Seizure freedom but not epilepsy surgery is associated with fewer neuropsychiatric difficulties in patients with tuberous sclerosis.

BACKGROUND: Drug-resistant epilepsy (DRE) in selected individuals with the rare tuberous sclerosis complex (TSC) may benefit from resective epilepsy surgery. Furthermore, associated neuropsychiatric disorders (TAND) are common in patients with TSC; however, long-term data on how surgery affects neuropsychiatric comorbidities are sparse. MATERIALS AND METHODS: Two retrospective approaches were used to identify children with TSC and DRE with onset at < 18 years of age. The study group (surgical) was identified through the Swedish National Epilepsy Surgery Registry (n = 17), a registry with complete national coverage since 1990 and prospective patient enrolment since 1995. The reference group (non-surgical) was identified by searching medical records retrieved from the tertiary hospital of Southern Sweden (n = 52). Eligible participants were invited to complete the validated TAND lifetime checklist. Those who did not complete the checklist, never had DRE, or were aged < 7 years old were excluded from the study. The reference group was balanced with the study group for putative confounders, in the following hierarchical order: DRE at the survey, age at seizure onset, age at follow-up, and sex. RESULTS: After the balancing procedure, both groups comprised 13 participants. The median time from epilepsy onset to the survey was 18.5 (range: 7.75-40.25) and 16.0 (7.33-33.5) years in the study and reference groups, respectively. The median time from surgery to the survey was 13 years (range: 4-22). No significant differences were found in behavioural problems, autism spectrum disorder diagnosis or symptoms, or intellectual disability between the groups, regardless of surgery. Seizure-free individuals (n = 11) performed better in social skills (p = 0.016), intellectual skills (p = 0.029), and overall TAND scores (p = 0.005) than the non-seizure-free group (n = 15). CONCLUSION: This is the first study to evaluate TAND comorbidities during the long-term follow-up after epilepsy surgery in patients with TSC. We found no evidence of the adverse effects of TAND comorbidities after tuberectomy. However, a larger study that allows for a better adjustment for confounders is needed. Following previous studies, seizure-free individuals had fewer symptoms within most TAND domains compared with the group with uncontrolled epilepsy, indicating less severe symptomatology.

The evolution of epilepsy surgery in tuberous sclerosis in Sweden: A national registry study.

PURPOSE: This study aimed to characterize the Swedish cohort of surgically treated patients with TSC and explore differences in preoperative investigation and outcome over time. METHODS: Data on patient and seizure characteristics were retrieved from the Swedish National Epilepsy Surgery Register. Two-year follow-up results were compared between the years 1997-2010 and 2011-2018. Preoperative investigations were re-evaluated. RESULTS: Eighteen tuberectomies and seven callosotomies were identified. Seizure freedom after tuberectomy was achieved in 11 % (1/9) 1997-2010 and 56 % (5/9) 2011-2018. The number of tuberectomies increased each decade. Patients operated on in 1997-2010 had higher seizure frequency (median 175 seizures/month vs. 102) and incidence of infantile spasms (4/9 vs. 1/9, none after 2011). There was a trend towards surgery at a younger age (median 86 months 1997-2010 vs. 48 months 2011-2018). None with >200 seizure/month, SEGA, or history of infantile spasms achieved seizure freedom. Two patients underwent anterior callosotomy (1992 and 1994) and became free of drop attacks. Five callosotomies were performed between 2011 and 2013, one patient became free of drop attacks. Two complications with new neurological deficits were reported. The median age at surgery was higher in the callosotomy group (14 years) than in the tuberectomy group (5 years). CONCLUSION: Seizure freedom after tuberectomy in patients with TSC has increased over time in our cohort. Signs of a heavier disease burden were more frequently observed 1997-2010 and associated with worse outcomes. Callosotomy operations were prevalent at the beginning of the 2010s.

Satisfaction and seizure outcomes of epilepsy surgery in tuberous sclerosis: A Swedish population-based long-term follow-up study.

PURPOSE: We conducted a cross-sectional study to evaluate long-term outcomes of epilepsy surgery in tuberous sclerosis complex (TSC) in a Swedish population. METHODS: Demographic and seizure data was retrieved from the Swedish National Epilepsy Surgery Registry and medical records. Patient reported outcome measurements (PROM) were determined by telephonic interviews at long term follow-up. RESULTS: Median follow-up was 6 y 8 m (range, 3-15 y 1 m) for tuberectomies (n = 15) and 3 y 6 m (range 2-10 y) for callosotomies (n = 7). Eight of the 15 tuberectomy participants were seizure-free. Four out of seven callosotomies were free from drop attacks. PROMs were provided by caregivers of 18/20 participants (data missing for two callosotomies). In the tuberectomy group, 6/8 patients were seizure-free and 3/7 had continued seizures; surgery was considered satisfactory and beneficial. Overall, satisfaction was high, even among patients who did not achieve remission; 13/15 tuberectomy responders recommended surgery to others with TSC and refractory epilepsy. None of the patients considered the surgery harmful. In the callosotomy group, satisfaction was low and congruent with the seizure outcome. All patients with continued drop attacks were unsatisfied; one considered surgery to be harmful. One participant, who would not recommend surgery to others, still perceived the surgery to be beneficial. CONCLUSIONS: This study confirmed that both tuberectomy and callosotomy are effective treatment options for TSC. Factors other than seizure outcomes seemed to have a major influence on satisfaction and perception of the benefit of surgery.

