Early Diagnosis and Monitoring of Neurodegenerative Langerhans Cell Histiocytosis.

BACKGROUND: Neurodegenerative Langerhans Cell Histiocytosis (ND-LCH) is a rare, unpredictable consequence that may devastate the quality of life of patients cured from LCH. We prospectively applied a multidisciplinary diagnostic work-up to early identify and follow-up patients with ND-LCH, with the ultimate goal of better determining the appropriate time for starting therapy. METHODS: We studied 27 children and young adults with either ND-LCH verified by structural magnetic resonance imaging (MRI) (group 1) or specific risk factors for (diabetes insipidus, craniofacial bone lesions), but no evidence of, neurodegenerative MRI changes (group 2). All patients underwent clinical, neurophysiological and MRI studies. RESULTS: Seventeen patients had MRI alterations typical for ND-LCH. Nine showed neurological impairment but only three were symptomatic; 11 had abnormal somatosensory evoked potentials (SEPs), and five had abnormal brainstem auditory evoked potentials (BAEPs). MR spectroscopy (MRS) showed reduced cerebellar NAA/Cr ratio in nine patients. SEPs showed sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for predicting ND-LCH of 70.6% (95%CI, 44.0%-89.7%), 100% (69.2%-100%), 100% (73.5%-100%), and 66.7% (38.4%-88.2%), respectively. Repeated investigations in group 1 revealed increasingly abnormal EP parameters, or neurological examination, or both, in nine of fifteen patients while MRI remained unchanged in all but one patient. CONCLUSION: A targeted MRI study should be performed in all patients with risk factors for ND-LCH for early identification of demyelination. The combined use of SEPs and careful neurological evaluation may represent a valuable, low-cost, well-tolerated and easily available methodology to monitor patients from pre-symptomatic to symptomatic stages. We suggest a multidisciplinary protocol including clinical, MRS, and neurophysiological investigations to identify a population target for future therapeutic trials.

Radiological contrast media in the breastfeeding woman: a position paper of the Italian Society of Radiology (SIRM), the Italian Society of Paediatrics (SIP), the Italian Society of Neonatology (SIN) and the Task Force on Breastfeeding, Ministry of Health, Italy.

OBJECTIVES: Breastfeeding is a well-recognised investment in the health of the mother-infant dyad. Nevertheless, many professionals still advise breastfeeding mothers to temporarily discontinue breastfeeding after contrast media imaging. Therefore, we performed this review to provide health professionals with basic knowledge and skills for appropriate use of contrast media. METHODS: A joint working group of the Italian Society of Radiology (SIRM), Italian Society of Paediatrics (SIP), Italian Society of Neonatology (SIN) and Task Force on Breastfeeding, Ministry of Health, Italy prepared a review of the relevant medical literature on the safety profile of contrast media for the nursing infant/child. RESULTS: Breastfeeding is safe for the nursing infant of any post-conceptional age after administration of the majority of radiological contrast media to the mother; only gadolinium-based agents considered at high risk of nephrogenic systemic fibrosis (gadopentetate dimeglumine, gadodiamide, gadoversetamide) should be avoided in the breastfeeding woman as a precaution; there is no need to temporarily discontinue breastfeeding or to express and discard breast milk following the administration of contrast media assessed as compatible with breastfeeding. CONCLUSIONS: Breastfeeding women should receive unambiguous professional advice and clear encouragement to continue breastfeeding after imaging with the compatible contrast media. KEY POINTS: • Breastfeeding is a well-known investment in the health of the mother-infant dyad. • Breastfeeding is safe after administration of contrast media to the mother. • There is no need to temporarily discontinue breastfeeding following administration of contrast media.

Herpes simplex encephalitis with occipital localization in an infant: a different route of entry in the brain system?

