Neurofilament Light Chain Is a Biomarker of Neurodegeneration in Ataxia Telangiectasia.

Ataxia telangiectasia (A-T) is a progressive and life-limiting disease associated with cerebellar ataxia due to progressive cerebellar degeneration. In addition to ataxia, which is described in detail, the presence of chorea, dystonia, oculomotor apraxia, athetosis, parkinsonism, and myoclonia are typical manifestations of the disease. The study aimed to evaluate the specificity and sensitivity of neurofilament light chain (NfL) as a biomarker of neurodegeneration in relation to SARA score. In this prospective trial, one visit of 42 A-T patients aged 1.3-25.6 years (mean 11.6 ± 7.3 years) was performed, in which NfL was determined from serum by ELISA. Additionally, a neurological examination of the patients was performed. Blood was collected from 19 healthy volunteers ≥ 12 years of age. We found significantly increased levels of NfL in patients with A-T compared to healthy controls (21.5 ± 3.6 pg/mL vs. 9.3 ± 0.49 pg/mL, p ≤ 0.01). There was a significant correlation of NfL with age, AFP, and SARA. NfL is a new potential progression biomarker in blood for neurodegeneration in A-T which increases with age.

Altered Cerebrospinal Fluid (CSF) in Children with Ataxia Telangiectasia.

Ataxia telangiectasia (A-T) is a devastating multi-system disorder characterized by progressive cerebellar ataxia and immunodeficiency. The neurological decline may be caused by multiple factors of which ongoing inflammation and oxidative stress may play a dominant role. The objective of the present investigation was to determine cerebrospinal fluid (CSF) proteins and possible low-grade inflammation and its relation to age and neurological deterioration. In the present study, we investigated 15 patients with A-T from 2 to 16 years. Our investigation included blood and CSF tests, clinical neurological examination, A-T score, and MRI findings. The albumin ratio (AR) was analyzed to determine the blood-brain-barrier function. In addition, inflammatory cytokines (IL-1α, IL-6, IL-8, IL-12 p40, IL-17A, IFN-γ, TNF-α) were measured by the multiplex cytometric bead array. We compared the results with those from an age-matched control group. Three of the A-T patients were analyzed separately (one after resection of a cerebral meningioma, one after radiation and chemotherapy due to leukemia, one after stem cell transplantation). Patient had significantly more moderate and severe side effects due to CSF puncture (vomiting, headache, need for anti-emetic drugs) compared with healthy controls. Total protein, albumin, and the AR increased with age indicating a disturbed blood barrier function in older children. There were no differences for cytokines in serum and CSF with the exception of IL-2, which was significantly higher in controls in serum. The AR is significantly altered in A-T patients, but low-grade inflammation is not detectable in serum and CSF.

Risk and risk factors for epilepsy in shunt-treated children with hydrocephalus.

OBJECT: Epilepsy is a major comorbidity in children with hydrocephalus (HC) and has a serious impact on their developmental outcomes. There are variable influencing factors, thus the individual risk for developing epilepsy remains unclear. Our aim was to analyse risk factors for developing epilepsy in children with shunted HC. METHODS: A retrospective, single-centre analysis of 361 patients with the diagnosis of HC was performed. Age at HC diagnosis, shunt treatment, development of epilepsy, epilepsy course, and the aetiology of HC were considered. The influence of shunt therapy, including its revisions and complications, on the development of epilepsy was investigated. RESULTS: One-hundred forty-three patients with HC (n = 361) had a diagnosis of epilepsy (39.6%). The median age at the first manifestation of epilepsy was 300 days (range:1-6791; Q1:30, Q3: 1493). The probability of developing epilepsy after HC decreases with increasing age. The most significant influence on the development of epilepsy is that of the HC itself and its underlying aetiology (HR 5.9; 95%-CI [3-10.5]; p < 0.001). Among those, brain haemorrhage is associated with the highest risk for epilepsy (HR 7.9; 95%-CI [4.2-14.7]; p < 0.01), while shunt insertion has a lower influence (HR 1.5; 95%-CI [0.99; 2.38]; p = 0.06). The probability of epilepsy increases stepwise per shunt revision (HR 2.0; p = 0.03 after 3 or more revisions). Five hundred days after the development of HC, 20% of the children had a diagnosis of epilepsy. Shunt implantation at a younger age has no significant influence on the development of epilepsy nor does sex. CONCLUSION: Children with HC are at high risk for developing epilepsy. The development of epilepsy is correlated mainly with HC's underlying aetiology. The highest risk factor for the development of epilepsy seems to be brain haemorrhage. The age at shunt implantation appears to be unrelated to the development of epilepsy, while structural brain damage at a young age, shunt revisions and complications are independent risk factors. The onset of epilepsy is most likely to take place within the first 500 days after the diagnosis of HC.

