Katarina Wide

Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nation‐wide, population‐based register study

Aim: Antiepileptic drugs (AEDs) are known teratogens. Some specificity between different AEDs has been noted in the literature. The aim was to compare the teratogenic effect of valproic acid (VPA) and carbamazepine (CBZ) in monotherapy. Methods: Infants exposed to AEDs (n= 1398) in early pregnancy were identified from the Swedish Medical Birth Registry. The number of infants with congenital malformations and exposed to AED was compared with the expected number estimated from all infants born (n= 582656). Results: 90% (1256) of the AED exposed children were exposed to AEDs in monotherapy, 56% were exposed to CBZ and 21% to VPA. The odds ratio (OR) for having a malformation in the AED exposed group was 1.86 [95% confidence interval (95% CI) 1.42‐2.44]. Exposure to VPA in monotherapy compared with CBZ in monotherapy gave OR = 2.51 (95% CI 1.43‐4.68) for a neonatal diagnosis of malformations. However, there is no information available on the number of therapeutic abortions, or the different types of epilepsy or drug dosage in the two treatment groups.

Distal 3p deletion syndrome: Detailed molecular cytogenetic and clinical characterization of three small distal deletions and review†

The distal 3p deletion syndrome is characterized by developmental delay, low birth weight and growth retardation, micro‐ and brachycephaly, ptosis, long philtrum, micrognathia, and low set ears. We have used FISH and BACs in order to map three 3p deletions in detail at the molecular level. The deletions were 10.2–11 Mb in size and encompassed 47–51 known genes, including the VHL gene. One of the deletions was interstitial, with an intact 3p telomere. In nine previously published patients with 3p deletions, the size of the deletion was estimated using molecular or molecular cytogenetic techniques. The genotype, including genes of interest, and the phenotype of these cases are compared and discussed. The localization of the proximal breakpoint in one of our patients suggests that the previously identified critical region for heart defects may be narrowed down, now containing three candidate genes. We can also conclude that deletion of the gene ATP2B2 alone is not enough to cause hearing impairment, which is frequently found in patients with 3p deletion. This is the third reported case with an interstitial deletion of distal 3p.

Pregnancy, delivery, and neonatal complications after treatment with antiepileptic drugs

Aim. To study the risk for complications during pregnancy, delivery, and neonatal period after the use of antiepileptic drugs (AEDs) during pregnancy.

Acute neurological complications after hematopoietic stem cell transplantation in children

Abstract:  Children undergoing hematopoietic stem cell transplantation (HSCT) may develop toxicity‐related neurological complications (NC). Known risk factors include total body irradiation (TBI) and the use of busulfan or cyclosporine A, but other risk factors might also be of importance. The medical records of 144 children (0–18 yr) who underwent their first HSCT at Karolinska University Hospital (Huddinge) between 1995 and 2002 were reviewed retrospectively concerning pretransplantation parameters and clinical course during the first 3 months after HSCT. Sibling donors were used in 49 transplantations, unrelated donors in 88 and haploidentical donors in seven cases. Nineteen patients (13%) developed NC within the first 3 months after HSCT. A significant association was seen between pretransplant viral status, defined as a higher number of positive herpes group viral serologies in the recipient before transplantation, and NC (p = 0.04). A significant association was also seen for CMV‐positive recipients and NC (p = 0.01) as well as for disturbances in serum levels of sodium, potassium and calcium and NC. No association was found between sex, age at HSCT, underlying disease, previous neurological symptoms, the conditioning regimen, GVHD, donor type and NC. Number of positive herpes group viral serologies in the recipient before transplantation and certain electrolyte disturbances may contribute to neurological complications after HSCT.

School performance at age 16 in children exposed to antiepileptic drugs in utero—A population-based study

Purpose:  In order to evaluate long‐term effects on neurodevelopment in children born to women with epilepsy during pregnancy we studied the children’s school grades at age 16.

