CNS angiitis in graft vs host disease.

Graft-vs-host disease (GVHD) is a potentially treatable cause of progressive neurologic decline after bone marrow transplantation (BMT). The authors present histologic confirmation of CNS granulomatous angiitis in a child with chronic GVHD after BMT. Since cranial MRI showed only nonspecific findings, CNS vasculitis associated with GVHD after BMT may be underdiagnosed.

Prevention and management of febrile seizures.

Febrile seizures are the most common seizures in childhood and, like all seizures, can be frightening to witness. Therefore, it is not surprising that febrile seizures have been the focus of intense research with an extensive literature describing various preventative measures. In addition, there is also an extensive and sophisticated epidemiological literature delineating the natural history of this disorder in American and British children. For simple febrile seizures, the most common form of this disorder, the epidemiological studies demonstrate a generally benign natural history, making it unlikely that any preventative measure could improve the long term outcome for most children. Children with simple febrile seizures have a slight increased risk of epilepsy, but there are no studies that demonstrate that phenobarbital or other therapy can alter this risk. Daily therapy with phenobarbital or valproic acid can reduce the number of subsequent simple febrile seizures. However, as a recent Practice Parameter from the American Academy of Paediatrics concludes, the risk of adverse effects from daily therapy appears to outweigh the benefit of preventing the short term recurrence of simple febrile seizures. It is possible that in some families, where the occurrence of an additional simple febrile seizure would be particularly distressing, the routine use of oral diazepam during febrile illnesses might be appropriate.

Treatment of children with simple febrile seizures: the AAP practice parameter. American Academy of Pediatrics.

Febrile seizures are the most common seizure disorder in childhood, occurring in 2-5% of children. Despite their frequency, there has been little unanimity of opinion regarding the need for long-term antiepileptic therapy. As such, the American Academy of Pediatrics formulated a subcommittee to study the subject. A Practice Parameter was developed that addressed the issue of whether continuous or intermittent antiepileptic therapy is necessary for children with simple febrile seizures. The committee determined that with the exception of a high rate of recurrence, no long-term adverse effects of simple febrile seizures have been identified. The risk of developing epilepsy is extremely low and, even in those patients who do, there is no evidence that recurrent simple febrile seizures produce structural central nervous system damage. Also, there is no evidence that recurrent simple febrile seizures cause either learning problems or premature death. The committee concluded that although there is the evidence that continuous antiepileptic therapy with phenobarbital or valproic acid and intermittent therapy with diazepam are effective in reducing the risk of recurrence, the potential toxicities associated with antiepileptic therapy outweigh the relatively minor risks associated with simple febrile seizures. As such, long-term treatment is not recommended.

Use and monitoring of bromides in epilepsy treatment.

Bromides are no longer a mainstay of epilepsy therapy because of the significant toxicity associated with their use and the availability of safer agents. However, bromides occasionally find a niche in the treatment of patients with refractory seizures, particularly in pediatrics. When the decision to utilize this therapy is made, the clinician may be frustrated by the lack of concise, current information regarding bromides. This review provides an update on the mechanism of action, efficacy, pharmacokinetics, dose, and adverse effects of bromides.

Acute disseminated encephalomyelitis after Rocky Mountain spotted fever.

Although acute disseminated encephalomyelitis has been observed after a variety of viral infections and an occasional bacterial infection, it has not been reported in association with rickettsial infections. Reported is a 7-year-old male with magnetic resonance images and clinical manifestations suggestive of acute disseminated encephalomyelitis after a tick bite and serologically proven Rocky Mountain spotted fever.

Technical report: treatment of the child with simple febrile seizures.