Comparison of the detectability of UBOs in Neurofibromatosis Type I patients with proton density-weighted and FLAIR sequences in 3T MRI.

OBJECTIVE: In NF 1 patients, significant numbers of so-called unidentified bright objects (UBOs) can be found. The aim of the study was to investigate whether the detectability of UBOs increases at 3T by comparing Proton density-weighted images (PDw) with fluid-attenuated inversion recovery (FLAIR) sequences. PATIENTS AND METHODS: A total of 14 NF1 patients (7 male, 7 female, between 8 and 26 years old, mean age 15.4 years) were examined by a 3T magnetic resonance scanner. The presence of UBOs was evaluated on PD-w and FLAIR images by 4 evaluators. Detectability was rated by a three-point scoring system: lesions which were "well defined/detectable", "suspicious" or "detected after a second look". The Wilcoxon signed-rank test was used for comparisons between the raters. The level of significance was P < 0.05. RESULTS: Significantly more lesions were marked as "well defined/detectable" in the PD-w Sequence compared to FLAIR at 3T (P < 0.001 for all four evaluators together, as well as for each evaluator separately). In particular, PD-w proved to be superior for detecting UBOs located in the medulla oblongata, dentate nucleus and hippocampal region, regardless of the level of the raters' experience. CONCLUSION: This is the first study which compares FLAIR and PD-w at 3T for the diagnosis of UBOs in NF1. At this field strength significantly more UBOs were detected in the PD-w compared to FLAIR sequences, especially for the infratentorial regions. As UBOs occur at very early stages of the disease in patients with suspected NF1, PD-w might aid in the early diagnosis when using 3T scanners.

[Failure to Attend Child Preventive Examination as a Possible Indication of Risk to Children's Welfare: Retrospective Analysis of 605 Cases Reported to the Child Protection Services]. / Nicht-Teilnahmen an Kindervorsorgeuntersuchungen als Indiz für Kindeswohlgefährdung? ­ Eine retrospektive Analyse von 605 an das Jugendamt gemeldeten Fällen.

Objective: The extent to which childrens's welfare is compromised when they do not attend compulsory prevention medical check-ups is yet to be determined. Together with the Hessen Prevention Center for Children (Hessisches Kindervorsorgezentrum), the Child Protection Services in the Main-Taunus district have conducted a study to investigate failure to attend child preventive examinations as a possible indication of risk to the welfare of such children. Method: 605 notifications of child preventive examinations that were not carried out, sent in 2012 to the Child Protection Services by the Hessen Prevention Center for Children, were analyzed retrospectively. Each case was recorded using a standardized questionnaire and, cases that were passed on to General Social Services within Child Protection Services were investigated with an additional interview with the employee responsible. Results: In 60 (10%) cases there was no certificate to show that the check-up had been conducted, while in 165 (27%) cases the check-up was conducted late, i. e. only after being contacted by the Child Protection Services. In 9 of the 605 cases (1.5%), the families involved were already known to Child Protection Services due to previous proceedings against them under endangering children's welfare act (known as § 8a cases). No new case of a risk to children's welfare was detected. In 58 cases, families gave reasons for the missed or late check-up. Reasons included being abroad and moving house (20 cases), forgetting (14 cases) and illness (11 cases), as well as lack of knowledge of the law (6 cases), lack of health insurance (4 cases), lack of language skills (2 cases) and objection to the law in principle (1 case). It was notable that, in 57% of the cases notified, documentary evidence could be provided by the end of the case work that the check-up had taken place within the recommended period (including additional discretionary period). The majority of these notifications of failure to attend can be prevented by an upstream clearing procedure.

