Elastosis perforans serpiginosa, Down syndrome, and moyamoya disease.

A 16-year-old girl with Down syndrome, moyamoya disease, and history of a previous stroke presented with acute onset of left hemiparesis and elastosis perforans serpiginosa. Elastosis perforans serpiginosa in a patient with Down syndrome and moyamoya disease is a novel finding. Development of elastosis perforans serpiginosa in association with progressive vaso-occlusive disease may be a biological marker of progression of moyamoya disease.

Lack of valproic acid-associated weight gain in prepubertal children.

We evaluated whether prepubertal children treated with valproic acid did not gain excessive weight. This retrospective study of children with epilepsy, aged <12 years at enrollment, examined weight gain associated with valproic acid or carbamazepine monotherapy. There was no significant difference between the valproic acid (n = 31) and carbamazepine (n = 49) treated groups in average duration of therapy or mean age. Body mass index scores at the beginning and end of the study were used to evaluate weight gain, while compensating for gains in height. For valproic acid, the linear mixed model detected no gain in body mass index z-scores over time (T = 0.25, DF = 17.3, P = 0.80), though it detected a significant gain in body mass index z-scores for carbamazepine (T = 2.32, DF = 36.7, P = 0.02). Results for McNemar chi-square tests were similar. No significant proportion change occurred among children on valproic acid (chi(2) = 2.0, P = 0.15), whereas a significant increase in the proportion of overweight children occurred on carbamazepine (chi(2) = 4.5, P = 0.03). We detected no excessive weight gain for children on valproic acid, whereas this was demonstrated for a similar socioeconomic group on carbamazepine.

Continuous Intravenous Valproate as Abortive Therapy for Pediatric Status Migrainosus.

OBJECTIVE: This study describes the use of continuous intravenous valproate as an abortive therapy for pediatric status migrainosus. BACKGROUND: Intravenous valproate as a bolus dose has been shown to be an effective abortive therapy for status migrainosus in children; however, Valproate's pharmacokinetic profile suggests that it would be safer and more therapeutic as a continuous infusion. This dosing strategy results in less serum concentration fluctuations, more consistent therapeutic effects, and less adverse effects. METHODS: A retrospective chart review between August 2009 and August 2012 identified 83 patients who had presented with status migrainosus and had received continuous intravenous valproate after failing to respond to initial abortive treatment. These patients had received a 20 mg/kg loading dose, followed by continuous infusion at 1 mg/kg/h. Serum valproate levels had been drawn 4 hours and 24 hours after the loading dose. Infusion rate had been adjusted to maintain serum levels of 80 to 100 mcg/mL. Age-appropriate pain assessments had been recorded at regular intervals. Excellent response was defined as a 100% reduction in pain scores, moderate response as 50% to 99% reduction, and poor response as <50% reduction. RESULTS: Of the 83 patients, 55 (66.2%) had reported an excellent response, 4 (4.8%) a moderate response, and 24 (28.9%) a poor response. Of those reporting an excellent response, 76% had responded within 24 hours. Nausea (8.4%) and vomiting (2.4%) had been the only reported side effects. Twenty-four hour serum levels had been within the goal range 91.9% of the time. CONCLUSIONS: Continuous intravenous valproate is safe, easy to monitor, and therapeutic in the abortive treatment of status migrainosus in pediatric patients.

Clinical utility of a continuous intravenous infusion of valproic acid in pediatric patients.

