Search

Macrophage (Mϕ) repolarization from a pro-tumor, immunosuppressive phenotype towards an anti-tumor, pro-inflammatory state represents a promising therapeutic strategy in patients with cancer1. Successful reprogramming of Mϕ in a clinical setting has not been documented. Here, we traced the evolution at single-cell resolution of a diffuse midline glioma (DMG) with H3K27M mutation which metastasized in the abdomen after placing a ventriculoperitoneal (VP) shunt and exploited this information for therapeutic decision-making. The primary tumor showed a complex cellular and genomic landscape characterized by heterogeneous cancer cells and a tumor-supportive immune microenvironment. Upon metastasis, malignant cells populated the peritoneum and triggered a massive anti-inflammatory immune cell infiltration and expansion of myeloid-derived suppressor cells (MDSCs) in peripheral blood. Hydroxychloroquine adjuvant treatment started to overcome the immunosuppressive milieu, which resulted in a decrease in peritoneal cancer cells and pro-tumor innate immune cells. Importantly, an emergence of anti-tumor, pro-inflammatory macrophages and cytotoxic T-cells was observed, accompanied by the activation of monocytes in the blood. Our study advocates the employment of single-cell technologies to better understand and inspire therapeutic regimens in patients with cancer.

In de loop van de tijd is de visie ten aanzien van afbouw van anti-epileptica na kinderepilepsiechirurgie veranderd. Hier wordt het onderzoek beschreven dat is gedaan naar het effect van afbouw van anti-epileptica bij deze kinderen. Ook wordt aangegeven hoe het resultaat van dit onderzoek heeft bijgedragen aan de verandering van het postoperatieve medicatiebeleid.

ObjectiveAntiepileptic drugs (AEDs) have cognitive side effects that, particularly in children, may affect intellectual functioning. With the TimeToStop (TTS) study, we showed that timing of AED withdrawal does not majorly influence long-term seizure outcomes. We now aimed to evaluate the effect of AED withdrawal on postoperative intelligence quotient (IQ), and change in IQ (delta IQ) following pediatric epilepsy surgery. MethodsWe collected IQ scores of children from the TTS cohort with both pre- and postoperative neuropsychological assessments (NPAs; n=301) and analyzed whether reduction of AEDs prior to the latest NPA was related to postoperative IQ and delta IQ, using linear regression analyses. Factors previously identified as independently relating to (delta) IQ, and currently identified predictors of (delta) IQ, were considered possible confounders and used for adjustment. Additionally, we adjusted for a compound propensity score that contained previously identified determinants of timing of AED withdrawal. ResultsMean interval to the latest NPA was 19.818.9 months. Reduction of AEDs at the latest NPA significantly improved postoperative IQ and delta IQ (adjusted regression coefficient [RC]=3.4, 95% confidence interval [CI]=0.6-6.2, p=0.018 and RC=4.5, 95% CI=1.7-7.4, p=0.002), as did complete withdrawal (RC=4.8, 95% CI=1.4-8.3, p=0.006 and RC=5.1, 95% CI=1.5-8.7, p=0.006). AED reduction also predicted 10-point IQ increase (p=0.019). The higher the number of AEDs reduced, the higher was the IQ (gain) after surgery (RC=2.2, 95% CI=0.6-3.7, p=0.007 and RC=2.6, 95% CI=1.0-4.2, p=0.001, IQ points per AED reduced). InterpretationStart of AED withdrawal, number of AEDs reduced, and complete AED withdrawal were associated with improved postoperative IQ scores and gain in IQ, independent of other determinants of cognitive outcome. Ann Neurol 2015;78:104-114