Body composition, muscle strength and hormonal status in patients with ataxia telangiectasia: a cohort study.

BACKGROUND: Ataxia-telangiectasia (A-T) is a devastating human autosomal recessive disorder that causes progressive cerebellar ataxia, immunodeficiency, premature aging, chromosomal instability and increased cancer risk. Affected patients show growth failure, poor weight gain, low body mass index (BMI), myopenia and increased fatigue during adolescence. The prevalence of alterations in body composition, muscle strength and hormonal status has not been well described in classical A-T patients. Additionally, no current guidelines are available for the assessment and management of these changes. METHODS: We analyzed body composition, manual muscle strength and hormonal status in 25 A-T patients and 26 age-matched, healthy controls. Bioelectrical impedance analysis (BIA) was performed to evaluate the body composition, fat-free mass (FFM), body cell mass (BCM), extracellular matrix (ECM), phase angle (PhA), fat mass (FM) and ECM to BCM ratio. Manual muscle strength was measured using a hydraulic hand dynamometer. RESULTS: The BMI, FFM and PhA were significantly lower in A-T patients than in controls (BMI 16.56 ± 3.52 kg/m(2) vs. 19.86 ± 3.54 kg/m(2); Z-Score: -1.24 ± 1.29 vs. 0.05 ± 0.92, p <0.001; FFM 25.4 ± 10.03 kg vs. 41.77 ± 18.25 kg, p < 0.001; PhA: 4.6 ± 0.58° vs. 6.15 ± 0.88°, p < 0.001). Manual muscle strength was significantly impaired in A-T patients compared with controls (10.65 ± 10.97 kg vs. 26.8 ± 30.39 kg, p < 0.0001). In addition, cortisol and dehydroepiandrosterone sulfate (DHEAS) levels were significantly lower in A-T patients than in controls. CONCLUSION: Altered body composition, characterized by depleted BMI, PhA and BCM; by the need to sit in a wheelchair; by altered hormone levels; and by poor muscle strength, is a major factor underlying disease progression and increased fatigue in A-T patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02345200.

[Status quo of children's preventative medicine programmes--results of the first German nationwide workshop 2011 in Frankfurt am Main]. / Zum aktuellen stand der kindervorsorgeprogramme--ergebnisse des ersten bundesweiten arbeitstreff ens 2011 in Frankfurt am Main.

10 of the 13 federal states presented their structures, implementation methods and results as part of the nationwide workshop for children's preventative medicine and early recognition projects for Germany on 9th September 2011 in Frankfurt am Main. This was the first time a full overview of all programmes of this kind in Germany has been possible. The programmes and data from these 10 presentations were analysed and compared. Despite the many differences between the legal frameworks and structural implementation, the programmes also displayed similarities in the implementation and in the problems which arise. Significantly improved participation rates for early recognition check-ups have been achieved in the context of the programmes. Previously, only a few detailed evaluations for the detection of risks to children's welfare and other effects such as vaccination rates and improvements in children's health through more advice and care were available.

Morphometry of the pituitary gland and hypothalamus in long-term survivors of childhood trauma.

PURPOSE: Chronic pituitary dysfunction is increasingly recognized as a sequela of traumatic brain injury (TBI). Our aim was to rule out any late morphometric changes of the pituitary gland and hypothalamus in survivors of TBI during childhood requiring intensive care. METHODS: We assessed morphometric abnormalities of the sella region and hypothalamus in patients who sustained TBI during childhood. The patients showed no clinical hormonal dysfunction at the acute phase and pituitary hormone levels at the time of our study were within normal limits. From the 18 enrolled patients in the magnetic resonance study, five were removed due to morphological changes or anatomical variations. We studied the MRI of 13 male survivors (mean age 27 years, mean time after trauma 20 years) and compared them to 13 male control subjects who were matched in terms of age (mean age, 26 years), education and ethnicity. Analyses of the pituitary gland and sella on a midsagittal T2- and T1-weighted image were performed. We used voxel-based morphometry (VBM), an unbiased MRI morphometric method to investigate hypothalamic region in this group of patients. RESULTS: There was only a trend towards a reduced pituitary gland width in the patient group compared to controls. However, no significant morphological and morphometric abnormality was seen and VBM showed no hypothalamic grey matter loss. CONCLUSION: In the absence of hormonal dysfunction, no persisting morphometric changes of the pituitary gland and hypothalamus were seen in survivors of childhood TBI requiring intensive care.

