Survival and long-term socioeconomic consequences of childhood and adolescent onset of brain tumours.

AIM: To evaluate survival distributions, long-term socioeconomic consequences, and health care costs in patients with childhood and adolescent onset of brain tumours in a Danish nationwide prospective cohort study. METHOD: A search of national registries identified 2283 patients (1198 males, 1085 females; mean age 9 years 6 months [SD 5 years 7 months]) diagnosed with a brain tumour between 1980 and 2015 and aged no older than 18 years at diagnosis. These were compared with sex-, age-, and residency-matched comparison individuals. Patients with malignant tumours were compared with those with benign tumours. Survival distributions were estimated by the Kaplan-Meier method and hazard ratio by the Cox proportional hazard model. Socioeconomic data at age 20 and 30 years were assessed. RESULTS: The probability of mortality was highest during the first year after tumour diagnosis. In young adulthood, the patients were generally less likely to be married, had lower grade-point averages, educational levels, and income, were less likely to be in employment, and had higher health care costs than comparison individuals. Patients with malignant tumours had worse outcomes with respect to education, employment, and health care costs than those with benign tumours. INTERPRETATION: A diagnosis of brain tumour in childhood and adolescence adversely affects survival and has negative long-term socioeconomic consequences, especially in patients with malignant tumours. These patients require continuous social support.

Brain tumours in children and adolescents may affect the circadian rhythm and quality of life.

AIM: Children with brain and cervical medulla tumours may experience circadian abnormalities and poor health. We aimed to examine their circadian rhythm, fatigue and quality of life (QoL). METHODS: Children with a brain or cervical medulla tumour were recruited from the Paediatric Department, Rigshospitalet, Copenhagen, Denmark, between 2016 and 2020. They were grouped by tumour location involving the circadian regulatory system, defined as diencephalon, pineal gland, brain stem and cervical medulla, or other areas. Saliva melatonin and cortisol concentrations were measured. Sleep diaries and actigraphy assessed sleep-wake patterns. The Pediatric Quality of Life Inventory, Multidimensional Fatigue Scale and Generic Core Scale measured fatigue and QoL. RESULTS: We included 68 children (62% males) with a median age (25th-75th percentiles) of 12.2 (7.7-16.3) years. Children with tumours involving the circadian regulatory system typically had a lower melatonin peak (p=0.06) and experienced significantly more fatigue and poorer QoL. Low melatonin profiles were observed in 31% and 4% had a phase-shifted daytime peak, compared with 14% and 0%, respectively, in children with tumours located elsewhere. Children with low melatonin profiles had significantly lower inter-daily stability than those with normal profiles. CONCLUSION: Tumours involving the circadian regulatory system adversely affected circadian function, fatigue and QoL.

Long-term health and socioeconomic consequences of childhood and adolescent onset of meningococcal meningitis.

We estimated the long-term socioeconomic consequences and health care costs of Neisseria meningitidis meningitis (NM). The prospective cohort study included Danish individuals with onset of NM in childhood and adolescence, diagnosed between 1980 and 2009. Health care costs and socioeconomic data were obtained from nationwide administrative and health registers. Two thousand nine hundred two patients were compared with 11,610 controls matched for age, gender, and other sociodemographic characteristics. In the follow-up analysis at the age of 30 years, 1028 patients were compared with 4452 controls. We found that (1) NM caused increased mortality at disease onset, but after adequate treatment, the mortality rate was similar to that of the general population; (2) neurological and eye diseases were more frequently observed in patients; (3) patients had significantly lower grade-point averages; (4) patients had lower income even when transfer payments were taken into account; and (5) patients' initial health care costs were elevated.Conclusion: NM has significant influence on mortality, morbidity, education, and income. We suggest that the management of patients with previous meningococcal meningitis should focus on early educational and social interventions to improve social and health outcomes. What is known: • Meningococcal meningitis is a severe infectious disease affecting children and adolescents with high rates of mortality and complications. What is new: • Meningococcal meningitis causes increased mortality at disease onset, but after adequate treatment the mortality rate is similar to that of the general population. • Meningococcal meningitis in childhood and adolescence has a major long-term effect on morbidity, health care costs, education, employment, and income.

Morbidity and mortality of childhood- and adolescent-onset epilepsy: A controlled national study.

