Intracellular RNAses are involved in various functions, including microRNA maturation and turnover. Mutations occurring in genes encoding RNAses cause Aicardi-Goutiéres syndrome (AGS). AGS mutations silence RNAse activity, thus inducing accumulation of endogenous RNAs, mainly consisting of short RNAs and microRNAs. Overload of intracellular RNA triggers Toll like receptor-dependent interferon-alpha production in the brain, which in turn activates neurotoxic lymphocytes and inhibits angiogenesis thus inducing the typical clinical phenotype of AGS. However, these pathogenic mechanisms are attenuated after three years of age by the endogenous production of DNAJP58IPK and Cystatin F, which arrest AGS progression. Because RNAses are involved in microRNA turnover, we evaluated the expression of 957 microRNAs in lymphocytes from AGS patients and control patients. Our results indicate that microRNA overload occurs in AGS patients. This upregulation inhibits microRNA turnover impeding the synthesis of the novel microRNAs required for the differentiation and myelination of the brain during the initial period of postnatal life. These pathogenic mechanisms result in AGS, a neurological syndrome characterized by irritability, mild hyperpyrexia, pyramidal and extrapyramidal signs, and spastic-dystonic tetraplegia. Typical cerebrospinal fluid alterations include lymphocytosis and elevated interferon-alpha levels. Brain imaging demonstrates cerebral calcifications, white matter abnormalities, and progressive cerebral atrophy.Thus, evidence exists that mutations silencing intracellular RNases affect microRNA turnover resulting in the severe clinical consequences in the brain characterizing the clinical feature of AGS.

HASH(0x1c3cee80)

BACKGROUND AND PURPOSE: To date, few studies have focused specifically on imaging findings in Aicardi-Goutières syndrome (AGS). We set out to evaluate retrospectively neuroradiologic data from a large sample of patients with AGS, focusing on the pattern of white matter abnormalities and the temporal evolution of the cerebral involvement to establish the radiologic natural history of the disease. MATERIALS AND METHODS: Thirty-six patients, 18 girls and 18 boys, were included. All had a clinical diagnosis of AGS, genetically confirmed in 31 of them. For every subject, we reviewed at least 1 CT and 1 MR imaging study; 19 (52.7%) had multiple examinations. In all, we reviewed 109 examinations. Clinical-neuroradiologic comparisons were analyzed by using the chi(2) test. RESULTS: Calcifications were found in all subjects, mainly in the basal ganglia, lobar white matter, and dentate nuclei. Abnormal white matter was present in all the subjects, showing 2 patterns of distribution: diffuse in 18 (50%) and an anteroposterior gradient in 18 (50%). Cystic areas were observed in the temporal and/or frontal lobes in 12/36 patients (33.3%). A correlation was found between early age at onset and severity of the leukoencephalopathy in the frontal (P =.024) and temporal (P =.034) regions. A significant degree of cerebral atrophy was found in 31/36 subjects (86.1%). The neuroradiologic presentation remained substantially stable with time. CONCLUSIONS: The different neuroradiologic presentations of AGS are here outlined for the first time in a large sample of patients. These findings may facilitate more precise and earlier diagnosis of this rare but probably underdiagnosed syndrome.

Introduction Aicardi-Goutières syndrome (AGS) is an autosomal recessive encephalopathy characterized by acquired microcephaly, cerebral calcifications, leukodystrophy, cerebral atrophy and cerebrospinal fluid findings of chronic lymphocytosis and raised interferon-alpha (INF-alpha). The main extraneurological symptoms are chilblain-like skin lesions, usually on the fingers, toes and ears. Sources of data This review is based on a search of the published literature on AGS from 1984 onwards (particularly the most recent papers) and on knowledge and experience gained through the authors' work with the International Aicardi-Goutières Syndrome Association (IAGSA). Areas of agreement It is accepted that AGS can be mistaken for a congenital infection and that the diagnostic significance of its cardinal signs (raised INF-alpha levels, basal ganglia calcifications) is different in different stages of the disease. Currently, we know of four genes that, if mutated, can give rise to AGS, but at least one other gene is believed to exist. These genes are involved in the DNA damage response, a defect of which could provoke an inappropriate innate immune response, triggering increased secretion of INF-alpha, ultimately responsible for the main features of the disease. Areas of controversy The natural history of AGS has not yet been definitively described given the lack of extensive, long-term neuroradiological follow-up studies. Furthermore, it is not yet clearly understood how the innate immune system is activated, what triggers the onset of the disease or why it tends to 'burn out' after several months. Immunosuppressive therapy in the active stage of the disease does not seem to produce any real change in the clinical course, but more data are needed. Growing points and areas timely for developing research Current studies aim to clarify the molecular mechanisms underlying the pathogenesis of AGS and to establish the exact pathway by which retained nucleic acids activate the immune system. This knowledge could allow the development of therapeutic strategies.