Voxel-based morphometry and diffusion-tensor MR imaging of the brain in long-term survivors of childhood leukemia.

The aims of this study were to detect morphological changes in neuroanatomical components in adult survivors of acute lymphoblastic leukemia (ALL). Voxel-based morphometry (VBM) can be used to detect subtle structural changes in brain morphology and via analysis of fractional anisotropy (FA), diffusion-tensor imaging (DTI) can non-invasively probe white matter (WM) integrity. We used VBM and DTI to examine 20 long-term survivors of ALL and 21 healthy matched controls. Ten ALL survivors received chemotherapy and irradiation; ten survivors received chemotherapy alone during childhood. Imaging was performed on a 3.0-T MRI. For VBM, group comparisons of segmented T1-weighted grey matter (GM) and WM images from controls and ALL survivors were performed separately for patients who received chemotherapy alone and who received chemotherapy and irradiation. For DTI, FA in WM was compared for the same groups. Survivors of childhood ALL who underwent cranial irradiation during childhood had smaller WM volumes and reduced GM concentration within the caudate nucleus and thalamus. The FA in WM was reduced in adult survivors of ALL but the effect was more severe after combined treatment with irradiation and chemotherapy. Our results indicate that DTI and VBM can reveal persistent long-term WM and caudate changes in children after ALL treatment, even without T2 changes in conventional imaging.

[Diagnostic difficulties in encephalitis and glioma]. / Differenzialdiagnostische Abgrenzung Enzephalitis versus Gliom mittels Magnetresonanzspektroskopie.

BACKGROUND: Glial neoplasms can infiltrate the central nervous system extensively with relative preservation of the underlying neuronal architecture. The differential diagnosis between cerebral glioma and infective lesions can be very difficult to distinguish by MRI only. CASE REPORT: We report a 7 year old boy with recurrent vomiting, fever, weakness, abdominal pain and diarrhea. Besides an expressive speech disturbance the neurological examination showed no pathological findings. The sonography revealed discrete hepatomegaly and small pericardial effusion. MRI showed a diffuse mesencephalic and pontine swelling without contrast medium enhancement possibly pointing to an infective lesion. Microbiological, serological and metabolic investigations of blood and CSF were normal. After initial improvement associated with antibiotic, antiviral and dexamethasone treatment the process relapsed progessively. The 1H-MR-spectroscopy showed elevated cholin and decreased N-acetyl-aspartate levels suspicious for a proliferating process. Brain biopsy revealed anaplastic astrocytoma (WHO III). Despite of radiation and chemotherapy the tumordisease deteriorated and the patient died because of progressive brainstem infiltration one year later. CONCLUSION: This case report shows that cerebral glioma can mimick infective brain disease and that MR-spectroscopy is an important non-invasive tool in this differential diagnosis.

Proton magnetic resonance spectroscopy in childhood brainstem lesions.