PURPOSE: Epilepsy is associated with significant morbidities and mortality. We aimed to evaluate the 30-year morbidities and mortality in a national group of patients after a first diagnosis of epilepsy. METHODS: From the Danish National Patient Registry (NPR), in total, 3123 patients with epilepsy aged 0-5years and 5018 patients aged 6-20years diagnosed in 1998-2002 were identified and compared with, respectively, 6246 and 10,036 persons matched for age, gender, and place of living with randomly chosen citizens from the Danish Civil Registration System Statistics. In the NPR, all morbidities in the following 30years were grouped into major WHO disease classes. KEY FINDINGS: Patients with epilepsy had significantly higher rates of comorbidities including almost all health-related comorbidities compared with controls. Mortality rates were elevated: the hazard ratio (5%; 95% CI) was 14.46 (11.8; 17.7, p<0.001) and 5.58 (4.9; 6.4, P<0.001) for patients aged 0-5years and 6-20years at first diagnosis of epilepsy, respectively. SIGNIFICANCE: Epilepsy is associated with significant comorbidities and mortality including all health care domains, especially among persons who were young at the onset of epilepsy.

Polysomnographic findings in craniopharyngioma patients.

PURPOSE: The purpose of this study is to evaluate whether damage to the hypothalamus due to craniopharyngioma or consequent surgery may involve the sleep-wake regulatory system, resulting in sleep disturbances and sleepiness. METHODS: Seven craniopharyngioma patients and 10 healthy controls were evaluated with sleep questionnaires including the Epworth Sleepiness Scale, polysomnography, and a multiple sleep latency test (MSLT). Five patients and eight controls had lumbar puncture performed to determine hypocretin-1 levels. RESULTS: Patients tended to feel sleepier than control individuals of the same age (p = 0.09). No subjects had symptoms of hypnagogic hallucinations, sleep paralyses, or cataplexies. Four patients and one control had periodic leg movements (PLMs). One patient had fragmented sleep pattern, rapid eye movement (REM) sleep without atonia, and PLMs. One patient had short sleep periods during the daytime. Four patients had fragmented sleep pattern. With the MSLT, four patients and two controls had mean sleep latency of < 8 min. One patient and three controls had sudden onset of REM sleep in 2/5 and 3/5 sleep periods, respectively. All subjects showed normal hypocretin-1 levels. Four patients had electrophysiological findings indicative of central hypersomnia including one patient meeting the criteria of narcolepsy. CONCLUSION: The sleep-wake regulatory system may be involved in craniopharyngioma patients.

Welfare cost of childhood- and adolescent-onset epilepsy: A controlled national study.

OBJECTIVES: Epilepsy is associated with a significant burden to patients and society. We calculated the factual excess in direct and indirect costs associated with childhood- and adolescent-onset epilepsy. METHODS: Using records from the Danish National Patient Registry (1998-2002), we identified 3123 and 5018 patients with epilepsy aged 0-5years and 6-20years at the time of diagnosis, respectively. The two age groups of patients with epilepsy were matched to 6246 and 10,036 control persons without epilepsy, respectively, by gender, age, and geography. The controls were randomly chosen from the Danish Civil Registration System. Welfare costs included outpatient services, inpatient admissions, and emergency room visits based on the Danish National Patient Registry and information from the primary health-care sector based on data from the Danish Ministry of Health. This allowed the total health-care cost of epilepsy to be estimated. The use and costs of drugs were based on data from the Danish Medicines Agency. The frequencies of visits to outpatient clinics and hospitalizations and costs from primary sectors were based on data obtained from the National Patient Registry. RESULTS: Children with epilepsy had higher welfare costs than controls. The highest cost was found one year after diagnosis, with higher costs up to 10years after diagnosis compared with controls. Children aged 0-5years incurred greater health-care costs than those aged 6-20years. CONCLUSION: Epilepsy has major socioeconomic consequences for the individual person with epilepsy and for society.

Systematic Review: Sleep Disorders Based on Objective Data in Children and Adolescents Treated for a Brain Tumor.

Background: Tumors of the central nervous system (CNS) are the most common solid childhood malignancy. Over the last decades, treatment developments have strongly contributed to the improved overall 5-year survival rate, which is now approaching 75%. However, children now face significant long-term morbidity with late-effects including sleep disorders that may have detrimental impact on everyday functioning and quality of life. The aims of this study were to (1) describe the symptoms that lead to polysomnographic evaluation; (2) describe the nature of sleep disorders diagnosed in survivors of childhood CNS tumor using polysomnography (PSG); and (3) explore the association between tumor location and diagnosed sleep disorder. Methods: An extensive literature search following the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines (PRISMA) was conducted. Inclusion criteria were children and adolescents diagnosed with a CNS tumor age <20 years having a PSG performed after end of tumor treatment. The primary outcome was sleep disorder confirmed by PSG. Results: Of the 1,658 studies identified, 11 met the inclusion criteria. All the included articles were appraised for quality and included in the analysis. Analyses indicated that sleep disorders commonly occur among childhood CNS tumor survivors. Symptoms prior to referral for PSG were excessive daytime sleepiness (EDS), fatigue, irregular breathing during sleep and snoring. The most common sleep disorders diagnosed were sleep-related breathing disorders (i.e., obstructive sleep apnea) and central disorders of hypersomnolence (i.e., narcolepsy). Conclusion: Our findings point to the potential benefit of systematically registering sleep disorder symptoms among CNS tumor patients together with tumor type and treatment information, so that at-risk patients can be identified early. Moreover, future rigorous and larger scale controlled observational studies that include possible modifiable confounders of sleep disorders such as fatigue and obesity are warranted. Clinical Trial Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021243866, identifier [CRD42021243866].

