Hypothalamus volumes in adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): impact of self-reported fatigue and illness duration.

Adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex illness of unknown aetiology. Emerging theories suggest ME/CFS may reflect a progressive, aberrant state of homeostasis caused by disturbances within the hypothalamus, yet few studies have investigated this using magnetic resonance imaging in adolescents with ME/CFS. We conducted a volumetric analysis to investigate whether whole and regional hypothalamus volumes in adolescents with ME/CFS differed compared to healthy controls, and whether these volumes were associated with fatigue severity and illness duration. 48 adolescents (25 ME/CFS, 23 controls) were recruited. Lateralised whole and regional hypothalamus volumes, including the anterior-superior, superior tubular, posterior, anterior-inferior and inferior tubular subregions, were calculated from T1-weighted images. When controlling for age, sex and intracranial volume, Bayesian linear regression models revealed no evidence for differences in hypothalamus volumes between groups. However, in the ME/CFS group, a weak linear relationship between increased right anterior-superior volumes and fatigue severity was identified, which was absent in controls. In addition, Bayesian quantile regression revealed a likely-positive association between illness duration and right superior tubular volumes in the ME/CFS group. While these findings suggest overall comparability in regional and whole hypothalamus volumes between adolescents with ME/CFS and controls, preliminary evidence was identified to suggest greater fatigue severity and longer illness duration were associated with greater right anterior-superior and superior-tubular volumes, respectively. These regions contain the anterior and superior divisions of the paraventricular nucleus, involved in the neuroendocrine response to stress, suggesting involvement in ME/CFS pathophysiology. However, replication in a larger, longitudinal cohort is required.

What lies beneath: White matter microstructure in pediatric myalgic encephalomyelitis/chronic fatigue syndrome using diffusion MRI.

Recent studies in adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suggest that changes in brain white matter microstructural organization may correlate with core ME/CFS symptoms, and represent a potential biomarker of disease. However, this has yet to be investigated in the pediatric ME/CFS population. We examined group differences in macrostructural and microstructural white matter properties, and their relationship with clinical measures, between adolescents recently diagnosed with ME/CFS and healthy controls. Forty-eight adolescents (25 ME/CFS, 23 controls, mean age 16 years) underwent brain diffusion MRI, and a robust multi-analytic approach was used to evaluate white and gray matter volume, regional brain volume, cortical thickness, fractional anisotropy, mean/axial/radial diffusivity, neurite dispersion and density, fiber density, and fiber cross section. From a clinical perspective, adolescents with ME/CFS showed greater fatigue and pain, poorer sleep quality, and poorer performance on cognitive measures of processing speed and sustained attention compared with controls. However, no significant group differences in white matter properties were observed, with the exception of greater white matter fiber cross section of the left inferior longitudinal fasciculus in the ME/CFS group compared with controls, which did not survive correction for intracranial volume. Overall, our findings suggest that white matter abnormalities may not be predominant in pediatric ME/CFS in the early stages following diagnosis. The discrepancy between our null findings and white matter abnormalities identified in the adult ME/CFS literature could suggest that older age and/or longer illness duration influence changes in brain structure and brain-behavior relationships that are not yet established in adolescence.

Health, Wellbeing, and Prognosis of Australian Adolescents with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Case-Controlled Follow-Up Study.