OVERVIEW: Simple febrile seizures that occur in children ages 6 months to 5 years are common events with few adverse outcomes. Those who advocate therapy for this disorder have been concerned that such seizures lead to additional febrile seizures, to epilepsy, and perhaps even to brain injury. Moreover, they note the potential for such seizures to cause parental anxiety. We examined the literature to determine whether there was demonstrable benefit to the treatment of simple febrile seizures and whether such benefits exceeded the potential side effects and risks of therapy. The therapeutic approaches considered included continuous anticonvulsant therapies, intermittent therapy, or no anticonvulsant therapy. METHODS: This analysis focused on the neurologically healthy child between 6 months and 5 years of age whose seizure is brief (<15 minutes), generalized, and occurs only once during a 24-hour period during a fever. Children whose seizures are attributable to a central nervous system infection and those who have had a previous afebrile seizure or central nervous system abnormality were excluded. A review of the current literature was conducted using articles obtained through searches in MEDLINE and additional databases. Articles were obtained following defined criteria and data abstracted using a standardized literature review form. Abstracted data were summarized into evidence tables (Tables 1 through 7). RESULTS: Epidemiologic studies demonstrate a high risk of recurrent febrile seizures but a low, though increased, risk of epilepsy. Other adverse outcomes either don't occur or occur so infrequently that their presence is not convincingly demonstrated by the available studies. Although daily anticonvulsant therapy with phenobarbital or valproic acid is effective in decreasing recurrent febrile seizures, the risks and potential side effects of these medications outweigh this benefit. No medication has been shown to prevent the future onset of recurrent afebrile seizures (epilepsy). The use of intermittent diazepam with fever after an initial febrile seizure is likely to decrease the risk of another febrile seizure, but the rate of side effects is high although most families find the perceived benefits to be low. Although antipyretic therapy has other benefits, it does not prevent additional simple febrile seizures. CONCLUSIONS: The Febrile Seizures Subcommittee of the American Academy of Pediatrics' Committee on Quality Improvement used the results of this analysis to derive evidence-based recommendations for the treatment of simple febrile seizures. The outcomes anticipated as a result of the analysis and development of the practice guideline include: 1) to optimize practitioner understanding of the scientific basis for using or avoiding various proposed treatments for children with simple febrile seizures; 2) to improve the health of children with simple febrile seizures by avoiding therapies with high potential for side effects and no demonstrated ability to improve children's eventual outcomes; 3) to reduce costs by avoiding therapies that will not demonstrably improve children's long-term outcomes; and 4) to help the practitioner educate caregivers about the low risks associated with simple febrile seizures.

Clomiphene analogs with activity in vitro and in vivo against human breast cancer cells.

Six hundred triphenylethylenes were assayed for antiproliferative activity against MCF-7, LY2, and MDA-MB-231 breast cancer cells using sulforhodamine B dye to measure proliferation. Here we report on just 63 of the compounds, mostly clomiphene analogs, with substitutions on the alpha' or beta ring, at the vinyl position or in the side chain, of which 23 were active, as defined by antiproliferation IC50 values < or =1 microM. Activity profiles showed that 23 and 11 analogs were active toward MCF-7 and LY2, respectively, but none were active against MDA-MB-231. The IC50 values of tamoxifen were 2.0 microM against MCF-7 and 7.5 microM against LY2 and MDA-MB-231. Estradiol reversed antiproliferative activities of several E isomers but not their Z isomer counterparts. Clomiphene side chain analogs 46 [(E)-1-butanamine, 4-[4-(2-chloro-1,2-diphenylethenyl) phenoxy]-N,N-diethyl-dihydrogen citrate (MDL 103,323)] and 57 [(E)-N-[p-(2-chloro-1,2-diphenylvinyl) phenyl]-N,N-diethylethylenediamine dihydrogen citrate (MDL 101,986)] were 4- to 5-fold more effective than tamoxifen. Methylene additions up to (-CH2-)12 in the clomiphene side chain showed that analog 46 [(-CH2-)4 side chain] had maximal antiproliferative activity, binding affinity, and inhibition of transcription of an estrogen response element luciferase construct in transfected MCF-7 cells. Intraperitoneal administration of 46 or 57 inhibited progression of MCF-7 breast tumor xenografts in nude mice with ED50 values of <0.02 mg/mouse/day. Both analogs may hold promise for treating ER positive breast cancer and are of interest for further development.

Fusiform P1 segment artery aneurysm in a pediatric patient: technical case report.

We present an unusual aneurysm in a pediatric patient. Due to the fusiform nature of the aneurysm and the small size of the patient, a unique surgical solution was applied. One year of clinical follow-up is also provided.

Magnetic resonance imaging of the brain in Aicardi's syndrome. Report of 20 patients.

Aicardi's syndrome consists of multiple anomalies of the eye, brain, and axial skeleton in females, and is associated with early-onset infantile spasms and severe developmental delay. For the present study, magnetic resonance images of 20 patients with Aicardi's syndrome were obtained and the neuroimaging findings catalogued. These were compared to previously reported results and the findings correlated with current theories of fetal brain development. The results revealed a high frequency of cortical migration defects (94%) and a wide variability in the callosal defect, migrational abnormalities, and other findings in Aicardi's syndrome.

Interobserver variability in the classification of neonatal seizures based on medical record data.