Prospective registration of symptoms and times to diagnosis in children and adolescents with central nervous system tumors: A study of the Swedish Childhood Cancer Registry.

BACKGROUND: The elapsed time taken to diagnose tumors of the central nervous system in children and adolescents varies widely. The aim of the present study was to investigate such diagnostic time intervals at a national level in Sweden as they correlate with clinical features. METHODS: Data prospectively accumulated over a 4-year period in the Swedish Childhood Cancer Registry from patients aged 0-18 years were pooled, and diagnostic time intervals were analyzed considering tumor location, tumor type, patient age and sex, initial symptoms, and clinical timelines. All six pediatric oncology centers in Sweden contributed to collection of data. Time points for calculating the total diagnostic interval (TDI) defined as the time from symptom onset to diagnosis were reported in 257 of 319 patients (81%). RESULTS: The time from symptom onset to the first healthcare consultation, median 2.6 weeks, did not vary significantly between patients categorized according to tumor type or location. The median TDI was 8.3 weeks for the 4-year study period. Patients with optic pathway glioma (TDI 26.6 weeks), those with tumors of the spinal cord (TDI 25.9 weeks), and those with midline tumors (TDI 24.6 weeks) had the longest lead times. Additionally, older age, too few initial symptoms, and seeking initial redress outside an emergency ward were factors associated with a longer time to diagnosis. CONCLUSION: This study identified several factors associated with delayed diagnosis of central nervous system tumors among Swedish children and adolescents. These novel data ought to help direct future efforts toward clinical improvement.

Acute manic state with psychotic features in a teenager with autoimmune encephalitis: a case report.

INTRODUCTION: Autoimmune disorders have become increasingly acknowledged as having a more causative role in encephalitis than previously assumed. Anti-N-methyl-D-aspartate receptor encephalitis seems to be the most prevalent disorder. Symptoms of the neuropsychiatric phase in children and adolescents include abnormal behavior, seizures, and neurologic symptoms. We present a report on a teenage girl with predominantly psychiatric symptoms, highlighting the need for awareness of the disease and multidisciplinary collaboration. CASE PRESENTATION: Our patient, a 17-year-old girl of Middle Eastern origin, had no earlier medical history, but a family history of autoimmune disease. One morning, she could not recognize her mother and soon developed increased energy and pressured speech. The condition worsened, with paranoid delusions. In the emergency unit, she ran around speaking incoherently. The condition was interpreted as a full-scale mania. After pediatric clearance, the patient was admitted to the Department of Child and Adolescent Psychiatry. Mood-stabilizing treatment was initiated with second-generation psychotics and lithium, but this brought no improvement. A multidisciplinary discussion was held with physicians from psychiatry and neurology. A lumbar puncture showed N-methyl-D-aspartate receptor antibodies, and autoimmune treatment was initiated. Computed tomography thorax/abdomen revealed a right-sided ovarian tumor. After salpingo-oophorectomy, our patient's mental status gradually improved, as demonstrated by repeated testing. Seven months post discharge she was in a stable relationship and performing well in school. CONCLUSION: This case underlines the importance of collaboration between child and adolescent psychiatry and pediatrics, and gives pointers for timely diagnosis. Manic adolescents who do not respond to mood-stabilizing treatment should be subjected to further consultations and investigations. Psychiatrists and neurologists should develop an integrated approach to the management of brain disorders.

Epilepsy in tuberous sclerosis patients in Sweden - Healthcare utilization, treatment, morbidity, and mortality using national register data.

PURPOSE: This study is designed to estimate the prevalence of epilepsy associated with TSC in Sweden and to describe treatment, morbidity, and mortality of TSC patients with epilepsy. METHODS: Register data for 2004-2014 was obtained from the National Board of Health and Welfare in Sweden. Patients with TSC were identified using ICD-10 codes. Epilepsy was identified using ICD-10 codes, interventions aimed to treat epilepsy, or prescriptions for antiepileptic drugs. RESULTS: The prevalence of TSC was 5.38 per 100 000 individuals. We identified 551 unique patients with TSC, of which 386 (70.1%) had epilepsy. The mean study period was 8.82 years. Antiepileptic drugs were dispensed to 97.9% of patients with epilepsy. The most prescribed antiepileptic drug was sodium valproate. Ketogenic diet was used in 6 (1.6%) patients, vagus nerve stimulation in 23 (6.0%) patients, and epilepsy surgery was performed in 25 (6.5%) patients. The mean number of outpatient visits per year was 4.70 (SD 4.17) and the mean number of inpatient days per year was 3.25 (SD 5.61). The mean number of outpatient visits per year with an ICD-10 code for epilepsy was 1.65 (SD 1.95) and the corresponding number of inpatient days was 2.06 (SD 4.50). A total of 30 patients with TSC and epilepsy died during the study period. CONCLUSIONS: The prevalence of epilepsy in this study was in the lower range of previously reported numbers, suggesting that epilepsy may be overestimated in non-population based studies. A substantial part of the healthcare utilization was directly related to epilepsy.