Aicardi-Goutières syndrome is an autosomal recessive encephalopathy characterised by acquired microcephaly, basal ganglia calcifications, leukodystrophy, cerebral atrophy, chronic cerebrospinal lymphocytosis, and raised titres of interferon alpha in the cerebrospinal fluid. The disease onset is generally within the first months of life. We here report a case of Aicardi-Goutières syndrome presenting atypically as a sub-acute leukoencephalopathy following satisfactory psychomotor development up to the age of 16 months. This case highlights the importance of considering Aicardi-Goutières syndrome in the differential diagnosis of an unexplained leukoencephalopathy and the possibility of later onset of the disease.

This study was conducted to evaluate whether microalbuminuria on admission and after 24 hrs of admission to intensive care unit (ICU) predicts outcome as well as the Acute Physiology and Chronic Health Evaluation (APACHE) II severity illness score, the current accepted method of doing so. The study was carried out in a 20 bed mixed medical-surgical ICU of a tertiary care hospital. Of 525 consecutive adult patients with ICU stay of more than 24 hrs, 238 were included for the study. Patients with pregnancy, menstruation, anuria, macroscopic hematuria, urinary tract infection, marked proteinuria due to renal and post-renal structural diseases, were excluded. Spot urine samples were collected on admission to ICU and 24 hrs thereafter. Urine albumincreatinine ratio (ACR) was measured on ICU admission (ACR1) and after 24 hrs (ACR2) and expressed in mg/g. Patient demographics were noted on admission. For disease severity scoring, APACHE II scores were calculated. Each patient was followed up throughout their ICU stay for a maximum of 28 days and the following outcome data were obtained: ICU length of stay and ICU mortality. Of the 238 patients, 196 survived while 42 patients died in the ICU. Non-survivors had a significantly higher median ACR2 [162.7 mg/g (IQR 69.5-344.3)] in comparison to the survivors who had a median ACR2 = 54.4 mg/g (IQR 19.0-129.1)(P< 0.0001). The median ACR1 [161.0 mg/g (IQR 29.0-369.3)] of non-survivors was higher than the median ACR1 [80.4 mg/g (IQR 35.1-167.6)] of survivors but failed to reach statistical significance (P= 0.0948). In a receiver operating characteristic curve (ROC) analysis, ACR2 emerged as the best indicator of mortality [(area under curve (AUC) of ACR2 = 0.71 > AUC (ACR1)=0.58 > AUC (ΔACR)=0.55] similar to the currently used APACHE II scores (AUC = 0.78)(P=0.3). At a cutoff of 101 mg/g, ACR2 had a sensitivity of 69%, specificity of 67%, positive predictive value of 31% and a negative predictive value of 91% for predicting mortality in the critically ill patients. Absence of significant microalbuminuria at 24 hrs of ICU admission may help to predict survival in the ICU.

INTRODUCTION An acoustic neuroma (also known as a vestibular schwannoma) is an intracranial tumour of the vestibular nerve that is commonly treated by surgical resection. Following resection of an acoustic neuroma, patients may experience a range of symptoms that include deficits in gaze stability, mobility and balance. Vestibular rehabilitation may be useful in reducing the severity and minimizing the impact of these symptoms. OBJECTIVE To systematically review the clinical trial evidence for the effectiveness of vestibular rehabilitation interventions following resection of an acoustic neuroma and provide a concise synthesis useful for informing clinical rehabilitation of this patient population. DATA SOURCES Electronic databases including Cochrane, PubMed, CINAHL, Embase and AUSThealth were searched with no time restriction. Search terms included combinations of MeSH terms ('acoustic neuroma''vestibular schwannoma''acoustic neurinoma''acoustic neurilemoma''acoustic neurilemmoma' or 'acoustic schwannoma') and ('rehabilitation''physiotherapy''physical therapy''adaptation''habituation''balance','exercise' or 'gaze stability'). STUDY SELECTION Randomized clinical trials of rehabilitation approaches following surgical research of acoustic neuroma among adults were included. Studies with mixed populations that included bilateral vestibular loss or vestibular dysfunction of central or unknown aetiology were excluded. The 591 hits were screened by title, abstract and then full text by two independent researchers who reached a consensus on the eligibility of each study (a third researcher was available to arbitrate but was not required). Six clinical trials fulfilled the inclusion criteria. DATA EXTRACTION The characteristics of each study including the trial design, sample, intervention, outcome measures and summary of results were extracted and tabulated. DATA SYNTHESIS Methodological quality was assessed independently by two researchers using the physiotherapy evidence database scale. The heterogeneity of both interventions and outcome measures did not allow a valid meta-analysis. CONCLUSION There is some evidence to support the use of adaptation exercises for this clinical group. Clinical trial evidence does not support the use of habituation exercises alone, although when combined with adaptation exercises and balance and gait training, habituation exercises may have some benefit. Further research is required to determine the optimal combination of vestibular rehabilitation interventions, as well as the volume and timing of interventions.

