Ictal and interictal electric source imaging in pre-surgical evaluation: a prospective study.

BACKGROUND AND PURPOSE: Accurate localization of the epileptic focus is essential for surgical treatment of patients with drug-resistant epilepsy. Electric source imaging (ESI) is increasingly used in pre-surgical evaluation. However, most previous studies have analysed interictal (II) discharges. Prospective studies comparing the feasibility and accuracy of II and ictal (IC) ESI are lacking. METHODS: We prospectively analysed long-term video-electroencephalography recordings (LTM) of patients admitted for pre-surgical evaluation. We performed ESI of II and IC signals using two methods, i.e. equivalent current dipole (ECD) and a distributed source model (DSM). LTM recordings employed the standard 25-electrode array (including inferior temporal electrodes). An age-matched template head model was used for source analysis. Results were compared with intracranial recordings, conventional neuroimaging methods [magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT)] and outcome at 1 year after surgery. RESULTS: A total of 87 consecutive patients were analysed. ECD gave a significantly higher proportion of patients with localized focal abnormalities (94%) compared with MRI (70%), PET (66%) and SPECT (64%). Agreement between the ESI methods and intracranial recording was moderate to substantial (k = 0.56-0.79). A total of 54 patients were operated (47 patients more than 1 year ago) and 62% of them became seizure-free. The localization accuracy of II-ESI was 51% for DSM and 57% for ECD, and that for IC-ESI was 51% for DSM and 62% for ECD. The differences between the ESI methods were not significant. Differences in localization accuracy between ESI and MRI (55%), PET (33%) and SPECT (40%) were not significant. CONCLUSIONS: The II-ESI and IC-ESI of LTM data have high feasibility and their localization accuracy is similar to that of conventional neuroimaging methods.

Risk of impaired cognition after prenatal exposure to psychotropic drugs.

OBJECTIVE: Prenatal exposure to psychotropic drugs may affect the trajectories of brain development. In a register study, we investigated whether such exposure is associated with long-term impaired cognitive abilities. METHOD: Individuals born in Denmark in 1995-2008 were included. As proxies for cognitive impairment, requiring special needs education, attending special needs school, diagnoses of neurological/mental disorder, missed final examinations, and low school grade average were used. We accounted for maternal confounders. RESULTS: We identified 868 159 individuals of whom 13 983 (1.6%) were prenatally exposed. The adjusted odds ratio (OR) was 0.97[0.92-1.02] for requiring special needs education, 1.28[1.14-1.43] for attending special needs school, 1.32[1.20-1.46] for a neurological/mental disorder diagnosis, 1.37[1.22-1.54] for missing the final examinations, and 1.13[0.82-1.55] for obtaining a low school grade average. Exposure to psycholeptics (primarily antipsychotics and sedatives) was correlated with significantly increased risk for four outcomes. The highest was the risk of missing the primary school examinations (OR: 1.51[1.29-1.76]). The overall highest risk concerned the presence of a neurological/mental disorder after prenatal exposure to psychoanaleptics (primarily antidepressants) (OR: 1.86[1.24-2.78). CONCLUSION: Prenatal exposure to psychotropic drugs affects proxy outcomes of cognitive disabilities at school age. Exposure to psycholeptics carries the largest risk. The role of psychoanaleptics is currently unclear.

Unstable insertion in the 5' flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1.

Progressive myoclonus epilepsy type 1 (EPM1, also known as Unverricht-Lundborg disease) is an autosomal recessive disorder characterized by progressively worsening myoclonic jerks, frequent generalized tonic-clonic seizures, and a slowly progressive decline in cognition. Recently, two mutations in the cystatin B gene (also known as stefin B, STFB) mapping to 21q22.3 have been implicated in the EPM1 phenotype: a G-->C substitution in the last nucleotide of intron 1 that was predicted to cause a splicing defect in one family, and a C-->T substitution that would change an Arg codon (CGA) to a stop codon (TGA) at amino acid position 68, resulting in a truncated cystatin B protein in two other families. A fourth family showed undetectable amounts of STFB mRNA by northern blot analysis in an affected individual. We present haplotype and mutational analyses of our collection of 20 unrelated EPM1 patients and families from different ethnic groups. We identify four different mutations, the most common of which consists of an unstable approximately 600-900 bp insertion which is resistant to PCR amplification. This insertion maps to a 12-bp polymorphic tandem repeat located in the 5' flanking region of the STFB gene, in the region of the promoter. The size of the insertion varies between different EPM1 chromosomes sharing a common haplotype and a common origin, suggesting some level of meiotic instability over the course of many generations. This dynamic mutation, which appears distinct from conventional trinucleotide repeat expansions, may arise via a novel mechanism related to the instability of tandemly repeated sequences.

