Elevated nocturnal blood pressure and heart rate in adolescent chronic fatigue syndrome

Aim: To compare ambulatory recordings of heart rate (HR) and blood pressure in adolescents with chronic fatigue syndrome (CFS) and healthy controls. We hypothesized both HR and blood pressure to be elevated among CFS patients. Methods: Forty‐four CFS patients aged 12–18 years were recruited from our paediatric outpatient clinic. The controls were 52 healthy adolescents having similar distribution of age and gender. 24‐h ambulatory blood pressure and HR were recorded using a validated, portable oscillometric device. Results: At night (sleep), HR, mean arterial blood pressure and diastolic blood pressure were significantly higher in CFS patients as compared with controls (p < 0.01). During daytime, HR was significantly higher among CFS patients (p < 0.05), whereas blood pressures were equal among the two groups. Conclusions: The findings support previous experimental evidence of sympathetic predominance of cardiovascular control in adolescent CFS patients. Also, the findings prompt increased focus on cardiovascular risk assessment and suggest a possible target for therapeutic intervention.     

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.     

Mepolizumab—a novel option for the treatment of hypereosinophilic syndrome in childhood

Background

Mepolizumab was originally intended as a therapeutic agent for atopic asthma in adults, and consequently, little is known about its use in children. Up to now, corticosteroids have formed the basis of the initial treatment of hypereosinophilic syndromes and are shown to be effective in most patients. To analyze the effect of mepolizumab in children is the aim of this study.

Methods

We are reporting the experience of the effect of mepolizumab in 2 pediatric patients with hypereosinophilic syndrome that was not sufficiently controlled by other drugs. In addition, the literature regarding the treatment with mepolizumab in pediatric and adult patients is reviewed for the most important studies regarding safety and efficacy.

Results

Mepolizumab therapy showed in 2 pediatric patients with severe hypereosinophilic syndrome a safe and efficient therapeutic approach. No significant intolerances appeared. Furthermore, treatment with systemic corticosteroids was terminated, and therefore, severe side effects were avoided in our pediatric cases.

Conclusions

Anti‐IL‐5 antibodies, which can be applied without substantial drug intolerances, are a new, safe, and effective treatment option for pediatric patients with hypereosinophilic syndrome.     

Polymorphisms of adrenergic cardiovascular control genes are associated with adolescent chronic fatigue syndrome

Aim: To explore the frequency of polymorphisms in adrenergic cardiovascular control genes in adolescent with chronic fatigue syndrome (CFS) and the relation of such polymorphisms to cardiovascular variables. Methods: DNA from 53 patients with CFS, 12–18 years old, was analysed for five single nucleotide polymorphisms (SNPs) in the genes catechol‐O‐methyltransferase (COMT), the β₂‐adrenergic receptor (two SNPs), the β₁‐adrenergic receptor and the α_2a‐adrenergic receptor. Frequencies were compared to a reference population constructed from the National Center for Biotechnology Information (NCBI) database, and associations between frequencies and autonomic cardiovascular responses during a 20° head‐uptilt‐test were explored. Results: For the COMT SNP Rs4680, patients with CFS had a higher frequency of the AA genotype and a lower frequency of the G containing genotypes (AG and GG), when compared to the reference sample (p = 0.046). Also, the AA genotype was associated with a smaller increase in LF/HF ratio (low‐frequency:high‐frequency heart rate variability ratio, an index of cardiac sympathovagal balance) during head‐up tilt when compared to the AG/GG genotypes. For the β₂‐adrenergic receptor SNP Rs1042714, patients with CFS had a lower frequency of the GG genotype and a higher frequency of the genotypes containing C (CG and CC) (p = 0.044). Conclusions: CFS might be related to polymorphisms of COMT and the β₂‐adrenergic receptor. More details of the molecular mechanisms remain to be investigated.     

How fatigue is related to other somatic symptoms

Aims

To assess the relation between fatigue and somatic symptoms in healthy adolescents and adolescents with chronic fatigue syndrome/myalgic encephalopathy (CFS/ME).