Herpes simplex encephalitis classically involves the periventricular white matter in infants and the mesial temporal lobes, inferior frontal lobes, and insula in older children and adults. However, the increasing use of polymerase chain reaction to detect viral DNA in the cerebrospinal fluid has allowed the expansion of the spectrum of radiologic findings possibly associated with herpes simplex encephalitis. This study presents a rare case of a previously healthy infant with herpes simplex encephalitis with occipital involvement and permanent visual impairment. Possible pathogenic mechanisms are discussed.

Giant aorto-pulmonary collaterals in pulmonary atresia and ventricular septal defect: long-term survival in unoperated adults.

The association of pulmonary atresia and ventricular septal defect (PA/VSD) can be considered the most severe form of tetralogy of Fallot. The main feature of this congenital heart disease is represented by discontinuity between the right ventricle and pulmonary trunk or its branches; the anatomy of central pulmonary arteries is often abnormal, consequently the type and the amount of sources of pulmonary blood flow are variable. Due to evolution in surgical techniques, definitive correction is now also considered in more complex cases. A small rate of unoperated patients with PA/VSD can survive until adulthood and the arterial blood supply to the lungs, provided by major aorto-pulmonary collateral arteries (MAPCAs), is one of the main determinants of survival. We report two unoperated cases of PA/VSD and MAPCAs with long-term survival. Giant MAPCAs can occasionally be found by chest radiography in adults with unrepaired PA/VSD. Moreover, non-invasive assessment of the pulmonary arterial bed with computer tomography or MRI is helpful in these patients during follow-up. Finally, we discuss the use of oral anticoagulants and/or 5-phosphodiesterase inhibitors in these patients.

Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI).

BACKGROUND: Despite progresses in neonatal care, the mortality and the incidence of neuro-motor disability after perinatal asphyxia have failed to show substantial improvements. In countries with a high level of perinatal care, the incidence of asphyxia responsible for moderate or severe encephalopathy is still 2-3 per 1000 term newborns. Recent trials have demonstrated that moderate hypothermia, started within 6 hours after birth and protracted for 72 hours, can significantly improve survival and reduce neurologic impairment in neonates with hypoxic-ischemic encephalopathy. It is not currently known whether neuroprotective drugs can further improve the beneficial effects of hypothermia. Topiramate has been proven to reduce brain injury in animal models of neonatal hypoxic ischemic encephalopathy. However, the association of mild hypothermia and topiramate treatment has never been studied in human newborns. The objective of this research project is to evaluate, through a multicenter randomized controlled trial, whether the efficacy of moderate hypothermia can be increased by concomitant topiramate treatment. METHODS/DESIGN: Term newborns (gestational age ≥ 36 weeks and birth weight ≥ 1800 g) with precocious metabolic, clinical and electroencephalographic (EEG) signs of hypoxic-ischemic encephalopathy will be randomized, according to their EEG pattern, to receive topiramate added to standard treatment with moderate hypothermia or standard treatment alone. Topiramate will be administered at 10 mg/kg once a day for the first 3 days of life. Topiramate concentrations will be measured on serial dried blood spots. 64 participants will be recruited in the study. To evaluate the safety of topiramate administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of topiramate, the neurologic outcome of enrolled newborns will be evaluated by serial neurologic and neuroradiologic examinations. Visual function will be evaluated by means of behavioural standardized tests. DISCUSSION: This pilot study will explore the possible therapeutic role of topiramate in combination with moderate hypothermia. Any favourable results of this research might open new perspectives about the reduction of cerebral damage in asphyxiated newborns.

Early predictors of juvenile sacroiliitis in enthesitis-related arthritis.