Multiplicity and early gestational age contribute to an increased risk of cerebral palsy from assisted conception: a population-based cohort study.

BACKGROUND: This paper assesses the risk of cerebral palsy (CP) in children born after assisted conception compared with children born after natural conception (NC). METHODS: This population based follow-up study included all 588,967 children born in Denmark from 1995 to 2003. Assisted conception was defined as IVF, with or without ICSI, and ovulation induction (OI), with or without subsequent insemination. RESULTS: There were 33 139 (5.6%) children born in Denmark from 1995 to 2003 as a result of assisted conception and through to June 2009, 1146 (0.19%) children received a CP diagnosis. Children born after assisted conception had an increased risk of a CP diagnosis, crude hazard rate ratio (HRR) 1.90 (95% CI: 1.57-2.31) compared with NC children. Divided into IVF and OI children compared with NC children, the risk was HRR 2.34 (95% CI: 1.81-3.01) and HRR 1.55 (95% CI: 1.17-2.06), respectively. When we included the intermediate factors multiplicity and gestational age in multivariate models, the risk of CP in assisted conception disappeared. In general, children with CP born after assisted conception had similar CP subtypes and co-morbidities as children with CP born after NC. CONCLUSION: The risk of CP is increased after both IVF and OI. The increased risk of CP in children born after assisted conception, and in particular IVF, is strongly associated with the high proportion of multiplicity and preterm delivery in these pregnancies. A more widespread use of single embryo transfer warrants consideration to enhance the long-term health of children born after IVF.

Intraoperative hyperventilation vs remifentanil during electrocorticography for epilepsy surgery - a case report.

BACKGROUND: Traditionally, intraoperative intracranial electroen-cephalography-recordings are limited to the detection of the irritative zone defined by interictal spikes. However, seizure patterns revealing the seizure onset zone are thought to give better localizing information, but are impractical due to the waiting time for spontaneous seizures. Therefore, provocation by seizure precipitants may be used with the precaution that spontaneous and provoked seizures may not be identical. OBJECTIVE: We present evidence that hyperventilation induced and drug induced focal seizures may arise from different brain regions in the same patient. METHODS: Hyperventilation and ultra short acting opioid remifentanil were used separately as intraoperative precipitatants of seizure patterns, while recording from subdural and intraventricular electrodes in a patient with temporal lobe epilepsy. Two different ictal onset zones appeared in response to hyperventilation and remifentanil. Both zones were resected and the patient has remained essentially seizure free for 1 year. Furthermore, this is the first description of hyperventilation used as an intraoperative seizure precipitant in human focal epilepsy.

Asphyxia-related risk factors and their timing in spastic cerebral palsy.

OBJECTIVE: To investigate the association of asphyxia-related conditions (reducing blood flow or blood oxygen levels in the fetus) with spastic cerebral palsy (CP) considering different gestational age groups and the timing of risk. DESIGN: Population-based case-control study. SETTING: Danish Cerebral Palsy Register in eastern Denmark and Danish Medical Birth Register. POPULATION OR SAMPLE: 271 singletons with spastic CP and 217 singleton controls, frequency matched by gestational age group, born 1982-1990 in eastern Denmark. METHODS: Data were abstracted from medical records, and a priori asphyxia-related conditions and other risk factors were selected for analysis. Each factor was classified according to the time at which it was likely to first be present. MAIN OUTCOME MEASURES: Spastic CP. RESULTS: Placental and cord complications accounted for the majority of asphyxia conditions. In multivariate analysis, placental infarction was significantly associated with a four-fold increased risk for spastic quadriplegia and cord around the neck was significantly associated with a three-fold increased risk for spastic CP overall. The combination of placental infarction and being small for gestational age (SGA) afforded an especially high risk for spastic quadriplegia. Placental and cord complications were present in 21% of cases and 12% of controls. CONCLUSIONS: The risk for spastic quadriplegia from placental infarction may be linked in some cases with abnormal fetal growth (17% of all children with spastic quadriplegia and 3% of control children both had an infarction and were SGA) -- suggesting an aetiologic pathway that encompasses both factors. The risk for spastic CP from cord around the neck is not accounted for by other prepartum or intrapartum factors we examined. Considering the relative timing of risk factors provides a useful framework for studies of CP aetiology.