This population-based, retrospective cohort study of neonatal seizures included all 16,428 neonates born to residents of Fayette County, Kentucky, from 1985 to 1989. Eighty potential cases were ascertained by computer search of hospital-based medical record systems, birth certificate data files, and multiple-cause-of-death mortality data files. Medical records for potential cases were abstracted, and relevant portions were reviewed independently by three neurologists using prospectively determined criteria. Both unweighted and weighted kappa statistics were used to measure agreement between each pair of observers in the classification of potential cases as seizures, possible seizures, or not seizures, adjusting for the proportion of agreement expected by chance. Agreement in the classification of potential cases was excellent (kappa = 0.72-0.79, average = 0.76; weighted kappa = 0.85-0.88, average = 0.87). The kappa extension statistic of Kraemer was used to assess agreement in the classification of seizure types by a simplification of the classification scheme of Volpe. This documented excellent agreement between raters in the classification of seizure types (kappa e = 0.72). Experienced raters can reliably classify potential cases of neonatal seizures using seizure descriptions transcribed from medical records.

Antitumor and chemopreventive effects of a clomiphene analog, MDL 103,323, in mammary carcinoma.

MDL 103,323, an enclomiphene analog, was tested for binding to the estrogen receptor, inhibition of human tumor xenografts and prevention of carcinogen-induced mammary tumors. MDL 103,323 had 5-6 fold greater affinity for the human estrogen receptor than did either tamoxifen or enclomiphene. Consistent with enhanced binding affinity, MDL 103,323 was more potent against MCF-7 cell proliferation and MCF-7 xenografts in nude mice were inhibited almost completely by MDL 103,323 doses > or = 0.02 mg/mouse/day (ED50 l 0.01 mg/mouse/day). N-methylnitrosourea induced rat mammary carcinomas were inhibited by > or = 50% at 0.003 mg/kg daily and by 90% at 0.1 mg/kg/day. The antitumor potency and efficacy of MDL 103,323 are striking and further evaluation of the compound for potential clinical utility is warranted.

Depletion of estrogen receptor in human breast tumor cells by a novel substituted indole that does not bind to the hormone binding domain.

Steroidal antiestrogens appear to have at least two major modes of action in breast cancer cells, direct antagonism of estrogen binding to its receptor and depletion of estrogen receptors (ER) due to inhibition of dimerization of the receptor and a resultant destabilization of the receptor protein. In a search for other classes of compounds which would act as dimerization inhibitors, a novel substituted indole (8-{2-[1-(4-chlorobenzoyl)-5-hydroxy-2-methyl-1H-indol-3-yl]-acetylamino} octanoic acid butyl-methyl amide, MDL 101,906) was synthesized. Binding of the ER to its consensus response element (ERE) was apparently decreased in nuclear extracts from MCF-7 human breast cancer cell treated with MDL 101,906. This decreased binding was found to be due to depletion of ER based on direct measurement of ER using an enzyme-linked immunoassay. Other transcription factors were apparently unaffected by MDL 101,906 treatment. Whereas depletion of ER with a steroidal antiestrogen was almost complete after 3 h of treatment of MCF-7 cells, the effect of MDL 101,906 took significantly longer to occur, suggesting a fundamental difference in the mechanisms of action of the two drugs. This was also evident in the lack of binding of MDL 101,906 to the hormone binding domain of ER. MDL 101,906 treatment also caused depletion of ER mRNA in MCF-7 cells. Depletion of ER mRNA was noted by 3 h of drug treatment and was apparently almost complete after 24 h of treatment. Depletion of ER from MCF-7 cells led to a dose-dependent decrease in the expression of luciferase by an ERE-driven luciferase reporter gene assay system. The mechanism of MDL 101,906 appears to be unique and additional studies with this chemical class seem to be warranted to assess the potential for therapeutic utility.

Progression of MCF-7 breast cancer cells to antiestrogen-resistant phenotype is accompanied by elevated levels of AP-1 DNA-binding activity.

We have isolated a variant of the MCF-7 human breast tumor that is characterized by a hormone-independent, yet hormone-responsive, phenotype. This tumor, designated MCF-WES, was derived from MCF-7 tumor cells implanted in the mammary fat pad of a nude mouse in the absence of estradiol supplementation. MCF-WES tumors remain responsive to estradiol; however, unlike the parental MCF-7 tumors, they are stimulated to grow by tamoxifen. Additionally, MCF-WES cells are resistant to the pure steroidal antiestrogen, ICI 182,780. To our knowledge, a tumor with this combination of properties has not yet been described. Nuclear estrogen receptor (ER) levels in MCF-WES cells were 10% of those for MCF-7 under steroid-depleted conditions. MCF-WES tumor ER levels were 32% of those in MCF-7 tumors. Similarly, in vivo expression of ER mRNA for MCF-WES was 20% of levels determined for MCF-7. Further characterization of MCF-WES cells showed that they have increased levels of AP-1 DNA-binding activity. The marked increase in AP-1 binding activity may act to bypass the hormone dependence that is a characteristic of MCF-7 cells. It is also probable that the increase in AP-1 binding activity is responsible for the finding that MCF-WES cells secrete greater quantities of metalloproteinase activity in comparison to parental MCF-7 cells, suggesting progression to a more invasive, malignant phenotype. More complete characterization of this new cell line will help elucidate hormone-independent breast cancer and possibly identify targets for therapy.