OBJECTIVE: To identify early predictors of sacroiliac (SI) involvement in a cohort of patients with enthesitis-related arthritis (ERA). METHODS: During a 7-year followup period, all consecutive patients fulfilling the ILAR classification criteria for ERA were enrolled. Data collected included demographic, clinical and laboratory variables at disease onset, at the onset of inflammatory back pain, and at the last available followup visit. Pelvis radiographs and dynamic magnetic resonance imaging (MRI) scans for SI joints were obtained simultaneously in all patients who developed inflammatory back pain. RESULTS: Fifty-nine children with ERA were studied; 40 male, 19 female; median age at disease onset 9 years 4 months (range 6 yrs 6 mo - 13 yrs 3 mo). At a median interval after disease onset of 1 year 3 months, 21 children reported symptoms of inflammatory back pain. In all cases, radiographs of SI joints were negative, while dynamic MRI revealed acute sacroiliitis in 17 cases. Multivariate analysis showed that the early predictors of SI were the number of active joints (p < 0.03) and the number of active entheses (p < 0.001) at onset. CONCLUSION: In our cohort, roughly 30% of children with ERA/juvenile idiopathic arthritis develop clinical and MRI evidence of sacroiliitis, detectable with dynamic MRI as early as 1 year after disease onset. Additional data from larger case series are needed to assess the specificity and sensitivity of this technique in the early phase of the disease and to confirm the rate of SI involvement reported in this cohort.

Relevance of cognitive deterioration in early relapsing-remitting MS: a 3-year follow-up study.

OBJECTIVE: To assess longitudinally cognitive functioning in relapsing-remitting multiple sclerosis (RRMS) patients and its relationship with clinical and MRI variables. METHODS: Early RRMS patients and matched healthy controls were assessed in parallel in three testing sessions over 3 years, using the Rao's Brief Repeatable Battery of Neuropsychological Tests. Patients also underwent an MRI analysis of T2-weighted lesion volume (T2LV), number of gadolinium-enhanced lesions and whole brain atrophy. Forty-nine RRMS patients (mean age 36.9 ± 8.9 years; mean disease duration 2.9 ± 1.7 years, mean Expanded Disability Status Scale, 1.7 ± 0.7) and 56 healthy controls were recruited. RESULTS: At baseline, cognitive impairment was detected in 15 patients (30.6%). After 3 years, cognitive functioning worsened in the 29.3% of patients, whereas Expanded Disability Status Scale progression was observed in only three patients. The most sensitive test to detect cognitive deterioration over time was the Symbol Digit Modalities Test (SDMT). Only the presence of moderate cognitive impairment at baseline predicted further cognitive deterioration (p = 0.03). Among MRI variables, T2LV showed a weak to moderate relationship with some cognitive tasks. CONCLUSIONS: Over a 3-year period cognitive deterioration can be expected in approximately one-third of MS patients with relatively short disease duration. The SDMT is particularly suitable for longitudinal assessment of MS-related cognitive changes.

Familial hemophagocytic lymphohistiocytosis: clinical and neuroradiological findings and review of the literature.

BACKGROUND: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare multisystem congenital disorder characterized by uncontrolled proliferation and infiltration of activated lymphocytes and histiocytes, secreting high amounts of inflammatory cytokines; this may affect multiple organs including liver, spleen, lymph nodes, bone marrow, and central nervous system (CNS; Janka, Eur J Pediatr 166:95-109, 1). OBJECTIVE: The objective of this study is to describe the characteristics of the encephalopathy and to correlate the neuroradiological findings with the clinical symptoms and the treatment response in a child with FHL type 3 studied by total body computed tomography and by brain magnetic resonance (MR) and MR spectroscopy. RESULTS: VF, a 14-month-old female, developed a full-blown FHL, with facial nerve palsy as the only CNS complication. Brain MR imaging showed several focal areas of pathological signal in the subcortical and periventricular white matter, left thalamus, cerebellum, and brain stem. Proton MR spectroscopy also demonstrated no elevated peak of Cho, no lactate peak, and elevated glutamine/glutamate complex. Moreover, an elevated N-acetyl aspartate (NAA) peak was detected. The follow-up MR study after hematopoietic stem cells transplantation showed a dramatic reduction of the lesions and normalization of the metabolic pattern at spectroscopy. CONCLUSION: Brain lesions and metabolic alterations documented by MR and spectroscopy during active FHL reverted during disease control achieved by therapy.