Methods

Seventy two adolescents with CFS were compared within a cross‐sectional study design with 167 healthy controls. Fatigue and somatic complaints were measured using self‐report questionnaires, respectively the subscale subjective fatigue of the Checklist Individual Strength (CIS‐20) and the Children''s Somatization Inventory.

Results

Healthy adolescents reported the same somatic symptoms as adolescents with CFS/ME, but with a lower score of severity. The top 10 somatic complaints were the same: low energy, headache, heaviness in arms/legs, dizziness, sore muscles, hot/cold spells, weakness in body parts, pain in joints, nausea/upset stomach, back pain. There was a clear positive relation between log somatic symptoms and fatigue (linear regression coefficient: 0.041 points log somatic complaints per score point fatigue, 95% CI 0.033 to 0.049) which did not depend on disease status.

Conclusions

Results suggest a continuum with a gradual transition from fatigue with associated symptoms in healthy adolescents to the symptom complex of CFS/ME.     

Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome.

OBJECTIVE: To report chronic fatigue syndrome (CFS) associated with both Ehlers-Danlos syndrome (EDS) and orthostatic intolerance. STUDY DESIGN: Case series of adolescents referred to a tertiary clinic for the evaluation of CFS. All subjects had 2-dimensional echocardiography, tests of orthostatic tolerance, and examinations by both a geneticist and an ophthalmologist. RESULTS: Twelve patients (11 female), median age 15.5 years, met diagnostic criteria for CFS and EDS, and all had either postural tachycardia or neurally mediated hypotension in response to orthostatic stress. Six had classical-type EDS and 6 had hypermobile-type EDS. CONCLUSIONS: Among patients with CFS and orthostatic intolerance, a subset also has EDS. We propose that the occurrence of these syndromes together can be attributed to the abnormal connective tissue in dependent blood vessels of those with EDS, which permits veins to distend excessively in response to ordinary hydrostatic pressures. This in turn leads to increased venous pooling and its hemodynamic and symptomatic consequences. These observations suggest that a careful search for hypermobility and connective tissue abnormalities should be part of the evaluation of patients with CFS and orthostatic intolerance syndromes.     

Orthostatic intolerance in adolescent chronic fatigue syndrome

OBJECTIVES: To demonstrate the association between orthostatic intolerance and the chronic fatigue syndrome (CFS) in adolescents and to delineate the form that orthostatic intolerance takes in these children. STUDY DESIGN: We investigated the heart rate and blood pressure (BP) responses to head-up tilt (HUT) in 26 adolescents aged 11 to 19 years with CFS compared with responses in adolescents referred for the evaluation of simple faint and to responses in 13 normal healthy control children of similar age. RESULTS: A total of 4/13 of the controls and 18/26 simple faint patients experienced typical faints with an abrupt decrease in BP and heart rate associated with loss of consciousness. One CFS patient had a normal HUT. A total of 25/26 CFS patients experienced severe orthostatic symptoms associated with syncope in 7/25, orthostatic tachycardia with hypotension in 15/25, and orthostatic tachycardia without significant hypotension in 3/25. Acrocyanosis, cool extremities, and edema indicated venous pooling in 18/25. None of the control or simple faint patients experienced comparable acral or tachycardic findings. CONCLUSIONS: We conclude that chronic fatigue syndrome is highly related to orthostatic intolerance in adolescents. The orthostatic intolerance of CFS often has heart rate and BP responses similar to responses in the syndrome of orthostatic tachycardia suggesting that a partial autonomic defect may contribute to symptomatology in these patients.     

慢性疲劳综合征

近年来,慢性疲劳综合征引起医学界广泛关注。慢性疲劳综合征发病机制复杂,病因尚不明确,学术界认为该病与心理因素、病毒感染、疲劳毒素、免疫功能失调、遗传等因素有关。慢性疲劳综合征治疗比较困难,目前国际上缺乏有效治疗手段,药物治疗效果不理想。     

慢性疲劳综合征

近年来,慢性疲劳综合征引起医学界广泛关注。慢性疲劳综合征发病机制复杂,病因尚不明确,学术界认为该病与心理因素、病毒感染、疲劳毒素、免疫功能失调、遗传等因素有关。慢性疲劳综合征治疗比较困难,目前国际上缺乏有效治疗手段,药物治疗效果不理想。     