Fatal hemothorax caused by a subclavian hemodialysis catheter. Thoughts on prevention.

A 19-year-old woman died when a subclavian catheter that had provided vascular access for plasmapheresis penetrated her right atrium, pericardium, and parietal pleural, causing a hemothorax. Precautions are recommended to minimize the risk of this complication in patients in whom subclavian catheters are used as a vascular access route for hemodialysis or plasmapheresis.

Whole-body protein turnover in adult hemodialysis patients as measured by 13C-leucine.

Muscle wasting may occur in patients with chronic renal failure (CRF). To determine whether this is due to a decrease in the synthesis or an increase in the breakdown of muscle protein, we evaluated postabsorptive whole-body protein breakdown, oxidation, and synthesis rates at steady state during a primed, continuous infusion of 13C-leucine. This was done in seven subjects on chronic maintenance hemodialysis (MHD) and in seven normal control subjects. The protein breakdown rate in MHD was not different from that in controls (103 +/- 19 and 106 +/- 19 mumol leucine.kg-1.h-1, respectively). In MHD, however, the protein oxidation rate was 43% greater than that in controls (20 +/- 6 and 14 +/- 4 mumol leucine.kg-1.h-1, p less than 0.05), whereas net protein synthesis was less (p less than 0.05). Reduced net synthesis and increased oxidation rates of protein in the postabsorptive state may therefore contribute to the muscle-wasting syndrome in patients with CRF.

Skeletal muscle function in chronic renal failure: an index of nutritional status.

To determine whether skeletal muscle function testing (SMF) provides an index of nutritional status in patients with chronic renal failure (CRF), two groups with comparable CRF were studied. In 48 well-nourished (WN) and 17 malnourished (MN) patients with stable CRF, and in 33 WN nonazotemic controls, adductor pollicis function was assessed. The force at 10 Hz was expressed as a % of force at 100 Hz (F10/F100), and maximal relaxation rate (MRR) as % force loss/10 ms. Standard nutritional assessment was also performed. The WN group was not significantly different from controls for either F10/F100 or MRR. The F10/F100 of the MN group was significantly greater than either the WN group or controls (p less than 0.001), while MRR was less (p less than 0.001). Significant malnutrition by conventional parameters was shown in patients with abnormal F10/F100, and also in patients with abnormal MRR. Hence, SMF as described is unaffected by azotemia, and provides a functional measure of nutritional status in CRF.

Relation of immediate post-transplant renal function to long-term function in cadaver kidney recipients.

Renal function studies 12 to 41 months after transplantation have been performed on seven cadaver renal allograft recipients who demonstrated immediate primary function after transplant (group A) and seven similar recipients who had delayed primary function (group B). The groups were matched as closely as possible for major physical characteristics and their postoperative management; in particular, only one patient had a post-transplant renal biopsy. Glomerular filtration rate was determined by 24-hr creatinine clearance, endogenous creatinine clearance, and inulin clearance was usually lower in those patients having delayed primary function and they excreted more glucose per 24 hr and reabsorbed a smaller proportion of the filtered glucose load under infusion conditions. These results are discussed in relation to the effect of immediate and delayed primary function on the long-term prognosis of such patients.

Immunosuppression with polyunsaturated fatty acids in renal transplantation.

A double-blind controlled trial has been undertaken to assess the value of a preparation containing polyunsaturated fatty acids (PUFA) in human cadaveric renal transplantation. Eighty-nine patients were studied and followed for 6 months after transplantation. Forty-four took the PUFA preparation and 45 the placebo (oleic acid). Other immunosuppression was standardised. Functional graft survival was significantly better in the PUFA group than in those taking the placebo during the first 3 to 4 months post-transplant. At 6 months, however, although the difference between the groups persisted, it was no longer statistically significant. Complications were equally distributed between the groups.

Validation of a cerebral palsy register.