STUDY OBJECTIVE: To describe the dose-concentration relationship of a continuous intravenous infusion of valproic acid (VPA) in pediatric patients when a dosing protocol is used. DESIGN: Retrospective and concurrent chart review. SETTING: Tertiary care, 473-bed, academic medical center with a 120-bed, dedicated children's hospital. PATIENTS: Twenty-six pediatric patients (< 18 yrs old) who received VPA according to the protocol for continuous intravenous infusions between January 1, 2004, and March 31, 2006, identified by using a pharmacy order-entry system. MEASUREMENTS AND MAIN RESULTS: Patient demographics, VPA treatment regimens, clinical responses, and safety data were recorded and analyzed. Median patient age was 8.5 years (range 1.4-16 yrs). Approximately two thirds received VPA for seizures, and one third for migraines. Patients were given a mean +/- SD VPA loading dose of 28.5 +/- 5.2 mg/kg followed by a continuous infusion rate of 1 +/- 0.2 mg/kg/hour. Mean +/- SD serum concentration measured 4.5 +/- 1.6 hours after the loading dose was 83.3 +/- 22.8 microg/ml. Steady-state concentration at 23.3 +/- 3.0 hours after the start of the continuous infusion was 80.0 +/- 26.0 microg/ml. Postload and steady-state serum concentrations were within the target concentration of 50-100 microg/ml in 77% and 69% of patients, respectively. On further analysis, when the target range was expanded to 50-125 microg/ml (125 microg/ml was deemed acceptable if no adverse effects were noted), 89% and 92% of patients, respectively, had postload and steady-state VPA serum concentrations within this range. The response rate was excellent, with nearly 85% of patients achieving a complete or partial response to therapy. Adverse effects were generally mild and uncommon. CONCLUSIONS: The continuous-infusion protocol permitted rapid intravenous loading of VPA in pediatric patients while minimizing adverse events and achieving concentrations in the upper region of the therapeutic range.

Surfer's myelopathy without surfing: a report of two pediatric patients.

INTRODUCTION: Surfer's myelopathy (SM) is a rare disorder described in subjects presenting with acute paraparesis while learning how to surf. It is thought to be secondary to spinal ischemia triggered by hyperextension. Spinal magnetic resonance imaging (MRI) shows changes consistent with spinal cord ischemia on T2-weighted and diffusion-weighted imaging (DWI). CASE PRESENTATION: We report two patients who presented with acute onset paraplegia shortly after spinal hyperextension. They had no physical or radiological evidence of soft tissue injury. Their clinical and imaging findings closely resemble those described in SM. DISCUSSION: We propose the use of the term 'acute hyperextension myelopathy' to categorize patients with spinal cord infarction secondary to hyperextension. DWI sequencing on MRI should be considered to evaluate for early signs of spinal cord ischemia in these patients. Use of a broader term for diagnostic classification can help include patients with spinal cord infarction due to a common mechanism.

Pharmacokinetics and Clinical Utility of Valproic Acid Administered via Continuous Infusion.

INTRODUCTION: Valproic acid is a versatile antiepileptic drug that is often used in the acute care setting. Intravenous valproic acid lends itself well to a continuous infusion as it exhibits a relatively short half-life. We evaluated the pharmacokinetics and clinical efficacy of continuous infusion valproic acid in hospitalized patients with migraine and seizures. METHODS: A retrospective cohort study was performed utilizing information from the medical records of patients receiving an intravenous continuous infusion of valproic acid. Patients were included if they were aged 1 month to 85 years and they received a continuous infusion of valproic acid. Therapeutic response, common adverse effects, and the pharmacokinetic profile of valproic acid were evaluated. RESULTS: Continuous infusion valproic acid led to a concentration within the desired range (50-100 µg/ml) in 83.4% of patients, a rate that was higher in pediatric patients. The clinical response rate was also higher in pediatric patients with seizures or migraines and appeared to be better when the concentration was >75 µg/ml. Analysis of safety parameters suggests similar safety considerations to valproic acid when administered via intermittent infusion. CONCLUSIONS: Continuous infusion valproic acid appears to be a safe, effective, and predictable manner by which to administer valproic acid to pediatric and adult patients admitted to the hospital.

Correlation of lamotrigine concentrations between serum and saliva.

