Subacute sclerosing panencephalitis during pregnancy. A surviving normal infant.

A normal infant was born to a 15-year-old girl who developed subacute sclerosing panencephalitis in the fifth month of pregnancy. The serum measles antibody titers of the infant gradually declined during the first year of life. The child, now age 3, has no neurological abnormalities.

Cerebral arteritis and bacterial meningitis.

Twelve cases of large- and medium-sized cerebral artery stenosis and/or occlusion associated with bacterial meningitis occurred. Neurological complication due to arterial involvement developed in seven patients on the third and fourth days of illness; in one patient, it developed on the fifth day, and in another it developed on the 14th day. In three cases, this could not be determined. Arterial stenosis is considered primarily to result from arterial spasm due to humoral factors that may be elaborated within the CSF or arterial wall, as in the cases of ruptured aneurysm; and secondarily, from to inflammatory involvement of major vessels at the base of the brain and from irritation by angiographic contrast material.

Epidemiologic studies of measles, measles vaccine, and subacute sclerosing panencephalitis.

Histories obtained in 350 of 375 clinically cofirmed cases of subacute sclerosing panencephalitis (SSPE) reported to a national registry showed that 292 patients had measles and 58 had no history of measles. Forty of the latter patients received live, attenuated measles virus vaccine. In patients with a history of measles, measles illness occurred before age 2 years in 46%, and a mean of 7.0 years before onset of SSPE. In contrast, there was no relationship of SSPE with age at vaccination in 35 of the 40 patients historically associated with measles vaccine, and SSPE occurred a mean of 3.3 years after vaccination. Based on estimated national measles morbidity data and national measles vaccine distribution data, the risk of SSPE following measles vaccination (0.5 to 1.1 cases/106) appears to be less than the risk following measles (5.2 to 9.7 cases/106). Because live measles vaccine is highly effective in preventing measles illness and a high proportion of children in the United States have received measles vaccine, these data are consistent with the observed downward trend in SSPE incidence since 1969.

Pharmacokinetics of sumatriptan nasal spray in children.

The authors studied the pharmacokinetics of sumatriptan nasal spray after a single dose in children migraineurs outside of migraine attack. Seventeen subjects (9 females) ages 6 to 11 years were given one dose of sumatriptan nasal spray based on age and weight; children 6 to 8 years of age weighing 25 kg and children ages 9 to 11 years of age weighing 40 kg received 20 mg (n = 4). Plasma sumatriptan concentrations were determined in serial blood samples obtained over 8 hours. Pharmacokinetic analysis included both noncompartmental and population modeling methods. The pharmacokinetic parameter estimates (geometric mean [95% confidence interval]) following 5, 10, and 20 mg sumatriptan were, respectively, as follows: maximum concentration = 8.1 ng/mL (3.6-18.4), 10.8 ng/mL (7.7-15.4), and 12.3 ng/mL (7.6-19.9); half-life = 1.4 hours (1.2-1.8), 1.7 hours (1.4-2.0), and 1.7 hours (1.3-2.3); and AUC = 27.8 ng*h/mL (9.7-79.8), 42.4 ng*h/mL (30.6-58.8), and 49.2 ng*h/mL (32.9-73.7). The median time to maximum concentration for all groups was 2 hours. Population pharmacokinetic modeling included pooled data from this study and from an adolescent study (n = 16). Clearance (CL/F) was 197 L/h for a 30-kg child with between-subject variability of 28%, and the volume of distribution was 751 L, normalized for an 11-year-old child with variability of 43%. The covariate analysis showed that volume increases with age and clearance increases with body size. The absorption was complex, often displaying double-peak plasma concentrations, with a rapid absorption phase and a delayed and rate-limited absorption phase. The dosing scheme based on age and weight resulted in maximal concentrations (C(max)) and systemic exposure (AUC) that were comparable to those observed in adolescents and adults treated with 20 mg. The age- and weight-adjusted dosing scheme appears to an appropriate initial dosing regimen for children with migraine headache. Appropriate safety and efficacy trials will need to be completed in children prior to recommending its use in children.

Pharmacokinetics of sumatriptan nasal spray in adolescents.