Kentuckians' attitudes toward children with epilepsy.

We explored Kentuckians' attitudes toward children with epilepsy. Questions compared respondents' attitudes about children with epilepsy, asthma, hyperactivity, and AIDS. Random digit dialing led to 617 completed interviews. The key questions asked concerned (a) how a pupil with each illness would alter the classroom environment, and (b) how the condition would affect the child's quality of life (QOL) at age 21 years. Respondents used a 0-10 rating scale (0 = worst, 5 = normal, 10 = best). A dichotomous variable divided respondents into those who rated below and those who rated at or above the norm: 24% predicted a deterioration of the classroom environment with the addition of a pupil with epilepsy (similar to AIDS at 26%); 41% predicted a lessened QOL at age 21 years (a worse rating than either asthma or hyperactivity). We created summary indexes, using difference scores between epilepsy ratings and ratings for the other conditions: Relative Educational Distance (RED) and Relative Quality of Life Distance (RQLD) measures. On the RED index, rural and Appalachian respondents showed the greatest prejudice toward pupils with epilepsy. Conversely, we noted the greatest prejudice in RQLD among urban residents (the best educated group). Our data do not support contentions that prejudices against persons with epilepsy are disappearing.

A population-based study of neonatal seizures in Fayette County, Kentucky.

This population-based, retrospective cohort study of neonatal seizures included all neonates born to residents of Fayette County, Kentucky, from 1985 to 1989. We ascertained potential cases by computer search of hospital-based medical record systems, Kentucky Center for Health Statistics birth certificate data files, and National Center for Health Statistics multiple-cause-of-death mortality data files. Medical records for potential cases were abstracted, and relevant portions were reviewed independently by three neurologists using prospectively determined case-selection criteria. Seizures occurred in 58 of 16,428 neonates (3.5/1,000 live births). An additional 15 neonates had possible seizures, for a combined risk of 4.4/1,000 live births. Neonatal seizure risk varied inversely with birth weight: 57.5/1,000 live births among very low birth weight infants (< 1,500 grams) compared with 4.4/1,000 for infants with moderately low birth weight (1,500 to 2,499 grams), 2.8/1,000 for those with normal birth weight (2,500 to 3,999 grams), and 2.0/1,000 for those with high birth weight (4,000 or more grams). Risk varied among the four hospitals in the county with obstetric units, the university hospital having the highest risk. Risk did not differ by race or gender. A Cox proportional hazards model confirmed the results of the simpler univariate analyses. Differences in birth weight of the subpopulations served by each hospital accounted for much but not all the differences in hospital-specific risk.

A population-based study of neonatal seizures in Fayette County, Kentucky: comparison of ascertainment using different health data systems.

Based on a population-based, retrospective cohort study of neonatal seizures in Fayette County, Kentucky, from 1985 to 1989, estimates of neonatal seizure risk were calculated from computerized databases including hospital medical records, birth certificates, and death certificates. Computerized tabulations of hospital discharge diagnoses identified 97% of cases with a positive predictive value of 75%. Birth certificates had poor sensitivity for neonatal seizures overall (37%), but identified 67% of infants who seized on the first day of life. However, careless completion of the birth certificate produced a high number of false positives. Death certificates identified no infants with neonatal seizures.

HMPAO scintigraphy, MRI, and CT of a vascular fibrous dysplasia of the craniofacial bones.

The authors present the case of a child with a predominantly unilateral craniofacial fibrous dysplasia and a substantial redirection of internal carotid blood flow to the dysplastic bone. The case illustrates the advantages of using multiple imaging modalities in the evaluation of this disorder. CT showed the diagnostic findings of fibrous dysplasia and demonstrated the extent of bony involvement. MRI showed the extent and vascularity of the intradiploic fibrous mass and best demonstrated the distortion of underlying cerebral structures. Tc-99m HM-PAO brain scintigraphy demonstrated adequate ipsilateral cerebral perfusion, thereby excluding any significant cerebral "steal."