BACKGROUND: The purpose of this study was to follow-up an Australian cohort of adolescents newly-diagnosed with ME/CFS at a tertiary paediatric ME/CFS clinic and healthy controls over a mean period of two years (range 1-5 years) from diagnosis. Objectives were to (a) examine changes over time in health and psychological wellbeing, (b) track ME/CFS symptomatology and fulfillment of paediatric ME/CFS diagnostic criteria over time, and (c) determine baseline predictors of ME/CFS criteria fulfilment at follow-up. METHODS: 34 participants aged 13-18 years (25 ME/CFS, 23 controls) completed standardised questionnaires at diagnosis (baseline) and follow-up assessing fatigue, sleep quality and hygiene, pain, anxiety, depression, and health-related quality of life. ME/CFS symptomatology and diagnostic criteria fulfilment was also recorded. RESULTS: ME/CFS patients showed significant improvement in most health and psychological wellbeing domains over time, compared with controls who remained relatively stable. However, fatigue, pain, and health-related quality of life remained significantly poorer amongst ME/CFS patients compared with controls at follow-up. Sixty-five percent of ME/CFS patients at baseline continued to fulfil ME/CFS diagnostic criteria at follow-up, with pain the most frequently experienced symptom. Eighty-two percent of patients at follow-up self-reported that they still had ME/CFS, with 79% of these patients fulfilling criteria. No significant baseline predictors of ME/CFS criteria fulfilment at follow-up were observed, although pain experienced at baseline was significantly associated with criteria fulfilment at follow-up (R = 0.6, p = 0.02). CONCLUSIONS: The majority of Australian adolescents with ME/CFS continue to fulfil diagnostic criteria at follow-up, with fatigue, pain, and health-related quality of life representing domains particularly relevant to perpetuation of ME/CFS symptoms in the early years following diagnosis. This has direct clinical impact for treating clinicians in providing a more realistic prognosis and highlighting the need for intervention with young people with ME/CFS at the initial diagnosis and start of treatment.

Development of the Fearless, Tearless Transition model of care for adolescents with an intellectual disability and/or autism spectrum disorder with mental health comorbidities.

AIM: First, to understand the barriers to achieving effective transition and the supports required from the perspective of parents and carers, adolescents with intellectual disability and/or autism spectrum disorder and co-existing mental health disorders (often termed 'dual disability'), and those who provide services to this group. Second, to develop an informed model of shared care to improve the transition of adolescents with dual disabilities. METHOD: Carers and a young adult with a dual disability were surveyed about their experience of transition care. Other key stakeholders including paediatricians, general practitioners, and policy makers were also interviewed. These data informed the model of care. RESULTS: Paediatricians and general practitioners reported difficulties establishing working relationships to foster smooth transitions, and carers reported lacking a regular general practitioner with adequate expertise to care for people with dual disabilities. A process of shared care between paediatricians and general practitioners was developed and initiated by a dedicated transition manager, who assisted with care coordination and service linkages. Standardized clinical assessment tools were also introduced to determine patient and carer support needs. INTERPRETATION: This study highlights the potential to improve transition outcomes for adolescents with dual disabilities and their carers through early transition planning, consistent methods of assessing patient and carer needs, and shared care. WHAT THIS PAPER ADDS: Adolescents with co-occurring disabilities require a collaborative health and disability service interface. Fearless, Tearless Transition is a new approach to transitioning adolescents with dual disabilities from paediatric to adult care. Carers of adolescents with dual disabilities require support navigating and negotiating services. Engaging general practitioners and paediatricians in shared care early during the transition process is essential.

Resting-state functional connectivity, cognition, and fatigue in response to cognitive exertion: a novel study in adolescents with chronic fatigue syndrome.

Emerging evidence suggests that central nervous system dysfunction may underlie the core symptoms of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) in adults, such as cognitive disturbance, fatigue and post-exertional malaise. Research into brain dysfunction in the pediatric CFS/ME context, however, is severely lacking. It is unclear whether the adolescent CFS/ME brain functions differently compared with healthy peers, particularly in situations where significant mental effort is required. This study used resting-state functional MRI in a novel repeated-measures design to evaluate intrinsic connectivity, cognitive function, and subjective fatigue, before and after a period of cognitive exertion in 48 adolescents (25 CFS/ME, 23 healthy controls). Results revealed little evidence for a differential effect of cognitive exertion in CFS/ME compared with controls. Both groups demonstrated a similar rate of reduced intrinsic functional connectivity within the default mode network (DMN), reduced sustained attentional performance, slower processing speed, and increased subjective fatigue as a result of cognitive exertion. However, CFS/ME adolescents consistently displayed higher subjective fatigue, and controls outperformed the CFS/ME group overall on cognitive measures of processing speed, sustained attention and new learning. No brain-behavior relationships were observed between DMN connectivity, cognitive function, and fatigue over time. These findings suggest that effortful cognitive tasks may elicit similar levels of energy expenditure across all individuals in the form of reduced brain functioning and associated fatigue. However, CFS/ME may confer a lower starting threshold from which to access energy reserves and cognitive resources when cognitive effort is required.