Sumatriptan is a potent and selective vascular 5-HT1 receptor agonist effective for the treatment of migraine. In adults, intranasal sumatriptan is well absorbed and tolerated. The authors evaluated the pharmacokinetics and tolerability of a single dose of 20 mg intranasal sumatriptan in healthy adolescent migraineurs ages 12 to 17 years, administered outside of migraine attack. Serum sumatriptan levels were measured by high-performance liquid chromatography (HPLC) with electrochemical detection in serial samples collected over 8 hours. Physical exam, vital signs, clinical laboratory tests, and electrocardiogram measurements were monitored to assess safety and tolerability. A total of 16 subjects (10 males and 6 females) had pharmacokinetic data that could be analyzed, 2 withdrew from the study 30 and 60 minutes after dosing following the loss of venous access for blood sampling, and a bioanalysis failure resulted in loss of data from 3 subjects. Noncompartmental pharmacokinetic parameters (geometric mean and 95% confidence interval) for the remaining 16 subjects were as follows: Cmax was 13.9 (11.0, 17.6) ng/mL, AUC infinity was 57.3 (47.6, 69.0) ng/mL.h, and t1/2 was 2.0 (1.8, 2.3) hours. Population pharmacokinetic analysis for all subjects (n = 21) showed that clearance and volume of distribution increase slightly with age and body size, but the changes were minimal and would not warrant dose adjustment: CL/F was 316 L (coefficient of variance [CV] = 25%) and Vd/F was 1070 L (CV = 46%). Sumatriptan was well tolerated with only minor adverse events reported, which all resolved spontaneously. The pharmacokinetic parameters in these adolescent subjects were similar to those previously reported in adults, suggesting that adolescents should be dosed similar to adults.

Comparative efficacy study of chewable aspirin and acetaminophen in the antipyresis of children.

Aspirin and acetaminophen are the most widely used antipyretics in pediatrics. Most clinicians believe the drugs to be equally effective, though clinical opinion often suggests that aspirin is more effective at higher temperatures. Fifty-nine outpatients (age range, 2-8 years), presenting with rectal temperatures of 38.8 to 40.5 degrees C, were enrolled in this double-blind trial. The children were stratified by weight and initial temperature. One dose of chewable aspirin or acetaminophen (10-15 mg/kg based on current recommendations for weight) was administered, and rectal temperatures were monitored for three hours. Of the 59 patients enrolled, 46 successfully completed the protocol. Both drugs significantly reduced temperatures in the groups studied. Age did not influence the response of the children to the antipyretic effects of either drug. Aspirin and acetaminophen appeared equally effective when initial temperatures were between 38.8 and 39.9 degrees C. However, when the initial temperature was between 40.0 and 40.5 degrees C, the duration of effect of acetaminophen was shorter than that for aspirin. This suggests that therapeutic differences in the antipyretic activities of aspirin and acetaminophen may exist at higher temperatures.

A survey of the use of antiepileptic and muscle relaxant medication in a sample of children with neuromotor disorders.

A survey of 424 children with neuromotor disorders served by a children's rehabilitation center was conducted to determine the number who were receiving muscle relaxant or anticonvulsant medication, and the average daily dosage. An increase in the number of antiepileptic prescriptions was found. The implications of these findings are discussed.

Long-term tolerability of sumatriptan nasal spray in adolescent patients with migraine.

OBJECTIVE: This 1-year, open-label, multicenter study was designed to assess the long-term tolerability and efficacy of sumatriptan nasal spray 20 mg in adolescent patients with migraine. METHODS: A prospective, multicenter, open-label study was conducted in patients aged 12 to 17 years who were allowed to treat an unlimited number of migraines at severe, moderate, or mild pain intensity with sumatriptan nasal spray for up to 1 year. All patients started the study at the 20-mg dose of sumatriptan nasal spray. Dose could be adjusted downward to 5 mg at the discretion of the investigator to optimize therapy. RESULTS: A total of 484 adolescent migraineurs treated 4676 migraines with sumatriptan nasal spray 20 mg (3593 during the first 6 months and 1083 during the second 6 months). A total of 3940 migraines and 699 migraines were treated with one and two 20-mg doses of sumatriptan nasal spray, respectively. Only 10 patients (treating 42 migraines) took the 5-mg dose of sumatriptan nasal spray. The overall percentage of migraines treated with either one 20-mg dose or one, two, or three 20-mg doses with at least 1 drug-related adverse event was 19%. The most common specific drug-related adverse event was unpleasant taste, reported in 17% of migraines. No other single drug-related adverse event was reported in more than 1% of migraines over the 1-year treatment period. When unpleasant taste was excluded from the adverse-event tabulations, the percentages of migraines with at least 1 drug-related adverse event after one or one, two, or three 20-mg doses declined to 4% and 3%, respectively. No patient experienced any drug-related changes in 12-lead ECGs, vital signs, or nasal assessments; and no clinically meaningful changes in clinical laboratory values were observed. Across all migraines with evaluable efficacy data (n=4334), headache relief was reported in 43% of migraines at 1 hour and in 59% at 2 hours after dosing with sumatriptan nasal spray 20 mg. Of the 2561 migraines with headache relief 2 hours postdose, headache recurrence was reported within 24 hours of initial dosing in 7% of migraines. None of the efficacy or tolerability results varied as a function of time in the study (ie, first 6 months vs. second 6 months). CONCLUSION: Sumatriptan nasal spray 20 mg is generally well tolerated and may be beneficial during long-term use by adolescent migraineurs ages 12 to 17 years.