OBJECTIVES: To analyse completeness and validity of data in the Cerebral Palsy Register in Denmark, 1979-1982. METHODS: Completeness has been assessed by comparing data from The Danish National Patient Register (DNPR) with the cases included in the Cerebral Palsy Register (CPR). Agreement between 12 variables in the CPR and obstetrical medical records has been analysed using kappa-statistics. RESULTS: Of 468 children in the DNPR, only 237 fulfilled the inclusion criteria of the CPR; and 35 (15%) of these cases had not been reported to the CPR. Data agreement was generally good, but gestational age was subject to a systematic error, and urinary infections in pregnancy (kappa = 0.43) and placental abruption (kappa = 0.52) were seriously under-reported in the CPR. CONCLUSIONS: Completeness of the Cerebral Palsy Register in Denmark, 1979-1982, has been assessed to maximal 85%, emphasizing the impact of using supplementary case ascertainment sources in the future. Validity of data varied according to definition and significance of the specific variable.

Proteins and fibrinolysis in recipients of renal allografts.

Studies of serum proteins, platelets, and fibrinolysis in patients after renal allografting show that a fall in plasma fibrinogen in the postoperative period can be associated with early rejection and that a rise in serum fibrin degradation products when accompanied by a fall in platelets is associated with rejection. Fibrinolysis is depressed in these patients until two months after transplantation and marked depression of fibrinolysis may precede rejection. The late coincidence of fibrinolytic depression with a rise in fibrin degradation products suggests chronic insidious rejection.

Altered reticuloendothelial function in long-term renal allograft recipients.

Using the clearance of microaggregated iodinated human serum albumin reticuloendothialial system (RES) phagocytic function was tested in 48 long-term renal allograft recipients and was found to be defective at the time of testing in 70%. Depression of RES phagocytosis could be related to total steroid dosage in the previous year and to the patients liability to bacterial infections. Evidence from this test does not suggest an immunosuppressive effect of cytomegalovirus. However, three patients are discussed who have developed chronic active hepatitis that is not due to type B virus.

Lamotrigine plasma levels reduced by oral contraceptives.

Although it is known that the use of oral contraceptives (OC's) can induce glucuronide conjugating enzymes, currently no data exists as to the potential that the elimination of the glucuronidated drug lamotrigine (LTG) is increased by OC's. We present seven cases in whom the plasma levels of LTG were significantly decreased by OC's (mean 49%, range 41-64%). The interaction was of clinical relevance in most of the patients who either experienced increased seizure frequency/recurrence of seizures after OC's had been added, or adverse effects following withdrawal of OC's.

Tiagabine adjunctive therapy in children with refractory epilepsy: a single-blind dose escalating study.

Tiagabine, a specific gamma-aminobutyric acid-uptake inhibitor, has been shown to be reasonably well tolerated and efficacious as adjunctive treatment for partial seizures in adults and is now being investigated in children. This 4-month, single-blind study evaluated the tolerability, safety and preliminary efficacy of ascending doses (0.25-1.5 mg/kg/day) of tiagabine add-on therapy in 52 children over the age of 2 years with different syndromes of refractory epilepsy. Adverse events, mostly mild to moderate, were reported by 39% of children during the single-blind placebo period and by 83% of children during tiagabine treatment. The events predominantly affected the nervous system with asthenia (19%), nervousness (19%), dizziness (17%) and somnolence (17%) being the most common. Only three children (6%) withdrew because of adverse events. Tiagabine appeared to reduce seizures more in localisation-related epilepsy syndromes than in generalised epilepsy syndromes. Twenty-three patients with localisation-related epilepsy syndromes were included and 17 of these patients entered the fourth dosing period. The 17 patients had a median reduction of seizure rate in the fourth month of treatment of 33% compared with baseline. In comparison, 13 of 22 children with seven different generalised epilepsy syndromes entered the fourth dosing period with a median change of seizure rate of 0%. Two patients experienced single episodes of status epilepticus during treatment; both cases resolved. Tiagabine showed efficacy mainly in localisation-related syndromes and was well tolerated by most children in a group of very refractory patients and warrants further study in children with epilepsy.

Landau-Kleffner syndrome with onset at 18 months and an initial diagnosis of pervasive developmental disorder.