Diagnostic value of actigraphy in hypersomnolence disorders.

OBJECTIVE: Differentiating between the central hypersomnias presents a challenge to the diagnosis of patients with hypersomnolence. Actitigraphy may support efforts to distinguish them. We aimed to evaluate: 1) the ability of actigraphy to quantify sleep continuity measures in comparison with polysomnography in patients with hypersomnolence; 2) whether actigraphy can distinguish patients with hypersomnolence with normal hypocretin-1 in cerebrospinal fluid from patients with narcolepsy type 1 and from sleep-healthy controls; and 3) the distinct activity profiles and circadian rhythms of patients with narcolepsy type 1, patients with hypersomnolence with normal hypocretin-1 in cerebrospinal fluid, and sleep-healthy controls. METHOD: Polysomnography, multiple sleep latency tests and actigraphy were conducted in 14 patients with narcolepsy type 1, 29 patients with hypersomnolence with normal hypocretin-1 in cerebrospinal fluid and 15 sleep-healthy controls. RESULTS: Actigraphy quantified several sleep continuity measures consistently with polysomnography in all the patients. Actigraphy distinguished patients with hypersomnolence with normal hypocretin-1 in cerebrospinal fluid from patients with narcolepsy type 1 and sleep-healthy controls. Patients with narcolepsy type 1 had poor sleep quality and altered circadian rest-activity rhythm compared with controls. CONCLUSION: Actigraphy is an adequate tool for establishing the amount of night sleep and supports the differential diagnosis of patients with hypersomnolence.

Brain tumours result in sleep disorders in children and adolescents.

BACKGROUND AND OBJECTIVES: Sleep disturbances are frequently reported in children with brain tumours. The objective of our cross-sectional study was to systematically examine sleep in these children. We hypothesised that children with tumours involving the sleep-wake-regulatory areas have an altered sleep-wake-regulation. METHODS: Sixty-one patients aged 0-18 years and with a diagnosis of a primary brain or cervical medullary tumour were included. They were categorised based upon tumour location into two groups - those affecting the sleep-wake regulatory regions, i.e. brain stem, basal forebrain, hypothalamus, thalamus, and posterior fossa compressing the brain stem and those that did not. Sleep history, questionnaire surveys, polysomnography, and multiple sleep latency test were used, as indicated clinically. Surveys included Pediatric Daytime Sleepiness Scale, Children's Sleep Habits Questionnaire, Strengths and Difficulties Questionnaire, and Pediatric Quality of Life Inventory, Multidimensional Fatigue Scale and Generic Core Scale. RESULTS: Patients with tumours involving the sleep-wake regulatory areas were sleepier/more fatigued (p = 0.03). Sleep apnoea was observed in 86% of all the patients and comorbid narcolepsy in 8%, without group differences (p ≥ 0.12). Patients with tumours involving the sleep-wake-regulatory areas had more emotional problems (p = 0.04), were more affected by mental health problems (p < 0.001), and had poorer quality of life (p ≤ 0.03). CONCLUSIONS: Many children with brain tumours suffer from disturbed sleep, poor mental health, and low quality of life. We recommend that systematic sleep evaluation is included in their routine care along with psychological and social support.

[Sleep and circadian rhythms].

The sleep-wake regulatory system and the circadian rhythm generating system are two brain networks integrated in the classical two-process model. These processes interact continuously, and to obtain an optimal sleep they must be correctly aligned. The suprachiasmatic nucleus located in the hypothalamus is crucial in the regulation of circadian rhythms, and the hypothalamus is a key component of the sleep-wake regulatory system in association with the thalamus, basal forebrain and brainstem. Alterations of these processes can result in a variety of sleep disturbances or sleep disorders.

Morbidity and mortality of middle-aged and elderly narcoleptics.