Summary This retrospective study evaluates the impact of postoperative antiepileptic drug (AED) withdrawal on psychomotor speed in seizure-free children, operated for medically refractory epilepsy. Post-surgical medication policy and neuropsychological assessments (performed shortly before and 6, 12 and 24 months after surgery), were evaluated in 57 children (32 female, median age at surgery 13 years). Patients were divided into a withdrawal ( n =29) and a no-withdrawal group ( n =28). Scores of four psychomotor tests performed at 12 and 24 months after surgery were compared with those of postoperative baseline measurements, performed 6 months after surgery. At 24 months, the withdrawal group had improved significantly more than the no-withdrawal group on three of four tests; reaction time to light ( p =0.031), reaction time to sound ( p =0.045) and tapping ( p =0.003). At 12 months, a non-significant tendency in the same direction was found for both reaction time tests. Drug withdrawal after surgery improves psychomotor speed and may unleash the potential for cognitive improvement.

Item does not contain fulltext Prediction of functional motor outcome after hemispherectomy is difficult due to the heterogeneity of motor outcomes observed. We hypothesize that this might be related to differences in plasticity during the onset of the underlying epileptogenic disorder or lesion and try to identify predictors of motor outcome after hemispherectomy. Thirty-five children with different etiologies (developmental, stable acquired or progressive) underwent functional hemispherectomy and motor function assessment before hemispherectomy and 24 months after hemispherectomy. Preoperatively, children with developmental etiologies performed better in terms of distal arm strength and hand function, but not on gross motor function tests. Postoperatively, the three etiology groups performed equally poor in muscle strength and hand function, but gross motor function improved in those with acquired and progressive etiologies. Loss of voluntary hand function and distal arm strength after surgery was associated with etiology, intact insular cortex and intact structural integrity of the ipsilesional corticospinal tract on presurgical MRI scans. In conclusion, postoperative motor function can be predicted more precisely based on etiology and on preoperative MRI. Children with developmental etiology more often lose distal arm strength and hand function and show less improvement in gross motor function, compared to those with acquired pathology.

We aimed to replicate the association of the IVS3-35A>G polymorphism in the activin receptor-like kinase (ACVRL) 1 gene and the 207G>A polymorphism in the endoglin (ENG) gene with sporadic brain arteriovenous malformations (BAVM) in Dutch BAVM patients. In addition, we assessed whether these polymorphisms contribute to the risk of BAVM in patients with hereditary haemorrhagic telangiectasia type 1 (HHT1). We genotyped 143 Dutch sporadic BAVM patients and 360 healthy volunteers for four variants in the ACVRL1 gene including IVS3-35A>G and two variants in the ENG gene including 207G>A. Differences in allele and genotype frequencies between sporadic BAVM patients and controls and their combined effect were analysed with a likelihood ratio test. Furthermore, we compared the allele and genotype frequencies between 24 HHT1 patients with a BAVM with those of a relative with HHT1 without a BAVM in a matched pair analysis using Wilcoxon signed rank test. No significant differences in allele frequency were found between sporadic BAVM cases and controls or between HHT1 patients with and without BAVM for any of the polymorphisms or the combination of ACVRL1 and ENG polymorphisms. Meta-analysis of the current and the two previous studies for the ACVRL1 IVS3-35A polymorphism showed a persisting association between the ACVRL1 IVS3-35A polymorphism and risk of sporadic BAVM (odds ratio, 1.86; 95% CI: 1.32-2.61, pG and BAVM in Dutch patients. However, meta-analysis did not rule out a possible effect.