Epidemiology of paediatric chronic fatigue syndrome in Australia.

OBJECTIVE: To estimate the paediatrician-diagnosed incidence of chronic fatigue syndrome (CFS) in Australia, and describe demographic and clinical features, as well as approaches to diagnosis and management. METHODS: The Australian Paediatric Surveillance Unit facilitates monthly national surveillance of uncommon conditions seen by paediatricians. Data from young people aged <18 years diagnosed with CFS were collected. Incidence was estimated based on new cases reported from April 2015 to April 2016. RESULTS: A total of 164 cases of newly diagnosed CFS in young people aged 4-17 years were identified for inclusion. The estimated national incidence for children aged 4-9 years was 0.25 per 100 000 per annum. In children aged 10-17 years, the estimated incidence of paediatrician-diagnosed cases for Victoria (17.48 per 100 000) was substantially greater than other Australian states (range 1.31-5.51 per 100 000). Most cases were female and Caucasian, most commonly presenting after an infectious illness with symptoms gradual in onset. The majority were diagnosed at least 13 months after symptom onset. Symptoms, associations, investigations and management strategies were highly variable. CONCLUSIONS: Current findings suggest that, consistent with other countries, the Australian incidence of CFS in children aged <10 years is very low. In contrast, the national incidence of CFS in older children and adolescents (aged 10-17 years) is more unclear, with marked variability between geographical regions apparent. This may be due to variation in service accessibility and clinician understanding of CFS. Accordingly, national initiatives to improve equity of care for children with CFS may be required.

How is paediatric chronic fatigue syndrome/myalgic encephalomyelitis diagnosed and managed by paediatricians? An Australian Paediatric Research Network Study.

AIM: The diagnosis and management of paediatric chronic fatigue syndrome/myalgic encepnalomyelitis (CFS/ME) represent ongoing challenges for paediatricians. A better understanding of current approaches at a national level is important in informing where research and education could improve treatment outcomes. We aimed to examine current diagnosis and management practices for CFS/ME by Australian paediatricians. METHOD: An online survey was sent to members of the Australian Paediatric Research Network. The primary outcomes of interest included diagnostic criteria used, medical investigations and management practices in paediatric CFS/ME. RESULTS: One hundred seventy-eight (41%) of 430 eligible paediatricians responded, with 70 of the 178 (39%) reporting that they diagnose and manage CFS/ME as part of their practice. Medical investigations used for diagnosis were variable. Conditions that more than half of the paediatricians reported as commonly co-occurring (i.e. present in >50% of cases) included somatisation disorders, anxiety, depression and fibromyalgia. There was wide variation in behavioural and pharmacological management strategies but most paediatricians commonly engaged a school teacher, physiotherapist and/or psychologist as part of their management. CONCLUSION: The diagnostic and management practices of paediatricians for CFS/ME within Australia vary widely. This likely reflects a paucity of paediatric-specific guidelines, together with limited evidence to guide best practice and limited training in this area. There is a need for guidance and education for the diagnosis and management of paediatric CFS/ME in Australia.

Paediatric chronic fatigue syndrome: complex presentations and protracted time to diagnosis.