Microangiopathic antiphospholipid antibody syndrome due to anti‐phosphatidylserine/prothrombin complex IgM antibody

Herein we describe a case of microangiopathic antiphospholipid syndrome (MAPS) due to anti‐phosphatidylserine/prothrombin complex (aPS/PT) IgM antibody successfully treated with rituximab. A significant correlation was observed between the clinical course and the aPS/PT IgM antibody titer, which can rise earlier before the appearance of clinical symptoms. Rituximab can be safely and effectively used for MAPS. Although detection of only aPS/PT IgM antibody is rare, aPS/PT IgM antibody might be associated with the pathogenesis of MAPS and might be a useful marker of disease activity.     

Characteristics of 2p15‐p16.1 microdeletion syndrome: Review and description of two additional patients

Many new microdeletion syndromes have been characterized in the past decade, including 2p15‐p16.1 microdeletion syndrome. More than 10 patients with this syndrome have been described. Recently, we encountered two additional patients with 2p15‐p16.1 microdeletion syndrome. All patients showed variable degrees of intellectual disability, with the autistic features characteristic of this syndrome. Seven out of 16 patients (44%) showed structural abnormalities in the brain, which is also an important feature of this syndrome. The shortest region of microdeletion overlap among the patients includes two genes, USP34 and XPO1. Although these genes have some functional relevance to cancer, they have not been associated with neurological functions. Diagnosis of additional patients with 2p15‐p16.1 microdeletion syndrome and identification of pathogenic mutations in this region will help identify the genes responsible for the neurological features of the syndrome.     

Pediatric patient with end‐stage kidney disease secondary to Eagle‐Barrett syndrome and metastatic unresectable hepatoblastoma treated successfully with chemotherapy and liver‐kidney transplant

HBL is the most common malignant liver neoplasm in children. The etiology of HBL is largely unknown but there are certain syndromes, such as Beckwith‐Wiedemann syndrome, that have been clearly associated with an increased incidence of this malignancy. EBS, also known as prune belly syndrome, is a congenital anomaly characterized by lax abdominal musculature, bilateral cryptorchidism requiring, in some cases, hemodialysis due to significant kidney and urinary tract dysfunctions. Despite an improvement on the survival rates of patients with advanced‐stage HBL, the presence of concomitant end‐stage renal disease that occurs in patients with EBS constitutes a therapeutic challenge for the clinician not only due to the use of nephrotoxic chemotherapy but also due to the potential need for multi‐organ transplant. We report case of a 2‐year‐old male patient with EBS diagnosed with stage IV, metastatic HBL successfully treated with multi‐agent chemotherapy while on dialysis whom then underwent a simultaneous liver‐kidney transplant followed by adjuvant chemotherapy. Ultimately, the patient achieved cancer remission with normalization of his renal function. Our report emphasizes that patients with HBL in the setting of EBS will not only require careful kidney function monitoring while receiving chemotherapy, but they might also need to undergo multi‐organ transplantation in order to achieve adequate cancer control and also normalization of their kidney function. Awareness of this unusual association calls for further investigation to potentially establish a genetic association between these two disease processes.     

Chronic fatigue syndrome: successful outcome of an intensive inpatient programme

OBJECTIVE: To study the outcome of adolescents with chronic fatigue syndrome (CFS) following an intensive multi-disciplinary inpatient programme. METHODS: A follow-up questionnaire was distributed to all 57 adolescents who had completed the CFS inpatient programme at the Austin and Repatriation Medical Centre. RESULTS: Forty-two adolescents (74%) returned follow-up questionnaires. Immediately following the programme and up to five years after the programme, the majority of participants had returned to school and were functioning better in terms of physical activity and social interactions as compared with before the programme. Before the programme, 94% of adolescents were attending school half-time or less. Up to 5 years after the programme, 78% of adolescents were attending school full-time or with occasional absences only. CONCLUSIONS: A multidisciplinary inpatient programme for CFS was successful in helping to rehabilitate this group of adolescents who were significantly incapacitated prior to entering the inpatient programme.     