Inner ear abnormalities in four patients with dRTA and SNHL: clinical and genetic heterogeneity.

A significant number of patients affected by autosomal recessive primary distal renal tubular acidosis (dRTA) manifest sensorineural hearing loss (SNHL). Mutations in ATP6V1B1 are associated with early onset SNHL, whereas ATP6V0A4 mutations have been described in dRTA and late-onset SNHL. Enlarged vestibular aqueduct (EVA) was described in patients with recessive dRTA and SNHL, and recently, this abnormality has been associated with mutations in the ATP6V1B1 gene. In our study, we evaluated the presence of inner-ear abnormalities in four patients affected by dRTA and SNHL, characterized by molecular analysis. Two patients affected by severe dRTA with early onset SNHL showed the same mutation in the ATP6V1B1 gene and bilateral EVA with a different degree of severity. The other two presented similar clinical manifestations of dRTA and different mutations in the ATP6V0A4 gene: one patient, showing EVA, developed an early SNHL, whereas in the other one, the SNHL appeared in the second decade of life and the vestibular aqueduct was normal. Our study confirms the association of EVA and mutations in the ATP6V1B1 gene and demonstrates that mutations in the ATP6V0A4 gene can also be associated with EVA probably only when the SNHL has an early onset. The pathophysiology of SNHL and EVA are still to be defined.

A study of feasibility of dose reduction in paediatric MSCT scanning with a constant image quality.

The aim of the work relies on the adjustment of scanning parameters, kV and mAs, in multislice computed tomography (MSCT) to reduce paediatric patient dose whilst keeping the same reference image quality. Only abdomen examinations are employed in this study. The measurement of noise in a region of interest (ROI) inside the liver in a reference adult man has been chosen as an image quality parameter. Paediatric patients are categorised according to the width and thickness of abdomen trunk. A relationship between patient size, image quality and dose reduction has been obtained. The study has been performed at the Meyer Children Hospital (1300 CT paediatric patient/year).

Proton magnetic resonance spectroscopy reveals central neuroaxonal impairment in systemic sclerosis.

OBJECTIVE: . Involvement of the central nervous system (CNS) in systemic sclerosis (SSc) is rare. Proton magnetic resonance spectroscopy (1H-MRS) assesses in vivo cerebral metabolites. We investigated the biochemical modifications of the CNS in SSc. METHODS: N-acetylaspartate/creatine ratio (NAA/Cr) and choline/creatine ratio (Cho/Cr) at right centrum semiovale (RCS) and at right basal ganglia (RBG) were evaluated by 1H-MRS in 12 patients with limited (lSSc) and 8 patients with diffuse SSc (dSSc) and 20 control subjects. RESULTS: With 1H-MRS, a significant reduction of NAA/Cr ratio at RBG (p < 0.02) and at RCS (p < 0.002) was detected in SSc patients. Cho/Cr ratio was increased (p < 0.02) in the RCS, but not in RBG. In patients with lSSc, a significant reduction of NAA/Cr was detected in RCS but not in RBG. CONCLUSION: Evidence of neuroaxonal damage strongly suggests the existence of CNS involvement in SSc.

Beyond the myth: the mermaid syndrome from Homerus to Andersen. A tribute to Hans Christian Andersen's bicentennial of birth.