AIM: The diagnosis and management of paediatric chronic fatigue syndrome (CFS) remain ongoing challenges for paediatric clinicians, particularly given its unknown aetiology and the little research on effective treatments for this condition. The aim of this study was to describe the presenting features of new patients attending a specialist chronic fatigue clinic at a tertiary-level Australian children's hospital. METHOD: The medical records of all patients with an initial consultation at the chronic fatigue clinic over a 12-month period were reviewed using a standardised data collection template. Functional impact was based on school attendance and classified according to the National Institute of Health and Clinical Excellence guidelines (2007). RESULTS: A total of 99 patients attending the clinic were identified. Of these, 59 were diagnosed with CFS. Median age was 15.4 years with almost two-thirds of patients of female sex. Median time between symptom onset and diagnosis was 15.5 months. There was a high occurrence of fatigue, sleep disturbance, pain, postexertional malaise, and autonomic and cognitive symptoms in the group. The functional impact of CFS was classified as mild for 20%, moderate for 66% and severe for 14% of patients. CONCLUSIONS: Most young people diagnosed with CFS experience symptoms for a protracted period, with considerable functional impact prior to initial tertiary service consultation. This audit has identified important areas for research, practice development and education in relation to the management of patients with CFS.

Graduated exercise training and progressive resistance training in adolescents with chronic fatigue syndrome: a randomized controlled pilot study.

OBJECTIVE: to investigate the differential effects of aerobic graded exercise and progressive resistance training on exercise tolerance, fatigue and quality of life in adolescent patients with chronic fatigue syndrome (CFS). DESIGN: single-blind, randomized controlled pilot trial. SETTING: a major metropolitan hospital in Melbourne, Australia. SUBJECTS: twenty-two adolescents aged 13-18 years diagnosed with CFS and admitted to the inpatient chronic fatigue rehabilitation programme. INTERVENTION: patients were randomized to either graded aerobic exercise training or a progressive resistance training programme, for five days/week for four weeks. The graded aerobic training consisted of 20-40 minutes of stationary cycling and treadmill exercise. The progressive resistance training involved 16 exercises performed with single set, moderate load and high repetitions. MAIN MEASURES: exercise tolerance (time to fatigue) measured on a graded sub-maximal treadmill test, metabolic equivalents and quality of life, along with muscular strength (maximium push-ups) and endurance (sit-to-stand) and questionnaires evaluating depressive symptoms and fatigue severity. RESULTS: no intervention was significantly better than the other for any outcome. However, physical capacity and quality of life significantly improved in both groups, while fatigue severity and symptoms of depression improved only with aerobic training. CONCLUSIONS: resistance and aerobic training resulted in similar changes to physical capacity, quality of life and fatigue severity. Generally, patients who completed resistance training or aerobic training experienced significant improvements in outcomes from baseline when they entered the programme. Whether these improvements can be attributed to the treatment is unknown.

Promising outcomes of an adolescent chronic fatigue syndrome inpatient programme.

INTRODUCTION: Chronic fatigue syndrome (CFS) is a condition of prolonged and disabling fatigue, which is accompanied by characteristic constitutional and neuropsychiatric symptoms. In children and adolescents, this condition occurring at a developmentally vulnerable time adds to the disability affecting self-concept, autonomy, body image, socialisation, sexuality and academic problems. This case series looks at the effects of a graded exercise programme on physical outcomes, fatigue and mental state in an adolescent population. METHODS: Data sets from 16 adolescents who completed combined exercise training as part of the 4-week inpatient intensive CFS programme at the Austin Hospital, Melbourne were analysed. All patients completed an exercise assessment and three questionnaires before beginning any training. A paediatrician (LL) confirmed the diagnosis according to the Fukuda criteria in all patients. Exercise was carefully supervised and prescribed daily by an exercise physiologist (BG) according to each individual's ability and response with the basic aim of increasing exercise tolerance and improving muscle strength and endurance. RESULTS: There was an 18% improvement in volitional time to fatigue (P= 0.02) and 17% improvement in peak oxygen uptake (VO(2peak)) (P= 0.01). Upper body strength and function improved with a remarkable 70% increase in the number of push-ups. Fatigue severity was reported to improve by 13% (P= 0.01) and depression index improved significantly by 42% (P= 0.02). CONCLUSIONS: The significance of these improvements cannot be underestimated as an improvement in physical capacity through increased time to fatigue and less severe fatigue allows adolescents to resume school, social and family activities.