Clinical Practice: Chronic fatigue syndrome

The diagnosis chronic fatigue syndrome (CFS) was conceptualized in the mid-1980s. It is a clinically defined condition characterized by severe and disabling new onset fatigue with at least four additional symptoms: impaired memory or concentration, sore throat, tender cervical or axillary lymph nodes, muscle pain, multi-joint pain, new headaches, unrefreshing sleep or post-exertion malaise. Chronic fatigue syndrome in adolescents is a rare condition compared to symptomatic fatigue. The estimated prevalence of adolescent CFS ranges between 0.11 and 1.29 % in Dutch, British, and US populations. Diagnosis of the chronic fatigue syndrome is established through exclusion of other medical and psychiatric causes of chronic fatiguing illness. Taking a full clinical history and a full physical examination are therefore vital. In adolescence, CFS is associated with considerable school absence with long-term detrimental effects on academic and social development. One of the most successful potential treatments for adolescents with CFS is cognitive behavioural therapy, which has been shown to be effective after 6 months in two thirds of the adolescents with CFS. This treatment effect sustains at 2–3-year follow-up. In conclusion, the diagnosis CFS should be considered in any adolescent patient with severe disabling long-lasting fatigue. Cognitive behavioural therapy is effective in 60–70 % of the patients. Prompt diagnosis favours the prognosis.     

1p36 deletion syndrome associated with Prader–Willi‐like phenotype

Background: 1p36 deletion syndrome is one of the most common subtelomeric deletion syndromes, characterized by moderate to severe mental retardation, characteristic facial appearance, hypotonia, obesity, and seizures. The clinical features often overlap with those of Prader–Willi syndrome (PWS). To elucidate the phenotype–genotype correlation in 1p36 deletion syndrome, two cases involving a PWS‐like phenotype were analyzed on molecular cytogenetics. Methods: Two patients presenting with the PWS‐like phenotype but having negative results for PWS underwent fluorescence in situ hybridization (FISH). The size of the chromosome 1p36 deletions was characterized using probes of BAC clones based on the University of California, Santa Cruz (UCSC) Genome Browser. Results: PWS was excluded on FISH and methylation‐specific polymerase chain reaction. Subsequent FISH using the probe D1Z2 showed deletion of the 1p36.3 region, confirming the diagnosis of 1p36 deletion syndrome. Further analysis characterized the 1p36 deletions as being located between 4.17 and 4.36 Mb in patient 1 and between 4.89 and 6.09 Mb in patient 2. Conclusion: Patients with 1p36 deletion syndrome exhibit a PWS‐like phenotype and are therefore probably underdiagnosed. The possible involvement of the terminal 4 Mb region of chromosome 1p36 in the PWS‐like phenotype is hypothesized.     

Diffuse alveolar hemorrhage secondary to ANCA‐associated vasculitis in a patient with Down syndrome

Diffuse alveolar hemorrhage (DAH) is a rare disease characterized by dyspnea, cough, hemoptysis, and new alveolar infiltrates. Among the various underlying disorders, vasculitis is believed to play a significant role in the pathogenesis of DAH. Here we report the first case of a patient with Down syndrome who developed DAH secondary to anti‐neutrophil cytoplasmic antibody‐associated vasculitis. This case highlights the significance of vasculitis as well as pulmonary hypoplasia and vulnerability associated with Down syndrome in the development of DAH.     

Hormonal alterations in adolescent chronic fatigue syndrome

Aim: The chronic fatigue syndrome is associated with alterations in the hypothalamus‐pituitary‐adrenal axis and cardiovascular autonomic nervous activity, suggesting a central dysregulation. This study explored differences among adolescent chronic fatigue syndrome patients and healthy controls regarding antidiuretic hormone, the renin‐angiotensin‐aldosterone‐system, sex hormones and cardiac peptides. Methods: We included a consecutive sample of 67 adolescents aged 12–18 years with chronic fatigue syndrome diagnosed according to a thorough and standardized set of investigations, and a volunteer sample of 55 healthy control subjects of equal gender and age distribution. Hormones were assayed with standard laboratory methods. Results: Among patients, plasma antidiuretic hormone was significantly decreased and serum osmolality and plasma renin activity were significantly increased (p ≤ 0.001). Serum concentration of aldosterone, cortisol, NT‐proBNP and sex hormones were not significantly different in the two groups. Conclusion: Chronic fatigue syndrome in adolescents is associated with alterations in hormonal systems controlling osmolality and blood volume, possibly supporting a theory of central dysregulation.     