BACKGROUND: Diagnosis of brainstem lesions in children based on magnetic resonance imaging alone is a challenging problem. Magnetic resonance spectroscopy (MRS) is a noninvasive technique for spatial characterization of biochemical markers in tissues and gives information regarding cell membrane proliferation, neuronal damage, and energy metabolism. METHODS: We measured the concentrations of biochemical markers in five children with brainstem lesions and evaluated their potential diagnostic significance. Images and spectra were acquired on a 1.5-T imager. The concentrations of N-acetylaspartate, tetramethylamines (e.g., choline), creatine, phosphocreatine, lactate, and lipids were measured within lesions located at the brainstem using Point-resolved spectroscopy sequences. RESULTS: Diagnosis based on localized proton spectroscopy included brainstem glioma, brainstem encephalitis, demyelination, dysmyelination secondary to neurofibromatosis type 1 (NF 1), and possible infection or radiation necrosis. In all but one patient, diagnosis was confirmed by biopsy or by clinical follow-up. CONCLUSIONS: This small sample of patients suggests that MRS is important in the differential diagnosis between proliferative and nonproliferative lesions in patients without neurofibromatosis. Unfortunately, in cases of NF 1, MRS can have a rather misdiagnosis role.

Accelerated myelination associated with venous congestion.

Magnetic resonance imaging is currently the gold standard in the assessment of brain myelination. The normal pattern of brain myelination conforms to a fixed chronological sequence. Focal accelerated myelination is a usual pathological state and previously has only been associated with Sturge-Weber syndrome. The purpose of our study is to describe alternate causes for accelerated myelination. We retrospectively reviewed serial MR scans, MR angiography, conventional angiography and the clinical progress of three children with accelerated myelination. Two patients with accelerated myelination had an underlying cerebral sinovenous thrombosis. The third patient had Sturge-Weber syndrome. Our study strongly suggests that cerebral venous thrombosis with the consequent restriction of venous outflow could be a key factor in the induction of accelerated myelination. We recommend that in patients with accelerated myelination, the search for an underlying etiology should include careful evaluation of the intracranial vascular pathology, especially cerebral venous thrombosis.

Central nervous system lymphoma in children.

This paper describes the rare MR and CT features of central nervous system (CNS) lymphoma in immunocompetent children and in survivors of childhood acute lymphoblastic leukemia (ALL) and discusses the causative role of cranial irradiation and/or leukoencephalopathy preceding central nervous system (CNS) lymphoma in survivors of childhood leukemia. The authors reviewed MR and CT scans of 3 children with biopsy-proved CNS lymphoma. One child had tumor infiltration within the optic nerve sheaths and optic chiasm by previously known non-Hodgkin lymphoma. In 2 patients, CNS lymphoma developed 8 and 10 years after initial ALL treatment. In both cases CNS lymphoma was preceded by cranial irradiation and leukoencephalopathy. A single lesion was present in 3 out of 4 patients. All lesions were isointense or hypointense on the T1-weighted images relative to gray matter and showed homogeneous enhancement. One lesion was centered in the central gray matter, one lesion was centered within a cerebral hemisphere, one lesion was in optic nerve, and there were 2 parasellar lesions. CNS lymphoma has a variable appearance in children. Knowledge of risk factors in children may help in the early recognition of disease, allowing for timely intervention. This may prompt early biopsy or a conservative management in the appropriate clinical setting.

Isolated CNS relapse in neuroblastoma.

We report three patients with primary extracerebral neuroblastoma and central nervous system (CNS) relapse. As the survival of children with metastatic neuroblastoma improves with recent advances in treatment, CNS involvement becomes more frequently detected. MR imaging of the brain and spine are strongly indicated in the follow-up of patients with increased risk of developing CNS disease.

Central nervous system imaging in childhood leukaemia.

The aim of this study was to document the imaging abnormalities seen in the central nervous system (CNS) in cases of childhood leukaemia or as complications of its treatment. Magnetic Resonance (MR) images and Computed Tomographic (CT) scans were reviewed retrospectively in 22 children and adolescents with neurological manifestations/complications of leukaemia or its treatment. Among the 22 patients, nine had two or more different CNS abnormalities. The imaging abnormalities seen in 15 patients before or during treatment included sinus thrombosis, cortical vein thrombosis, cerebral haemorrhage, meningeal leukaemia, infections, skull leukaemic infiltration and treatment-related neurotoxicity. After therapy, seven patients had CNS abnormalities, including secondary brain tumours, skull tumour, mineralising microangiopathy, leucoencephalopathy, transient white matter abnormalities, spinal intradural haematoma, chronic subdural haematoma, radiation necrosis, meningeal leukaemia and leukaemic infiltration at the vertebral body. CNS complications are related to the inherent risk of leukaemia itself, to the treatment method and to the duration of survival.