STUDY OBJECTIVE: To compare the relationship between serum and salivary concentrations of lamotrigine in pediatric and adult epilepsy populations. DESIGN: Paired-sample pharmacokinetic study. SETTING: University neurology clinic. PATIENTS: Thirty-seven patients with epilepsy, aged 2-60 years, who were taking lamotrigine and whose physicians had ordered a lamotrigine serum concentration. MEASUREMENTS AND MAIN RESULTS: Patients spit a minimum of 0.25 ml into a cup to provide saliva samples. Blood samples were obtained by phlebotomy. Serum and salivary lamotrigine concentrations were determined by high-performance liquid chromatography. Linear regression analysis was used to evaluate correlations. Six patients' results were omitted due to the lack of a serum or saliva specimen or clearly erroneous results, leaving 31 patients for analysis. There was a strong correlation between the serum results reported by two reference laboratories (coefficient of correlation [r] = 0.988). The correlations between salivary and serum lamotrigine concentrations were similar for reference laboratory A (r = 0.81) and reference laboratory B (r = 0.84). Saliva:serum concentration ratios ranged from 0.41-1.26 (mean +/- SD 0.62 +/- 0.19) for reference laboratory A and from 0.40-1.19 ((mean +/- SD 0.64 +/- 0.18) for reference laboratory B. CONCLUSION: There is a good correlation between salivary and serum concentrations for lamotrigine. However, there is wide interpatient variability in the saliva:serum ratio. The data suggest that salivary monitoring may play a role in the monitoring of lamotrigine for adult and pediatric patients.

Behavioral treatment of migraine in children and adolescents.

Behavioral interventions, particularly biofeedback and relaxation therapy, have demonstrated their effectiveness in the treatment of both adults and older children with migraine in controlled trials. The physiological basis for their effectiveness is unclear, but data from one trial suggest that levels of plasma beta-endorphin can be altered by relaxation and biofeedback therapies. The data supporting the effectiveness of behavioral therapies are less clear-cut in children than in adults, but that is also true for the data supporting medical treatment. This is due in part to methodological issues, especially the lack of a specific test for migraine, which has hampered research and helped lead to an inappropriate de-emphasis on care for childhood headache. In addition, migraine headaches in children are often briefer and have a higher rate of spontaneous remission than those experienced by adults, making it difficult to separate effective from ineffective treatments. While it is widely believed that stress is a major factor in childhood migraine, well-designed studies have had difficulty developing data to support this viewpoint. Many clinicians utilize 'confident reassurance', reassuring the family that the child is not seriously ill, in the belief that having migraine headaches can be stressful. They also modify behaviors that are believed to trigger migraine headaches, such as poor sleep habits or irregular meal times. Relaxation therapies use techniques such as progressive relaxation, self-hypnosis, and guided imagery. Several studies have found relaxation therapies to be as effective, or more effective, in reducing the frequency of migraine headaches than modest doses of a beta-blockade medication, although one study found relaxation therapy to be no more effective than a control program. Several studies have demonstrated that these therapies can be taught to children in a low cost but effective manner. Biofeedback therapies commonly use an apparatus to demonstrate a physiological effect. Most commonly in pediatrics, children are taught to raise the temperature of one of their fingers. This can be done with or without a thermometer. Several groups have shown that these techniques can be taught to children and that their use is associated with fewer and briefer migraine headaches. People who experience migraines can also experience episodic headaches throughout life. An important consideration is preparing children to deal with future headaches, allowing them to feel in control of their health. Behavioral therapies have the potential to do this, giving the child access to a technique that can be easily resumed without a medical visit or prescription.

Valproate-associated stomatitis.

The purpose of this article is to report a case of severe stomatitis in a patient with pediatric epilepsy taking divalproex sodium. The case was reviewed with detailed oral examinations. This 5-year-old child developed severe stomatitis 18 months after institution of divalproex sodium. Cessation of the medication was associated with resolution of the stomatitis. A review of the pertinent literature is also provided. Stomatitis is a rare but potentially serious adverse effect of divalproex sodium administration.

Physician preference for antiepileptic drug concentration testing.