OBJECTIVES: The objective of the study was to evaluate the morbidities and mortality in a national group of middle-aged and elderly narcolepsy patients before and after the first diagnosis of the condition. METHODS: From the Danish National Patient Registry (NPR), 1174 patients (45.1% males) aged 20-59 years and 339 patients (44.8% males) aged 60+ who received a diagnosis of narcolepsy between 1998 and 2014 were compared, respectively, with 4716 and 1353 control citizens matched for age, gender and geography, who were randomly chosen from the Danish Civil Registration System Statistics. In the NPR, all morbidities are grouped into major WHO classes. RESULTS: Middle-aged and elderly patients had more health contacts before and after their narcolepsy diagnosis with respect to several disease domains: infections, neoplasm, endocrine/metabolic diseases/diabetes, mental/psychiatric, neurological (including epilepsy), eye, cardiovascular (hypertension, ischemic heart disease), respiratory (upper-airway infections, sleep apnea), gastrointestinal, musculoskeletal (including discopathies) and skin diseases. Narcolepsy patients had lower reproductive rates. Furthermore, patients showed significantly more health contacts due to the evaluation and control contacts for disease and symptoms. Patients suffered from significantly more multiple diseases than did controls. The 17-year hazard ratio mortality rates were 1.35 (95% CI, 0.94-1.95, p = 0.106) among 20-59 year-olds, and 1.38 (1.12-1.69, p = 0.002) among those aged 60+ years. CONCLUSION: There are higher rates of morbidity in several disease domains before and after a diagnosis of narcolepsy. Elderly narcolepsy patients have higher mortality rates.

Morbidity of childhood onset narcolepsy: a controlled national study.

Narcolepsy is associated with significant morbidities. We evaluated the morbidities and mortality in a national group of child and adolescent patients after a first diagnosis of narcolepsy. METHODS: Identified from the Danish National Patient Registry (NPR), 243 patients (128 boys) aged 0-19 years diagnosed with narcolepsy between 1998 and 2012 with follow-up until 2014 were compared with 970 controls who were randomly chosen from the Danish Civil Registration System Statistics and matched by age, gender and geography. Comorbidities were calculated three years before and after diagnoses. RESULTS: In addition to the more frequent health contacts due to neurological diseases, patients showed elevated odds ratios before and after diagnosis of endocrine and metabolic conditions (4.4 (95% CI, 1.9-10.4); 3.8 (1.7-8.4)), nervous disorders (16.6 (8.0-34.4); 198 (49.0-804)), psychiatric illnesses (4.5 (2.3-9.1)/5.8 (2.8-12.1)), pulmonary diseases, and other diseases (3.1 (2.0-4.9); 3.1 (2.0-4.9)). Congenital abnormalities (2.5 (1.1-5.5)), respiratory (2.9 (1.5-5-5)) and eye (5.7 (2.2-15.0)) diseases were more common before diagnosis. Injuries were also more common after diagnosis (1.5 (1.0-2.1)). Narcoleptic children presented significantly more diagnoses of multiple comorbidities than controls before and after diagnosis. CONCLUSION: Before and after a diagnosis of narcolepsy in children, morbidity is more frequent in several domains, including metabolic, psychiatric, neurological and other diseases.

Sleep-wake and melatonin pattern in craniopharyngioma patients.

OBJECTIVE: To assess the influence of craniopharyngioma or consequent surgery on melatonin secretion, and the association with fatigue, sleepiness, sleep pattern and sleep quality. DESIGN: Cross-sectional study. METHODS: A total of 15 craniopharyngioma patients were individually matched to healthy controls. In this study, 24-h salivary melatonin and cortisol were measured. Sleep-wake patterns were characterised by actigraphy and sleep diaries recorded for 2 weeks. Sleepiness, fatigue, sleep quality and general health were assessed by Multidimensional Fatigue Inventory, Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Short-Form 36. RESULTS: Patients had increased mental fatigue, daytime dysfunction, sleep latency and lower general health (all, P≤0.05), and they tended to have increased daytime sleepiness, general fatigue and impaired sleep quality compared with controls. The degree of hypothalamic injury was associated with an increased BMI and lower mental health (P=0.01). High BMI was associated with increased daytime sleepiness, daytime dysfunction, mental fatigue and lower mental health (all, P≤0.01). Low midnight melatonin was associated with reduced sleep time and efficiency (P≤0.03) and a tendency for increased sleepiness, impaired sleep quality and physical health. Midnight melatonin remained independently related to sleep time after adjustment for cortisol. Three different patterns of melatonin profiles were observed; normal (n=6), absent midnight peak (n=6) and phase-shifted peak (n=2). Only patients with absent midnight peak had impaired sleep quality, increased daytime sleepiness and general and mental fatigue. CONCLUSION: Craniopharyngioma patients present with changes in circadian pattern and daytime symptoms, which may be due to the influence of the craniopharyngioma or its treatment on the hypothalamic circadian and sleep regulatory nuclei.