Granulocytic sarcoma in children.

We report three children with leukaemia (two acute myeloid and one acute lymphoblastic) and granulocytic sarcoma in the skull, orbit and sinuses. Lesions in these sites in children, with or without bone changes, are suggestive of systemic diseases such as lymphoproliferative conditions. Although involvement by granulocytic sarcoma, with or without acute myeloid leukaemia, is described, an association with acute lymphoblastic leukaemia is rare. Recognition of this rare entity is important, because early aggressive chemotherapy can bring about regression of the tumour and improve survival.

Increase of fetal hemoglobin synthesis indicating differentiation induction in children receiving valproic acid.

Differentiation induction is a distinct concept in the treatment of malignant diseases, considering that malignant cells share many features with immature progenitor cells that are capable of terminal differentiation. Treatment of tumor cells with short-chain fatty acid treatment of erythroid progenitors in vitro and in vivo induces cellular differentiation resulting in gamma-globin, i.e., fetal hemoglobin synthesis. Valproic acid (VPA) is a branched-chain fatty acid that is able to inhibit growth of human and rodent tumor cells and to induce a mature phenotype. The antitumoral effects observed in preclinical studies were reached at concentrations that are readily achieved in patients treated with VPA for epilepsy. Hypothesizing that anticonvulsive VPA levels may be used for antitumoral differentiation induction therapy of pediatric malignant tumors, the authors studied fetal hemoglobin-inducing capacity of VPA in children treated with VPA for epilepsy. Fetal hemoglobin was significantly increased in 30 children with epilepsy treated with VPA monotherapy for at least 3 months when compared to untreated control patients. Furthermore, fetal hemoglobin levels correlated with VPA serum levels. The study confirms the dose-dependent stimulating effect of VPA on fetal hemoglobin synthesis at anticonvulsive doses. The results suggest that nontoxic VPA levels reached in pediatric epilepsy patients should be capable of inducing cellular differentiation of pediatric malignant tumors for therapeutic purposes. Broad clinical experience with VPA and its low toxicity further encourage the evaluation of VPA in pediatric oncology for differentiation induction therapy.

[Diagnosis and outcome of neurotropic enterovirus infections in childhood]. / Diagnostik und klinischer Verlauf neurotroper Enterovirusinfektionen im Kindesalter.

BACKGROUND: Enterovirus infections are among the most common causes of aseptic meningitis. Worldwide there are reports about recurring outbreaks, especially during the summer. They are favoured by conditions of bad hygiene and contaminated water, transmission is predominantly through the faeco-oral route or by droplet infection. The most common species are Coxsackie B and ECHO (Enteric Cytopathogenic Human Orphan) virus. ECHO viruses have a worldwide distribution and usually occur as "summer flu" or aseptic meningitis and meningoencephalitis in toddlers and infants. Type 30 caused an outbreak of aseptic meningitis in the Rhein-Main region in summer 1997. During five months 63 children younger than 16 years were reported. PATIENTS AND METHODS: During this outbreak 18 children with prooved enterovirus infections were treated at the Frankfurt/Main University Children's Hospital. Standardized infectiological diagnostic procedures were performed and risc factors, clinical symptoms, inflammatory marker, neurophysiological findings (electroencephalography, evoked potentials) and outcome were assessed. RESULTS: The affected children were between 3 and 11 years old. Clinical symptoms were cephalgia, nausea, vomiting, meningism and seizures with fever. Virus isolation from faecal and cerebrospinal fluid (CSF) samples and the use of polymerase chain reaction (PCR) was superior to serological methods. Erythrocyte sedimentation rates showed more significant increase than C-reactive protein (CRP) and blood leukocytes. CSF pleocytosis showed high variation. Clinical course as well as prognosis and outcome were favourable. CONCLUSION: Virusisolation in stool and CSF is most promising in the diagnostic of cerebral enterovirus infections. Usually the outcome is favourable, encephalitis can occur as serious complication.