A four-item questionnaire asked active U.S. members of the Child Neurology Society to value painless antiepileptic drug concentration monitoring, whether members had ordered a saliva level (the best established painless method) in the last year, and whether such levels were available. Value was quantified by time per patient that the physician would willingly expend to arrange for the test. Of 945 questionnaires sent, 544 (58%) were returned. When asked the value of a painless method for children, 286/522 (55%) reported willingness to expend 10 to 30 minutes to arrange the test; 498/522 (95%) would use a painless method if available. When asked the value of an immediate sample at home during a seizure or adverse event, a substantial majority, 370/526 (70%), would make an important donation of their own time to arrange for the sample. Only 5% would not use it. Just 2/544 respondents had obtained a painless (saliva) concentration, and merely 33/544 (6%) perceived such tests as being available. We conclude that child neurologists put a high value on painless antiepileptic monitoring. These data suggest that a painless method of measuring antiepileptic drug concentrations--especially if it could be performed at home--would fulfill an unmet need in the care of children with epilepsy.

Herpes simplex encephalitis and radiotherapy.

The pathogenesis underlying the reactivation of latent herpes simplex virus remains undefined. This article presents the case of a 15-year-old male who developed herpes simplex encephalitis, as proven by a positive cerebrospinal fluid polymerase chain reaction and supported by magnetic resonance imaging findings during radiotherapy for pontine glioma. The temporal relation of radiotherapy to the occurrence of herpes simplex encephalitis suggests that cranial irradiation may play a role in the reactivation of latent herpes simplex virus. This finding suggests that herpes simplex encephalitis should be a part of the differential diagnosis of acute neurologic decline in patients undergoing cranial radiotherapy.

Topiramate concentration in saliva: an alternative to serum monitoring.

This study examines the relationship between serum and saliva topiramate concentrations, and attempts to determine if saliva may be a useful alternative to serum for therapeutic monitoring. Saliva and blood specimens were collected from 31 epilepsy patients (mean age 10.5 +/- 6.0 years; range 2.5 years to 24.8 years), and topiramate concentrations were determined by fluorescence polarization immunoassay. One patient's results were omitted because the saliva concentration was below the limit of quantitation of the assay. A strong correlation exists between serum and saliva topiramate concentrations (adjusted r(2) = 0.97, n = 30, P < 0.0001). The mean fraction of saliva to serum concentration is 89.8% +/- 12.1% (range 62.9% to 112.7%). The results of this study support the use of saliva as a viable alternative to serum for monitoring topiramate therapy. Topiramate concentration in saliva: an alternative to serum monitoring.

Conversion to lamotrigine monotherapy from valproate monotherapy in older adolescent patients with epilepsy.

BACKGROUND: Pharmacokinetic interactions can make necessary anti-epileptic medication (AED) changes hazardous for children with epilepsy. We report the utility of a dosing algorithm designed to maintain stable trough lamotrigine (LTG) concentrations during conversion from valproate (VPA) to LTG monotherapy in adolescents aged 16-20 years. METHODS: Patients were enrolled into the study if they required a change in their AED regimen due to lack of efficacy or intolerable side effects. Conversion to LTG monotherapy took place in a four part treatment algorithm. Lamotrigine was escalated according to a target dose of 200 mg/day over 8-weeks. Valproate was withdrawn over a period of 2-6 weeks, depending on the initial dose. Lamotrigine dose was further escalated to 500 mg/day and continued for four weeks as mono therapy. Trough serum concentrations of LTG were measured during each phase of the trial. RESULTS: Twelve of 16 patients completed the study. After the LTG escalation to 200 mg/day, mean trough serum concentrations of 8.0 microg/mL did not differ significantly from the 9.5 microg/mL after VPA withdrawal or the 9.2 microg/mL after 4 weeks of monotherapy at 500 mg/day. Adverse events led to premature discontinuation for one subject. Two subjects withdrew due to worsening seizures during LTG monotherapy possibly due to non-compliance. Limitations of the trial include the open label design and small sample size of the sub-analysis. CONCLUSION: In adolescent patients, this algorithm produces stable LTG serum concentrations with favorable tolerability during a transition from VPA to LTG mono therapy.