Objective: To explore whether EEG and MRI abnormalities in the “healthy” hemisphere influence seizure and cognitive outcome after functional hemispherectomy. Methods: This is a retrospective consecutive cohort study of 43 children who underwent functional hemispherectomy between 1994 and 2008. Results of preoperative EEG recordings were reviewed for the existence of (inter)ictal epileptic or background abnormalities in the contralateral hemisphere. Preoperative MRIs were reexamined for the existence of unequivocal contralateral abnormalities. Postoperative seizure status was assessed, and of 34 children, IQ or mental developmental index (MDI) scores were obtained preoperatively and postoperatively. Seizure freedom was defined as Engel 1A. Contralateral EEG and MRI abnormalities were studied in relation to seizure and cognitive outcome. Results: Thirty-three children achieved seizure freedom (77%). Of the 11 patients with contralateral MRI abnormalities, only 45% were seizure free, compared with 88% of the 32 patients without contralateral MRI lesions ( p = 0.030). Children with contralateral MRI abnormalities more often were severely retarded after surgery (MDI/IQ p = 0.030). Postoperative MDI/IQ scores improved in none of the children with, but in 38% of those without contralateral MRI abnormalities ( p = 0.034). Contralateral epileptic or background EEG abnormalities did not affect seizure outcome or postoperative cognitive performance. Four of 6 children with bilateral epileptic encephalopathy reached seizure freedom. Conclusion: Unambiguous contralateral MRI abnormalities are significantly associated with seizure recurrence, severe mental delay, and lack of cognitive improvement and may be considered a relative contraindication for hemispherectomy. Contralateral EEG abnormalities do not negatively influence postsurgical outcome.

The postsurgical medication policy was reviewed for 109 children (age at surgery, 0-16 years) who had epilepsy surgery between 1991 and 2005. Intervals between surgery and both start (n = 84) and completion (n = 68) of withdrawal of antiepileptic drugs (AEDs) were calculated and analyzed in relation to demographic and epilepsy variables and to recurrent seizures. Postoperative seizure freedom was associated with completeness of surgical resection, defined as complete removal of the cortical region exhibiting ictal or interictal abnormalities on intracranial electroencephalography and lesion on magnetic resonance imaging (P = 0.008). Etiology seemed to be related, but numbers were too small for statistical analysis. In 24 children (22%), seizures recurred postoperatively, and in 19 of these 24 children the AEDs were never withdrawn. Two of the five children in whom seizures recurred after medication withdrawal regained seizure freedom. Mean interval from surgery to start of drug withdrawal was 1.71 years (n = 84), and 2.86 years (n = 68) from surgery to complete withdrawal. Seizure recurrence seemed not associated with withdrawal decisions. Timing of seizure relapse was identical in children still on AEDs and in those who stopped. Eight children with early discontinuation (0.6 years from surgery to start of withdrawal and 0.8 years to complete withdrawal) had no seizure recurrence. Long-term continuation of AEDs is probably not indicated in children with complete resection of the epileptogenic zone. The optimal timing needs to be further explored.

Objective Over the past decades, the number of epilepsy surgeries in children has increased and indications for surgery have broadened. We studied the changes in patient characteristics between 1990 and 2011 in a nationwide cohort and related these to seizure outcome and postoperative medication status. Second, we tried to identify predictors for seizure outcome after pediatric epilepsy surgery. Methods To study changes over time, we divided this retrospective cohort of 234 children into two consecutive time periods of 11 years, and statistically compared the epochs in terms of patient characteristics, surgical variables, complications, seizure outcome, and postoperative medication status. To identify predictors of postoperative seizure freedom, we performed univariable and multivariable logistic regression analyses. Results The number of surgeries per year increased from an average of 5 in the first, to 16 in the past epoch. Over time, significantly more surgeries were performed for malformations of cortical development, and more patients underwent magnetoencephalography (MEG) and invasive monitoring. Four percent of patients had a serious complication. Complete seizure freedom (Engel class IA) at 2 years after surgery was achieved in 74% of patients, which did not change significantly over time. The proportion of patients who were free from seizures and antiepileptic medication 2 years after surgery significantly increased from 13% to 32%. Factors predictive of seizure recurrence were preoperative intracranial monitoring, multilobar surgery, etiology, and longer duration of epilepsy before surgery. Significance Although more complex cases were operated over time and medication was withdrawn earlier after surgery, success rates at 2 years remained stable. In combination with low complication rates, this underscores the efficacy and safety of pediatric epilepsy surgery. It is important to consider epilepsy surgery early, as longer duration of epilepsy increased the risk of postoperative seizure recurrence.

