (TT) and Haemophilus influenzae type b-conjugate (HIB) vaccines of BMT patients immunized at 6, 12 and 24 months (6 month group, n = 21) and compared them to those previously reported for patients immunized at 3, 6, 12 and 24 months (3 month group, n = 74) or at 12 and 24 months (12 month group, n = 17) following transplantation. Geometric mean total anti-HIB and IgG anti-TT concentrations were significantly higher after the 12 month dose in the 3 and 6 month immunization groups compared to the group who received their first dose at 12 months. Although HIB antibody concentrations were higher in the 3 month and 6 month groups 12 to 24 months after BMT, the proportion of patients with protective levels was not significantly different from the proportion protected in the 12 month group. Following the 24 month immunizations, geometric mean antibody concentrations to HIB and TT were similar for all three immunization groups. The proportion of patients in each group with protective levels of HIB antibody after the 24 month dose was > or = 80%. A two dose schedule of HIB and TT vaccines at 12 and 24 months after BMT should afford protection.     

The novel anti-migraine compound zolmitriptan (Zomig 311C90) has no clinically significant interactions with paracetamol or metoclopramide

OBJECTIVE: This study investigated potential pharmacokinetic or pharmacodynamic interactions between the novel anti-migraine compound zolmitriptan (Zomig, formerly 311C90) and paracetamol and/or metoclopramide. METHODS: In an open-label, randomised, crossover study, 15 healthy volunteers received single oral doses of 10 mg zolmitriptan alone, 1 g paracetamol alone, 10 mg zolmitriptan + 1 g paracetamol, 10 mg zolmitriptan + 10 mg metoclopramide or 10 mg zolmitriptan + 1 g paracetamol + 10 mg metoclopramide on five separate occasions. RESULTS: Metoclopramide had no significant effects on the pharmacokinetics of zolmitriptan or the active zolmitriptan metabolite 183C91, nor did it affect interactions between zolmitriptan and paracetamol. Paracetamol marginally increased the maximum plasma concentration (Cmax) (11%) and the area under the curve (AUC) (11%) and reduced the renal clearance of zolmitriptan (9%); similar small effects were seen on 183C91. The AUC, Cmax and half-life of paracetamol were reduced by concomitant zolmitriptan (by 11%, 31% and 8%, respectively), whilst the mean residence time showed a small increase (+0.7 h). There was a trend towards a transient increase in blood pressure following all regimens containing zolmitriptan; this effect was small, was consistent between all zolmitriptan regimens as well as with previous studies, and was considered to be clinically insignificant. Zolmitriptan was well tolerated after all treatment regimens. CONCLUSION: Concomitant administration of zolmitriptan and paracetamol resulted in a slight increase in bioavailability of zolmitriptan and a reduced rate and extent of paracetamol absorption. These findings are considered to be of no clinical significance and there is no reason to avoid concomitant administration of paracetamol and/or metoclopramide with zolmitriptan.     

Video game-related seizures: a report on 10 patients and a review of the literature

OBJECTIVE: To further describe the features, postulated pathophysiology, treatment, and outcome of seizures occurring while playing or watching video games (video game-related seizures (VGRS)). DESIGN: We evaluated retrospectively 10 patients with VGRS seen by us and reviewed 25 reported cases. RESULTS: The 35 patients ranged in age from 1 to 36 years (mean: 13.2); and 26 subjects (74%) were male. Eight individuals (29%) had prior infrequent nonfebrile seizures, 4 (11%) had febrile convulsions, and 2 (6%) had a family history of epilepsy. VGRS consisted of generalized tonic-clonic seizures in 22 of 35 individuals (63%); absences in 2 (6%); simple partial seizures in 6 (19%); complex partial seizures in 4 (11%); and other manifestations in 4. Neurologic examination and computed tomographic and magnetic resonance imaging scans were normal. Electroencephalograms demonstrated generalized or focal, interictal or ictal epileptic patterns in 11 of 21 patients (52%) and photoparoxysmal responses in 17 of 32 (53%). Eleven of 15 individuals (73%) treated with video game (VG) abstinence alone, 3 of 6 who received anticonvulsants but played VGs, and 7 of 12 treated with combined VG abstinence and anticonvulsants had no further seizures. CONCLUSIONS: We postulate that a special convulsive susceptibility of selected neurons in striate, peristriate, infratemporal, and posterior parietal cortices to particular visual stimuli plays a major role in VGRS. VG abstinence is the treatment of choice of VGRS. Anticonvulsant medication is suggested only for those individuals who continue to play VGs or suffer from seizures triggered by other, unavoidable visual stimuli, or from unprovoked attacks.     

Epipodophyllotoxin-related acute myeloid leukemia: a study of 35 cases

To define better the risk of epipodophyllotoxin-related acute myeloid leukemia (AML) after extended follow-up and to assess responses to intensive salvage therapy, all patients who developed this complication after treatment for acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) in consecutive clinical trials at St Jude Children's Research Hospital from 1979 to 1994 were studied. Cases with 'lineage switch' or 'clonal selection' were excluded. Epipodophyllotoxin-related AML developed in 32 of 1140 patients treated for ALL and in three of 332 treated for NHL; it was a first adverse event in 25 and two cases, respectively. The complication was diagnosed at 12-130 months (median 34 months) after the initiation of treatment with epipodophyllotoxins; all but one of the cases occurred within 73 months, indicating that the risk is negligible after 6 years. The predominant karyotypic feature was 11q23 translocations (71% of cases); 21q22 rearrangements were rare. In a stepwise Cox regression analysis, two factors increased the risk of this complication: weekly or twice weekly administration of epipodophyllotoxins (P < 0.001); and the administration of asparaginase immediately before epipodophyllotoxin therapy (P < 0.001). Initial responses to salvage therapy were comparable to those reported for de novo AML: 92% of the evaluable patients entered complete remission after combination treatment. Single-agent therapy with 2-chlorodeoxyadenosine induced complete or partial remissions in one-half of the patients treated. The long-term survival rate was dismal. Of the 17 evaluable patients treated exclusively with chemotherapy, only one is alive at 84 months, compared to three of 16 patients who underwent bone marrow transplantation (alive at 10, 23 and 73 months). Cases of epipodophyllotoxin-related AML constitute a unique clinical syndrome that will require innovative strategies for cure.