An unusual complication of cancer treatment for acute lymphoblastic leukemia.

Childhood cancer is a leading cause of mortality in children less than 15 years of age, accounting for about 10.4 of total childhood deaths [Robinson LL: In: Pizzo PA, Polack DA (eds) Principles and Practice of Pediatric Oncology, 3rd edn. Lippincott--Raven, Philadelphia--NewYork, 1997, pp. 1-10.]. As more aggressive therapeutic regimens have been adopted and ostensibly cured patients are being followed for longer periods of time, it has become increasingly clear that the treatment of cancer can have significant late effects on the growing child, one of the more troublesome of which is the induction of secondary malignancy. We report an 11-year-old child who, as supported by both clinical course and neuroimaging studies, developed an unusual complication eight years after completing therapy for acute lymphoblastic leukemia, gliomatosis cerebri.

Stability of salivary concentrations of the newer antiepileptic drugs in the postal system.

Saliva antiepileptic drug (AED) concentrations strongly correlate with serum concentrations. Saliva collection is painless and noninvasive, and untrained personnel can easily be taught the collection process. Remote patients could mail saliva samples to a laboratory for monitoring, and samples could be obtained in the immediate postictal state to provide a "real-time" concentration. The objectives of this study were to assess the stability of saliva lamotrigine (LMT), levetiracetam (LEV), oxcarbazepine (OXC), topiramate (TPM), and zonsiamide (ZNS) concentrations sent through the United States Postal Service (USPS) and to quantify the amount of time needed for patients and the USPS to return samples to clinic. Saliva samples were obtained from patients currently taking 1 of the targeted AEDs. Samples were split into 2 storage vials. One sample was sealed in an addressed envelope, which the patient mailed from home, whereas the other sample was frozen immediately. Postmark date and day returned were collected for mailed samples. Saliva concentrations were determined using HPLC. Wilcoxon rank sum tests were used to compare the immediately-frozen and mailed sample means. Correlations were determined by the Spearman test. Thirty-seven patients were enrolled in the study. The median time between collection and postmark was 1 day (range 0-6 days); and between collection and receipt was 4 days (range 1-160 days). The mean concentrations for mailed and immediately frozen samples were similar for each AED (P > 0.15). Spearman rank order correlations between mailed and immediately frozen aliquots were strong (LMT rs = 1, LEV rs = 1, OXC rs = 0.964, TPM rs = 0.90, and ZNS rs = 1). Saliva samples mailed by patients maintain stability and can be returned in a reasonable length of time. Further studies are needed to assess patient/caretaker capability of obtaining an adequate sample.

Neurosarcoid presents differently in children than in adults.

BACKGROUND: Neurosarcoid is seldom recognized in children. In the absence of any large pediatric series, it has been assumed that the presenting signs and symptoms are identical in adults and children. OBJECTIVE: To test the hypothesis that childhood neurosarcoid differs in presenting signs and symptoms from neurosarcoid in adults. METHODS: We tabulated the initial neurologic signs and symptoms in all reported cases of childhood sarcoid with evidence of central nervous system involvement. These data then were compared with published studies of adult neurosarcoid. RESULTS: Twenty-nine cases (from the English, French, and German literature) had descriptions of presenting signs and symptoms. Ages were 3 months to 18 years; 48% (14 of 29) presented before 13 years. Seizures were the most common presenting symptom (38%, 11 of 29), and 73% of these children (8 of 11) were <13 years old at presentation. Twenty-one percent (6 of 29) had cranial nerve involvement at presentation, and all were >or=12 years old. Twenty-one percent (6 of 29) had hypothalamic dysfunction. Five children presented with headache, 4 with motor signs, and 3 with papilledema. Twenty-four percent (7 of 29) had mass lesions on imaging. CONCLUSIONS: Children with neurosarcoid present differently than do adults. Children are more likely to have seizures, less likely to have cranial nerve palsies, and perhaps more likely to have a space-occupying lesion. Our analysis of the cases available for review in the published literature suggests that children evolve to an adult pattern as they progress through adolescence.