Age and Comedications Influence Levetiracetam Pharmacokinetics in Children

The pharmacokinetics of many antiepileptic drugs differs between adults and children. The influence of age and concomitant medications on the dose/concentration ratio of levetiracetam was examined in 103 children with epilepsy. Dosing and plasma levels of levetiracetam and concomitant antiepileptic drugs were reviewed retrospectively. The dose/concentration ratio was calculated as the weight-normalized dose (mg/kg/day) divided by the steady-state trough plasma drug level, which was used as a measure of apparent oral clearance of levetiracetam. Children were classified into age groups and treatment groups: levetiracetam given with enzyme inducers (n = 24) or nonenzyme inducers (n = 69), or as monotherapy (n = 10). Levetiracetam clearance differed significantly between age groups (0-4, 5-11, and 12-17 years), i.e., the younger the child, the higher the clearance. The increase was 1.7-fold between the youngest and oldest age groups. Children on enzyme inducers exhibited significantly higher clearance (1.3-fold), compared with those on nonenzyme inducers and monotherapy. Levetiracetam did not influence the clearance of lamotrigine, valproate, topiramate, or clonazepam. In conclusion, younger age and comedication with an enzyme inducer increased levetiracetam clearance. This finding should be taken into account when treating individual patients.

Pediatric tick-borne infections of the central nervous system in an endemic region of Sweden: a prospective evaluation of clinical manifestations

Tick-borne encephalitis (TBE) and neuroborreliosis (NB) are well-known central nervous system (CNS) infections in children. Childhood tick-borne CNS infections are generally described as mild conditions. However, this view has recently been challenged, and the natural course, including potential sequelae, has been debated. If the diseases present with nonspecific symptoms and signs, some children may elude diagnosis. This study estimates the incidence of symptomatic tick-borne CNS infections in children under medical care and describes the spectrum of manifestations. One hundred twenty-four children with neurologic symptoms attending the Pediatric Emergency Department were included prospectively. Anti-TBE virus and anti-Borrelia serology results were analyzed together with inflammatory parameters in the blood and cerebrospinal fluid. Nearly one fourth of the children with neurologic symptoms were diagnosed with a tick-borne CNS infection (TBE, n = 10 [8%] and NB, n = 21 [16.8%]). In general, these children displayed an indistinct medical history and presented with nonspecific signs such as malaise/fatigue and headache. Diagnosis was based on analysis of acute and convalescent sera. Blood inflammatory parameters were nonspecific and did not contribute to the diagnostics. Conclusion: Pediatric tick-borne CNS infections are unexpectedly common and should be considered in children with unspecific and unexplained acute CNS-related symptoms.

Tick-borne encephalitis in childhood: rare or missed?

Retrospective evaluation of medical history and 3635 anti-TBE (tick-borne encephalitis) serologies during the years 2003–2008 indicates that childhood TBE is characterized by vague symptoms. Clinical findings suggest a nonspecific inflammatory disease with restricted encephalitic profile compared with adult TBE. Childhood TBE might elude diagnosis, which is unsatisfactory because of potential long-term consequences.

Intrathecal chemoprophylaxis after HSCT in children.

Abstract:  At present, the literature on the efficacy and risks of i.t. chemotherapy to children after HSCT is scarce. Current practices to reduce the risk of leukemic relapse in the CNS after HSCT differ between centers of transplantation. We compared 74 patients (56 ALL/18 AML), who received i.t. therapy post‐HSCT with 46 patients (36 ALL/10 AML) who did not receive post‐HSCT i.t. therapy. The patients were transplanted at the University Children’s Hospital, Uppsala or the Karolinska University Hospital, Huddinge, two Swedish transplantation units with different routines concerning i.t. therapy after HSCT. The primary end‐point was the number of isolated CNS relapses. Secondary end‐points were other types of relapse, death, and neurological complications. There was no statistically significant difference in the incidence of CNS relapses between the groups (p > 0.05). I.t. therapy did not reduce the overall incidence of isolated CNS relapse or mortality. Our study did not demonstrate a protective effect of i.t. therapy indicating that post‐HSCT i.t. therapy may only be of limited use in the treatment of acute childhood leukemia. We conclude that with the risks present, i.t. therapy should be carefully evaluated, and only considered in high‐risk cases.

Plasma nitrate/nitrite removal by peritoneal dialysis might predispose infants with low blood pressure to cerebral ischaemia

The underlying pathogenic mechanisms of neurological complications in infants undergoing peritoneal dialysis (PD) are poorly understood. We report on four male infants treated with PD who developed symptomatic cerebral ischaemia. Blood pressure (BP) levels were low both before the event and at presentation. In two patients, we observed that the removal of nitrate and nitrite by PD could have impaired the nitrate/nitrite–-nitrite oxide (NO) pathway, a system that generates NO independently of NO synthase. Our observation suggests that low BP and reduced NO bioavailability puts infants treated with PD at risk for impaired cerebral blood flow and consequently for brain ischaemia.