Cerebellar mutism syndrome in children with brain tumours of the posterior fossa.

BACKGROUND: Central nervous system tumours constitute 25% of all childhood cancers; more than half are located in the posterior fossa and surgery is usually part of therapy. One of the most disabling late effects of posterior fossa tumour surgery is the cerebellar mutism syndrome (CMS) which has been reported in up to 39% of the patients but the exact incidence is uncertain since milder cases may be unrecognized. Recovery is usually incomplete. Reported risk factors are tumour type, midline location and brainstem involvement, but the exact aetiology, surgical and other risk factors, the clinical course and strategies for prevention and treatment are yet to be determined. METHODS: This observational, prospective, multicentre study will include 500 children with posterior fossa tumours. It opened late 2014 with participation from 20 Nordic and Baltic centres. From 2016, five British centres and four Dutch centres will join with a total annual accrual of 130 patients. Three other major European centres are invited to join from 2016/17. Follow-up will run for 12 months after inclusion of the last patient. All patients are treated according to local practice. Clinical data are collected through standardized online registration at pre-determined time points pre- and postoperatively. Neurological status and speech functions are examined pre-operatively and postoperatively at 1-4 weeks, 2 and 12 months. Pre- and postoperative speech samples are recorded and analysed. Imaging will be reviewed centrally. Pathology is classified according to the 2007 WHO system. Germline DNA will be collected from all patients for associations between CMS characteristics and host genome variants including pathway profiles. DISCUSSION: Through prospective and detailed collection of information on 1) differences in incidence and clinical course of CMS for different patient and tumour characteristics, 2) standardized surgical data and their association with CMS, 3) diversities and results of other therapeutic interventions, and 4) the role of host genome variants, we aim to achieve a better understanding of risk factors for and the clinical course of CMS - with the ultimate goal of defining strategies for prevention and treatment of this severely disabling condition. TRIAL REGISTRATION: Clinicaltrials.gov : NCT02300766 , date of registration: November 21, 2014.

Lower incidence of procoagulant abnormalities during follow-up after creation of the Fontan circulation in children.

OBJECTIVE: Children who undergo surgery for complex congenital cardiac disease are reported to be at increased thrombotic risk. Our aim was to evaluate long-term changes in the haemostatic system after surgery, to compare markers of activated coagulation in children having surgery with those in a healthy control population, and to relate them to adverse clinical outcome. PATIENTS AND METHODS: We studied, prior to surgery, the coagulation profiles of a cohort of 28 children admitted for a modified Fontan operation, studying them again after a period of mean follow-up of 9.6 years. Median age at the time of final surgery was 18.5 months, with a range from 12 to 76 months. We compared generation of thrombin, and levels of the activated protein C-protein C inhibitor complex to controls at follow-up. Thrombophilia and clinical outcome were evaluated. RESULTS: At long-term follow-up, a lower incidence of procoagulant abnormalities was observed compared to that before surgery. Of 27 patients, 3 (11%), but none of 45 controls, had levels of activated protein C-protein C inhibitor complex above the reference range. There were no significant differences in generation of thrombin between patients and controls. No thrombotic events were recorded, and the patients were generally in good clinical condition. CONCLUSIONS: Overall, haemostasis appeared to be in balance, and less prothrombotic, after surgery. A subset of the cohort did show indications of activated coagulation. The current therapeutic approach seems to be sufficient to protect the majority of patient. New tests of global coagulation, nonetheless, may be helpful in improving identification of individuals at increased thrombotic risk.

Oestrogen treatment of constitutional tall stature in girls: is there a risk of thrombosis or bleeding?

AIM: To evaluate haemostatic effects and clinical outcome of oestrogen treatment of constitutionally tall stature in girls. METHODS: We conducted a single-centre cohort study, 63 girls referred over a period of 15 years were investigated. The girls were given oestrogen treatment for constitutional tall stature at a median initial dose of 300 ug ethinyl estradiol/day and were consecutively examined for changes in coagulation. Medical records were retrospectively reviewed, additional data were collected at follow-up by blood sampling and interviews. RESULTS: After 1 year of treatment, levels of antithrombin and von Willebrand factor (VWF) were significantly decreased (p<0.001 and p=0.015, respectively), whereas there was no significant change in levels of plasminogen inhibitor type 1. No venous thromboembolism (VTE) or major side effects were observed. Genetic risk factors for thrombosis were present, as was expected. The mean height reduction was 5.5 cm. The height-reducing effect was inversely correlated with chronological age (r=-0.44, p<0.01) and bone age (r=-0.61, p<0.01). CONCLUSIONS: Changes in coagulation parameters occurred both towards pro- and anticoagulation. Treatment with high-dose ethinyl estradiol can successfully limit final height, and it is most effective when started at a younger bone age.