Mermaid or sirens have been part of the cultural tradition of the sailors during the first expeditions in the western world. The Siren's Myth appeared for a first time with Homer, who described in the Odyssey some singing creatures that lured the enchanted sailors to death. More frequently described with a bird body and a female head, sometimes the female part was extended to torso, with arms prolonged in sturdy claws. In the Latin literature Publius Ovidius Naso presented in the Métamorphoses these creatures. Proposed ethymology for the word "siren" seems to confirm the prerogatives of these creatures, related to magnetism, seduction, charm. The first figuration of Sirens resembling to fish-women was in the second century bc. Hans Christian Andersen provided to leave us the strongest legend of Siren in the well-known fairy tale "The Little Mermaid". Following this story, Sirens are definitely considered as beautiful half-fish women who lived in the bottom of the sea, having a lovely voice to be used when they rise up to allow sweeter the agony of the wrecked sailors. Beyond the Myth, may the Siren really exist? It can be hypothesized that these creatures probably were individuals affected by sirenomelia. In our literature and medical review, we describe the etiology of the disease, and we illustrated the anatomical features of fetuses affected by this pathology using MDCT 3D reconstructions. Syrenomelia is a condition not compatible with the normal life, however nine cases of "mermaid" survived to reconstructive surgery have been reported until now. In our report we also presented a case of survival baby girl affected by sirenomelia, before and after surgery, with correlative radiologic imaging findings. The most important characteristic that seems to allow survival of the affected individuals is the presence of one functional kidney, displaced in pelvis. As so dramatically tragic was the history of the Andersen Little Mermaid, so unattended pleasant would be the destiny of a modern mermaid, who can hope to finally marry her prince, without the risk to "loose her head", as the Copenhagen City's Symbol did in the past years, for a story beyond the Myth.

Bronze baby syndrome and the risk of kernicterus.

AIM: The problem of kernicterus in infants with bronze baby syndrome (BBS) has been reviewed on the basis of cases reported in the literature. In addition, a new case concerning an infant with severe Rh haemolytic disease, who presented with BBS and who has developed neurological manifestations of kernicterus with magnetic resonance images showing basal ganglia abnormalities, is presented. In this patient, the total serum bilirubin (TSB) concentration ranged from 18.0 to 22.8 mg/dl (306 to 388 micromol/l) and the bilirubin/albumin (B/A) ratio was 6.0 (mg/g) (6.8 is the value at which an exchange transfusion should be considered). The case presented is important due to the fact that kernicterus appeared after an exchange transfusion was performed when the TSB level reached 22.8 mg/dl (388 micromol/l) on 6th day of life while the haematocrit was 30%. From this case and from other cases reported in the literature, we must stress that, even if the level at which hyperbilirubinemia poses a threat remains undefined, BBS may constitute an additional risk of developing kernicterus. CONCLUSION: The possible strategies for implementing an approach to the management of hyperbilirubinemia (especially the haemolytic kind) in the presence of BBS may include an exchange transfusion carried out at lower TSB concentration than previously recommended or an early administration of Sn-mesoporphyrin.

Diffusion-weighted MR of the brain: methodology and clinical application.