Clinical predictors of pathological gastro-oesophageal reflux in infants with persistent distress.

BACKGROUND: Gastro-oesophageal reflux (GOR) is common in infants with persistent crying. Empirical treatment with antireflux medications is common practice, although on clinical grounds it may be difficult to determine whether GOR is abnormal. AIMS: To examine the diagnostic accuracy of clinical predictors of pathological GOR in infants with persistent crying. METHODS: One hundred and fifty-one infants (82 male; median age 2.5 months, range 0.5-8.2 months) with persistent crying were prospectively studied. Crying and fussing were charted for 24 h, and parents completed a validated questionnaire on reflux symptoms. All infants underwent oesophageal 24-h pH monitoring. RESULTS: Twenty-seven (17.9%) infants had pathological GOR with a fractional reflux time (FRT) >10%. There was no significant association between total crying duration per 24 and FRT (P = 0.84) or the number of reflux episodes (P = 0.68). Pathological GOR was more common in infants under 3 months, compared to older infants (P = 0.04). Feeding difficulties were significantly associated with pathological GOR (P = 0.02). Backarching was not increased in infants with GOR (P = 0.30). Pathological GOR was significantly associated with the frequency of regurgitation (P = 0.04), but not with vomitus volume (P = 0.62). Regurgitation more than 5 times daily was the most specific reflux symptom (specificity 70.9%), but was a poor predictor of pathological GOR (positive predictive value 22.2%). In the absence of frequent regurgitation or feeding difficulties, pathological GOR was unlikely (negative predictive value 87-90%). CONCLUSIONS: Investigation and treatment of GOR in infants with persistent crying should be primarily directed at infants presenting with frequent regurgitation or feeding difficulties.

Effect of antireflux medication, placebo and infant mental health intervention on persistent crying: a randomized clinical trial.

OBJECTIVE: To assess the effect of medical antireflux treatment, and of an infant mental health consultation (IMHC), on persistent crying in infants and maternal distress. METHODS: Infants under 9 months of age with persistent crying, and their mothers, were enrolled in a randomized placebo-controlled trial. At enrollment, a questionnaire on demographic and clinical details was completed by mothers, and maternal distress was measured (Experience of Motherhood Questionnaire; EMQ). Oesophageal 24-h pH monitoring was performed in all infants on day 2. At week 4, the cry chart and EMQ were repeated in conjunction with a final interview. RESULTS: One hundred and three infants (56 under 3 months of age; 55 male) who were randomized to active medication (ranitidine plus cisapride; n = 34), placebo (n = 29) or IMHC (n = 40) completed the trial. There was a significant reduction in crying duration from baseline to week 4 (253 +/- 96.5 min vs 159 +/- 92.3 min per 24 h; P < 0.001), without differences between treatment groups (AVOVA: F = 0.75; P = 0.48). There was a modest improvement in EMQ scores from 44.9 +/- 8.6 at day 1 to 42.8 +/- 9.4 at week 4; P = 0.006. The improvement in maternal stress was similar in all treatment groups (Kruskal-Wallis chi2 = 0.354; P = 0.84), but subsequent admission to a mother-infant unit was significantly less frequent in the IMHC group (P < 0.05). CONCLUSION: Antireflux medications and IMHC were not superior to placebo in treating infants with persistent crying. Although the reduction in maternal distress was similar in all treatment groups, the individualized IMHC reduced the need for subsequent admission to a mother-infant unit.