Acute rejection associated with donor-specific anti-MICA antibody in a highly sensitized pediatric renal transplant recipient

Allograft rejection in HLA identical transplant recipients and in patients without detectable donor-specific anti-HLA antibodies has lead to the identification of non-HLA antigens as targets of the alloimmune response. MICA antigen has been recognized as an important non-HLA target in renal transplantation. Recent studies have shown that anti-MICA antibodies are associated with acute renal allograft rejection and failure. Current cross match procedures using donor lymphocytes fail to detect MICA antibodies. Transplant candidates are not routinely tested for pre-sensitization to MICA antigens nor are transplant donors typed for MICA alleles. Optimal classification and treatment of acute rejection associated with MICA antibody remains unknown. In this case report, we are the first to describe the clinical course and treatment of donor-specific MICA antibody associated with both Banff type II A ACR and AMR in a highly sensitized pediatric renal re-transplant recipient. This case also emphasizes the importance of pre-transplant screening for donor-specific MICA antibody especially in highly sensitized renal transplant patients.     

Idiopathic thrombocytopenic purpura in childhood: Twenty years of experience in a single center

Background: Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder with a variable clinical course. Methods: A retrospective analysis was carried out of ITP patients presenting to a pediatric hematology‐oncology department during a period of 20 years, with a focus on treatment and outcome. Results: One hundred and twenty‐four cases were recorded (mean patient age, 8.4 years). Forty‐nine children (39.5%) had platelet counts <10 000/µL at diagnosis. No episode of severe bleeding was observed. Peak incidence was observed during spring and summer. Respiratory infections proceeded in 58% of cases. Treatment consisted of i.v. immunoglobulin (IVIG) in 93 children at four dosing schedules. Sixteen children received corticosteroids, 10 children received anti‐D immunoglobulin and 14 received no treatment. Recovery was observed in 67% of children on IVIG and in 50% on anti‐D globulin. Eight patients did not respond initially and received corticosteroids. Three children with refractory thrombocytopenia received anti‐CD20 (rituximab). Fourteen children (11%) had persistent/chronic disease. In 10 of them recovery was observed in 13 months–8 years. Splenectomy was performed in six children with resistant/chronic disease. Conclusion: ITP has a benign course in the majority of cases. Anti‐D globulin can effectively be used as an alternative first‐line treatment. Rituximab can successfully be used in refractory cases, while splenectomy has currently limited indications.     

Joint hypermobility is more common in children with chronic fatigue syndrome than in healthy controls

OBJECTIVE: To determine whether children with chronic fatigue syndrome (CFS) have a higher prevalence of joint hypermobility than gender-matched controls.Study design: Matched case-control study comparing the Beighton joint hypermobility scores in 58 consecutive children with CFS (incident cases) with 58 otherwise healthy controls referred to a dermatology clinic for evaluation of common skin problems. A second group of 58 patients previously diagnosed with CFS (prevalent cases) was matched by gender to the incident cases to evaluate temporal changes in referral patterns. RESULTS: Of the 58 patients in each group, 71% were female. The median Beighton scores were higher in incident CFS cases than in healthy controls (4 vs 1, P <.001). More incident CFS cases had Beighton scores >/=4 (consistent with joint hypermobility), 60% versus 24%, P <.0001. Incident and prevalent CFS cases had similar Beighton scores. The odds ratio for hypermobility in all patients with CFS versus healthy controls was 3.5 (P <.001; 95% CI, 1.6-7.5). CONCLUSIONS: Joint hypermobility is more common in patients with CFS than in otherwise healthy children with common skin disorders. The etiologic significance of the observed association remains to be defined.