Clinical diffusion magnetic resonance (MR) imaging in humans started in the last decade with the demonstration of the capabilities of this technique of depicting the anatomy of the white matter fibre tracts in the brain. Two main approaches in terms of reconstruction and evaluation of the images obtained with application of diffusion sensitising gradients to an echo planar imaging sequence are possible. The first approach consists of reconstruction of images in which the effect of white matter anisotropy is averaged -- known as the isotropic or diffusion weighted images, which are usually evaluated subjectively for possible areas of increased or decreased signal, reflecting restricted and facilitated diffusion, respectively. The second approach implies reconstruction of image maps of the apparent diffusion coefficient (ADC), in which the T2 weighting of the echo planar diffusion sequence is cancelled out, and their objective, i.e. numerical, evaluation with regions of interest or histogram analysis. This second approach enables a quantitative and reproducible assessment of the diffusion changes not only in areas exhibiting signal abnormality in conventional MR images but also in areas of normal signal. A further level of image post-processing requires the acquisition of images after application of sensitising gradients along at least 6 different spatial orientations and consists of computation of the diffusion tensor and reconstruction of maps of the mean diffusivity (D) and of the white matter anisotropic properties, usually in terms of fractional anisotropy (FA). Diffusion-weighted imaging is complementary to conventional MR imaging in the evaluation of the acute ischaemic stroke. The combination of diffusion and perfusion MR imaging has the potential of providing all the information necessary for the diagnosis and management of the individual patient with acute ischaemic stroke. Diffusion-weighted MR, in particular quantitative evaluation based on the diffusion tensor, has a fundamental role in the assessment of brain maturation and of white matter diseases in the fetus, in the neonate and in the child. Diffusion MR imaging enables a better characterisation of the lesions demonstrated by conventional MR imaging, for instance in the hypoxic-ischaemic encephalopathy, in infections and in the inherited metabolic diseases, and is particularly important for the longitudinal evaluation of these conditions. Diffusion-weighted MR imaging has an established role in the differential diagnosis between brain abscess and cystic tumour and between epidermoid tumour and arachnoid cyst. On the other hand, the results obtained with diffusion MR in the characterisation of type and extension of glioma do not yet allow decision making in the individual patient. Diffusion is one of the most relevant MR techniques to have contributed to a better understanding of the pathophysiological mechanisms of multiple sclerosis (MS). In fact, it improves the specificity of MR in characterising the different pathological substrata underlying the rather uniform lesion appearance on the conventional images and enables detection of damage in the normal-appearing white and grey matter. In MS patients the ADC or D values in the normal-appearing white matter are increased as compared to control values, albeit to a lesser degree than in the lesions demonstrated by T2-weighted images. In addition, the D of the normal appearing grey matter is increased in MS patients and this change correlates with the cognitive deficit of these patients. Histogram analysis in MS patients shows that the peak of the brain D is decreased and right-shifted, reflecting an increase of its value, and the two features correlate with the patient's clinical disability. Ageing is associated to a mild but significant increase of the brain ADC or D which is predominantly due to changes in the white matter. Region of interest and histogram studies have demonstrated that D or ADC are increased in either the areas of leukoaraiosis or the normal-appearing white matter in patients with inherited cerebral autosomal dominant arteriopathy with subcortical infarcts and stroke or sporadic ischaemic leukoencephalopathy. Diffusion changes might be a more sensitive marker for progression of the disease than conventional imaging findings. In neurodegenerative diseases of the central nervous system such as Alzheimer's disease, Huntington's disease, hereditary ataxias and motor neuron disease, quantitative diffusion MR demonstrates the cortical and subcortical grey matter damage, which is reflected in a regional increase of D or ADC, but also reveals the concomitant white matter changes that are associated with an increase in D or ADC and decrease in FA. In all these diseases the diffusion changes are correlated to the clinical deficit and are potentially useful for early diagnosis and longitudinal evaluation, especially in the context of pharmacological trials.

Acute hypoxic encephalopathy in the full-term newborn: correlation between Magnetic Resonance Spectroscopy and neurological evaluation at short and long term.

PURPOSE: To determine which brain metabolite ratios have the strongest correlation with poor neurological outcome in newborns with perinatal asphyxia, whether the correlation is stronger with basal ganglia (BG) and whether a combined approach using Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) can be used to evaluate the severity of neonatal asphyxia. MATERIALS AND METHODS: Twenty newborns with perinatal asphyxia were studied within the first week from the hypoxic insult with MRI and MRS. The MRS variables were compared with the assessment of general movements (GMs). The brain metabolite levels measured by MRS were N-acetylaspartate (NAA), creatine (Cr), choline (Cho) and lactate and the ratios NAA to Cr, Lac to Cr, Cho to Cr, mI to Cr. RESULTS: High lactate levels and low NAA levels were found in the newborns with the worst outcome; the levels in newborns with good outcome were within normal limits. CONCLUSIONS: Correlations between NAA/Cr and Lac/Cr ratios, general movements and outcome at 6 months are stronger in the basal ganglia regions than in the frontal border zone. The presence or absence of lactate may indicate the severity of the brain insult and the combination of MRS, MRI and evaluation of general movements may assist in localising and predicting a long-term brain injury.