BACKGROUND: The goals of intentional curative pediatric epilepsy surgery are to achieve seizure-freedom and antiepileptic drug (AED) freedom. Retrospective cohort studies have indicated that early postoperative AED withdrawal unmasks incomplete surgical success and AED dependency sooner, but not at the cost of long-term seizure outcome. Moreover, AED withdrawal seemed to improve cognitive outcome. A randomized trial is needed to confirm these findings. We hypothesized that early AED withdrawal in children is not only safe, but also beneficial with respect to cognitive functioning. DESIGN: This is a multi-center pragmatic randomized clinical trial to investigate whether early AED withdrawal improves cognitive function, in terms of attention, executive function and intelligence, quality of life and behavior, and to confirm safety in terms of eventual seizure freedom, seizure recurrences and "seizure and AED freedom." Patients will be randomly allocated in parallel groups (1:1) to either early or late AED withdrawal. Randomization will be concealed and stratified for preoperative IQ and medical center. In the early withdrawal arm reduction of AEDs will start 4 months after surgery, while in the late withdrawal arm reduction starts 12 months after surgery, with intended complete cessation of drugs after 12 and 20 months respectively. Cognitive outcome measurements will be performed preoperatively, and at 1 and 2 years following surgery, and consist of assessment of attention and executive functioning using the EpiTrack Junior test and intelligence expressed as IQ (Wechsler Intelligence Scales). Seizure outcomes will be assessed at 24 months after surgery, and at 20 months following start of AED reduction. We aim to randomize 180 patients who underwent anticipated curative epilepsy surgery below 16 years of age, were able to perform the EpiTrack Junior test preoperatively, and have no predictors of poor postoperative seizure prognosis (multifocal magnetic resonance imaging (MRI) abnormalities, incomplete resection of the lesion, epileptic postoperative electroencephalogram (EEG) abnormalities, or more than three AEDs at the time of surgery). DISCUSSION: Growing experience with epilepsy surgery has changed the view towards postoperative medication policy. In a European collaboration, we designed a multi-center pragmatic randomized clinical trial comparing early with late AED withdrawal to investigate benefits and safety of early AED withdrawal. The TTS trial is supported by the Dutch Epilepsy Fund (NL 08-10) ISRCTN88423240/ 08/05/2013.

A 64-year-old man (GK) was referred to our memory clinic because of progressive memory and concentration problems. His symptoms had started 3 years earlier with gradually increasing visual problems for which no ophthalmologic explanations could be found. Neuropsychological assessment with detailed examination of the visuoperception revealed striking impairments in the higher-order visual functions, leading to a probable diagnosis of posterior cortical atrophy (PCA). The results of magnetic resonance imaging and cerebrospinal fluid examination supported the diagnosis. PCA is considered the posterior variant of Alzheimer's disease that typically presents with problems in visuoperception or, less frequent, apraxia. Despite its clear clinical features, the diagnosis of PCA is often delayed because of the focus on ophthalmologic examination. In this case report, the diagnosis of PCA in a 64-year-old man was not considered until further neuropsychological decay was evident. We argue that screening of higher-order visual functions can significantly contribute to an early diagnosis and treatment of PCA.

“Legal highs,” intoxicating substances not prohibited by laws, are gaining popularity in Europe and the United States. The bath salt “Ivory wave” is one of these substances and contains methylenedioxypyrovalerone (MDPV), a synthetic cathinone. Methcathinone was originally developed in the 1930s as an antidepressant, but due to its strong addictive potential was never clinically used. Nowadays, the group of “legal highs” is sold in local shops, and even in gas stations. It can be taken orally, IV, IM, or by means of inhalation.1,2 In March 2011, a 27-year-old man presented at another hospital because of sudden left-sided weakness. …