Measurement of true salicylate concentrations in serum from patients with Reye's syndrome.

Patients with Reye's syndrome who have been given aspirin are said to maintain higher-than-anticipated salicylate concentrations in blood, for longer than expected. We explored whether this could be attributed to spurious results from nonsalicylate compounds in the Trinder reaction for salicylates. All of 63 organic acids and amines examined that form colored complexes with Trinder's reagent had detectable absorbance at 540 nm at 0.2 g/L, including some endogenous compounds known to be increased in Reye's syndrome patients and many others endogenous in humans. By subjecting deproteinized sera to thin-layer chromatography and eluting the salicylate fraction before complexing it with ferric ion, true salicylate can be measured quantitatively and differentiated from interfering compounds. In addition, when we examined the effect of salicylate on palmitate binding to serum proteins, we found that salicylate concentrations of 0.2 g/L displaced [16-14C]palmitate binding to protein more in Reye's syndrome patients than in Reye's syndrome survivors or children with influenza. This suggests the presence of atypical binding characteristics for salicylate and palmitate in the acute disorder but not in survivors or children with influenza.

Possible influence of carbamazepine on plasma imipramine concentrations in children with attention deficit hyperactivity disorder.

The effect of carbamazepine on the plasma concentration of imipramine and its metabolite desipramine was examined retrospectively in 36 sex- and age-matched children with attention deficit hyperactivity disorder. One-half of the children received imipramine and the other half received combined carbamazepine and imipramine for 1-6 months. The imipramine dosage was significantly higher in the combined treatment group than in the imipramine-only group. Despite receiving larger doses, the combined treatment group had significantly lower mean levels of imipramine, desipramine, and total tricyclic antidepressant compared with those children receiving imipramine alone. Lowered plasma concentrations of tricyclic antidepressants with carbamazepine coadministration have not been reported previously. Although more rigorous studies are needed to confirm these findings, our data suggest that increased imipramine doses may be necessary for adequate response in children on combined therapy. Moreover, toxicity could result upon withdrawal without imipramine dosage adjustment.

Inosiplex therapy in subacute sclerosing panencephalitis. A multicentre, non-randomised study in 98 patients.

Inosiplex was administered to 98 patients with subacute sclerosing panencephalitis (SSPE) in the United States and Canada for variable periods of time up to 9.5 years. Survival data from these 98 patients were compared by life-table analysis with survival in three SSPE control groups drawn from SSPE patients contracting the disease in Israel, Lebanon, or the United States at about the same time as the inosiplex-treated patients but treated differently or not at all. In the inosiplex-treated patients the actuarial probability of survival at 2, 4, 6, and 8 years from onset of SSPE was 78%, 69%, 65%, and 61%, compared with 38%, 20%, 14%, and 8% in a composite control group (p less than 0.01 for all four comparisons). Statistical adjustments for time-to-treatment bias did not affect this result: a modified logrank procedure demonstrated that the risk of dying in the treatment group was 43% of that in the controls. Inosiplex seems to be able to prolong life in patients with SSPE.

Rectal thiopental versus an intramuscular cocktail for sedating children before computerized tomography.