Correlation of levetiracetam concentrations between serum and saliva.

PURPOSE: More than 100 drugs have been evaluated for salivary therapeutic drug monitoring since the 1970s. The most studied drugs are the anticonvulsants phenytoin, phenobarbital, and carbamazepine, demonstrating strong correlations between serum and saliva concentrations. No published data exist for levetiracetam (LEV) to the authors' knowledge. This study's objective is to determine the correlation between LEV serum and saliva concentrations. METHODS: Investigators identified subjects seen in neurology clinics at the University of Kentucky. Patients were eligible if they agreed to participate in this study, were taking LEV for a minimum of 4 weeks, and if a serum LEV concentration had been ordered by their physician. Patients spit a minimum of 0.25 mL into a cup to obtain saliva samples. Blood samples were obtained by phlebotomy. RESULTS: Serum and saliva LEV concentrations were determined via high-performance liquid chromatography (HPLC) in two separate reference laboratories. Linear regression analysis was used to evaluate correlations. Serum and saliva samples were obtained from 40 patients (22 female, 18 male), ranging from 3 to 57 years of age. The mean +/- SD serum LEV concentration for reference laboratory A was significantly lower (P < 0.0001) than reference laboratory B, 23.6 +/- 13.8 microg/mL and 27.0 +/- 16.9 microg/mL, respectively. The mean +/- SD saliva to serum concentration fraction was also different for the two laboratories, i.e., 41.0% +/- 0.15% for lab A and 36.0% +/- 0.15% for lab B (P = 0.001). The correlation coefficients for the two laboratories were similar, 0.87 and 0.86 (both P < 0.0001) for labs A and B, respectively. CONCLUSION: A significant positive correlation exists between LEV saliva and serum concentrations. The ability to monitor LEV therapy using saliva may provide benefits that include facilitating sample collection and improving the quality of life for persons with epilepsy. Patients with poor venous access, such as children and elderly patients, and persons afraid of needles may particularly benefit from this method.

Feasibility and limitations of oxcarbazepine monitoring using salivary monohydroxycarbamazepine (MHD).

The purpose of this study is to determine the feasibility of using 10-hydroxy-10,11-dihydrocarbazepine (MHD) concentration in saliva as an alternative to serum for the therapeutic monitoring of oxcarbazepine (OXC) treatment. Investigators identified subjects seen in neurology clinics at the University of Kentucky Chandler Medical Center. Patients were eligible if they agreed to participate in this study, were taking oxcarbazepine, and if a serum MHD concentration had been ordered by their physician. Unstimulated saliva specimens (0.25 mL minimum) were collected in the clinic and frozen until analysis. Blood samples were obtained by phlebotomy. Serum specimens were analyzed by a reference laboratory. Saliva MHD concentrations were determined by high-performance liquid chromatography in the Clinical Laboratory at the Cincinnati Children's Hospital Medical Center. Linear regression analysis was used to evaluate correlations. Saliva and blood specimens were collected from 28 epilepsy patients, but usable samples were obtained from only 23. The mean serum MHD concentration was 23.9 +/- 10.0 microg/mL, and the mean saliva concentration was 23.1 +/- 10.1 microg/mL. There was a significant positive correlation between the serum and saliva concentrations: saliva (y) = 0.95 serum (x) + 0.39; r = 0.941; n = 23; P < 0.001). The mean saliva:serum MHD concentration ratio was 0.96 +/- 0.15. The results of the current study indicate that the relationship between freely flowing (unstimulated) saliva and serum concentrations of MHD is sufficient for therapeutic drug monitoring. A limitation of saliva MHD monitoring is that individuals who have difficulty producing small quantities of saliva or who have viscous saliva should generally be avoided for this type of monitoring. It is also recommended to avoid saliva collection within 8 hours after OXC dosing to allow complete absorption and transformation of the parent drug.