We report one of the youngest and most intensively studied cases of Landau-Kleffner syndrome, with a follow-up of 5 years. The boy developed normally until the age of 18 months when he had two attacks, possibly epileptic. Electroencephalogram (EEG) was normal. Over the next 5 months he lost his six to ten words, did not engage with other children and became mute. When he was 34 months old a child-psychiatrist suggested a diagnosis of pervasive developmental disorder or developmental dysphasia. An EEG 3 months later showed abnormalities typical of Landau-Kleffner syndrome. His non-verbal abilities were normal as well as his neurological examination and brain magnetic resonance imaging (MRI). A trial of clobazam and vigabatrin was unsuccessful. When he was 4 years and 9 months old he was treated with corticosteroids and within 3 months his vocabulary increased from the standard for 1 1/2 years of age to that for 2 1/2 years of age. His language abilities continued to improve slowly until a stagnation period at the age of 6 years and 9 months. A second course of corticosteroids improved his comprehension and vocabulary to an almost normal level, and his EEG normalized. A total of 11 EEGs were obtained; all included sleep, but continuous spike and wave during slow sleep was never documented. This report illustrates that Landau-Kleffner syndrome should be considered as an alternative diagnosis in children diagnosed with developmental dysphasia. An EEG including sleep should be considered, and in the presence of abnormalities a trial of anti-epileptic drugs or corticosteroids should be undertaken.

Clinical experiences with topiramate in children with intractable epilepsy.

At a tertial referral epilepsy centre 39 children were consecutively enrolled in an open add-on study with topiramate (TPM). All children had intractable epilepsy; the mean seizure frequency was 36 per month, and 31 children were treated with polypharmacy. All but five children were mentally retarded. The initial dose of TPM was 0.5-1 mg/kg daily, slowly titrated with 1-3 mg/kg daily every second week with an estimated target dose of 10 mg/kg daily. At latest follow-up 19 children continued on TPM, three (8%) were seizure-free, eight (21%) had a seizure reduction of more than 50% and eight (21%) improved their general condition. Mean follow-up was 13 months (range 9-36 months). Seizure reduction was seen in focal as well as generalized epilepsies. Adverse effects were reported in 21 cases (54%), weight loss and sedation being most frequent. The mean steady state dose in the children continuing on TPM was at latest follow-up: 14 mg/kg daily (< 5 years), 10 mg/kg daily (5-7 years), 5.8 mg/kg daily (8-17 years). The corresponding plasma level varied from 3 to 45 mumol/litre, and a significant correlation between the daily dose in mg/kg and the plasma level was found. Two patients with progressive myoclonus epilepsy are described separately; one had a dramatic general improvement. It is concluded that TPM seems to be a promising new broad-spectrum anti-epileptic drug, which is efficacious even in epilepsy syndromes, intractable to other new anti-epileptic drugs such as vigabatrin and lamotrigine.

Provocation of non-convulsive status epilepticus by tiagabine in three adolescent patients.

Three girls, two aged 12 years and one aged 17 years with refractory localization-related epilepsy were treated on an add-on basis with tiagabine. At dosages 22.5-30 mg/day (0.45-0.57 mg/kg/day) longstanding non-convulsive status epilepticus was noted in all three patients. The events of non-convulsive status epilepticus subsided following reduction in tiagabine dosages. In two cases, tiagabine was withdrawn, whereas it was continued at a lower dosage in one case. This is the first report of non-convulsive status epilepticus provoked by tiagabine in adolescent patients.

Vigabatrin in pediatric epilepsy--an open study.

The antiepileptic effect of vigabatrin in adults has been demonstrated in a number of controlled studies. In children, the effect of vigabatrin has been investigated only to a limited extent. In order to assess the long-term effect and safety of vigabatrin in patients with severe epilepsy, an open, add-on, dose-ranging study was initiated. To date, 27 children with partial epilepsy, two with generalized epilepsy, two with Lennox-Gastaut syndrome, and one with nonclassifiable epilepsy have been enrolled in the trial. Fifty-four percent of patients have experienced a greater than 50% reduction in seizure frequency, and four patients have become seizure free. A significant reduction in seizures was noted across the patient population, although patients who were recorded as seizure free at 3 and 6 months did suffer some recurrence of seizures. However, when seizures recurred, they did so at much lower frequency than recorded at the start of the study. Thirteen patients (39%) reported adverse events attributable to vigabatrin; one was immediately withdrawn from the study, and six had their vigabatrin dose reduced. No physiologic effects were noted on normal growth or clinical physical examination.