The sedative effects of rectal thiopental sodium and an intramuscular cocktail of meperidine hydrochloride, chlorpromazine hydrochloride and promethazine hydrochloride were compared in 72 pediatric patients undergoing computerized tomography (CT). Pediatric patients scheduled were randomly assigned to receive either the i.m. cocktail (2.0 mg/kg of meperidine, 1.0 mg/kg of both chlorpromazine and promethazine) or 25--45 mg/kg of thiopental rectally before scanning. Side effects, and onset, duration and depth of sedation were recorded by 14 unblinded investigators. Clarity of CT scans was rated by two blinded radiologists. Additional doses of sedatives were administered as necessary. Sedation was not achieved in 3% of the thiopental group or in 14+ of the i.m. cocktail group. Additional sedatives were required by eight patients in the thiopental group and by five patients in the cocktail group. The mean time for onset of sedation was 8 minutes with thiopental and 18 minutes with the cocktail. The mean duration of sedation was 7 hours for the cocktail group and 2.75 hours for the 25-mg/kg rectal thiopental group. All scans were diagnostic (acceptable) in the rectal thiopental group, but 14% of those in the i.m. cocktail group were nondiagnostic. Rectal thiopental is an effective alternative to an i.m. cocktail for sedating children before CT scans and may reduce the number of nondiagnostic scans.

Risk factors in subacute sclerosing panencephalitis: a case-control study.

Fifty-two persons with subacute sclerosing panencephalitis (SSPE) were compared with playmate and hospital controls matched for age, sex, and race. Persons with SSPE were more likely to have had measles than their age-matched controls. The age at measles infection for children with SSPE was significantly younger than that for controls who had had measles. Persons with SSPE were less likely to have received measles vaccine than were playmate or hospital controls. There were no differences with regard to the average age at vaccination, having received more than one measles vaccination, or having received measles vaccine after natural measles. Although measles vaccine may rarely predispose a child to develop SSPE, the overall impact of vaccination has been to prevent SSPE by preventing natural measles. No significant differences were observed between cases and controls for infections other than measles, or for vaccines other than measles vaccine. Previous epidemiologic studies have noted significant geographic clustering of SSPE and higher rates in children living in rural areas. These findings suggest that environmental factors other than measles are important in the pathogenesis of SSPE. In this study, children with SSPE were more likely to have suffered a serious head injury and to have come from larger families and more crowded homes than control children. Persons with SSPE were significantly more likely to have close exposure to birds (p less than 0.001) and to swine (p less than 0.05) than were control persons. No differences between cases and controls were found for exposure to other animals. These data suggest that some infectious agent(s), transmitted from birds to man, may have contributed to the development of SSPE in predisposed individuals. A variety of other factors were investigated and found not to correlate with SSPE. These included birth weight, breastfeeding, maternal age at birth, nutritional status, source of drinking water, development, and allergic or atopic disorders.

Development of encephalopathic features similar to Reye syndrome in rabbits.

The progression of neurological abnormalities through four or five clinically distinguishable levels of deepening coma and the development of a fatty liver are the hallmarks of Reye syndrome. A number of animal models have been described that result in fatty liver formation with minimal, static, or catastrophic neurological changes. In this study, we attempted to produce neurological features in rabbits that reflected a rostral-caudal progression of abnormalities that could be categorized into clinically distinguishable levels reminiscent of Reye syndrome. This was accomplished by the intracisternal administration of 0.5-25 mg of 11,14-icosadienoic acid (20:2 omega 6) suspended in a mixture of rabbit serum and isotonic saline solution. A reproducible, dose-titratable spectrum of at least four levels of deepening coma could be produced at will. Increases in serum glutamate-oxaloacetate transaminase and creatine kinase and changes in serum glucose resulted 1-2 hr after the neurological abnormalities were evoked. Other unsaturated fatty acids produced similar responses. Those tested included 18:1 omega 9, 18:2 omega 6, 18:3 omega 3, 20:3 omega 6, 20:4 omega 6, and 22:4 omega 6 fatty acids. Saturated fatty acids, including 6:0, 8:0, 16:0, 18:0, and 20:0, failed to elicit these effects. The abnormalities were sustained for 30-120 min after a single dose. Full recovery was observed in some animals that had not reached the fourth level of our grading system for coma. Pretreatment of the rabbits with aspirin modulated the neurological abnormalities. Twenty micrograms of bee venom melittin, which activates endogenous phospholipase A2, administered intracisternally into rabbits also produced signs of level 3 (our grading system) coma for several hours. These findings suggest a possible role for polyunsaturated fatty acids in the development of Reye syndrome and offer a means of producing the neurological components of that syndrome in a laboratory animal.