This work addresses the problem of real-time online reconstruction of dynamic MRI sequences. The proposed method reconstructs the difference between the previous and the current image frames. This difference image is sparse. We recover the sparse difference image from its partial k-space scans by using a non-convex Compressed Sensing algorithm. As there was no previous fast enough algorithm for real-time reconstruction, we derive a novel algorithm for this purpose. Our proposed method has been compared against state-of-the-art offline and online reconstruction methods. The accuracy of the proposed method is less than offline methods but noticeably higher than the online techniques. For real-time reconstruction we are also concerned about the reconstruction speed. Our method is capable of reconstructing 128 x 128 images at the rate of 6 frames per second, 180 x 180 images at the rate of 5 frames per second and 256 x 256 images at the rate of 2.5 frames per second.

BACKGROUND: Aicardi-Goutières syndrome (AGS) is a severe familial, mostly autosomal recessive encephalopathy, first described in 1984. The clinical picture and genetic abnormalities are heterogeneous. US findings in AGS have thus far not been systematically described. OBJECTIVE: The purpose of this study was to analyse sonographic features in AGS and to compare them to CT/MRI. MATERIALS AND METHODS: Four male infants with AGS, two brothers, underwent imaging between the ages of 4 weeks and 6 months. RESULTS: Sonographically isolated mineralization of lenticulostriate vessels, dilatation of the lateral ventricles, subependymal cysts, and diffuse and focal hyperechogenicity of the periventricular white matter and basal ganglia, respectively, were the abnormal findings, that may be present even before the development of major neurological symptoms. CONCLUSION: Early cranial US is able to visualize the whole spectrum of cerebral anomalies in AGS: calcifying microangiopathy, white matter disease and unusual subependymal cysts. The imaging pattern is similar to that of congenital viral infection of the central nervous system, which may mislead the genetic counseling.

Aim  To describe the clinical and radiological features of four new families with a childhood presentation of COL4A1 mutation. Method  We retrospectively reviewed the clinical presentation. Investigations included radiological findings and COL4A1 mutation analysis of the four cases. Affected family members were identified. COL4A1 mutation analysis was performed in all index cases and, where possible, in affected family members. Results  The three male and one female index cases presented with recurrent childhood-onset stroke, infantile hemiplegia/spastic quadriplegia, and infantile spasms. Additional features such as congenital cataracts and anterior segment dysgenesis were present. Microcephaly and developmental delay/learning difficulties were present in three cases. Three cases had one or more family member affected in multiple generations, with a total of 11 such individuals identified. The clinical features showed a wide intrafamilial variation. Magnetic resonance imaging (MRI) showed bilateral white matter change in all cases, except in one mutation-positive family member. Unilateral or bilateral porencephaly was present in cases with infantile hemiplegia, and a diagnosis of clinical stroke was supported by the presence of intracerebral haemorrhage. The age at diagnosis was between 1 year and 6 years for the children with presentation in infancy and 12 months after stroke in a 14-year-old male. Three new pathogenic mutations were identified in the COL4A1 gene. Interpretation  COL4A1 mutations can present in children with infantile hemiplegia/quadriplegia, stroke or epilepsy, and a motor disorder. The presence of eye features and white matter change on MRI in childhood can help point towards the diagnosis. Once the diagnosis is made, a careful search can identify affected family members.

HASH(0x25072b80)

HASH(0x750bc00)

Congenital CYTOMEGALOVIRUS (CMV) infection and periventricular leukomalacia (PVL) both lead to static cerebral white matter lesions. In contrast to PVL, the neuropathologicAL substrate of these lesions in congenital CMV is not clear. By comparing changes in quantitative magnetic resonance (MR) parameters and MR spectroscopy metabolite concentrations we wanted to determine whether the nature of the white matter pathology in congenital CMV infection could be similar to the known pathology of PVL. Diffusion parameters, apparent diffusion coefficient (ADC) and fractional anisotropy (FA), magnetization transfer ratio (MTR) and MR spectroscopy concentrations were studied in white matter lesions in five patients with a congenital CMV infection and six patients with PVL. In both groups ADC values were increased, FA and MTR values were reduced, concentrations of total N-acetylaspartate and choline-containing compounds were reduced; and MYO-inositol concentrations were slightly increased. No differences were found between the two groups, suggesting that the pathology of the white matter lesions in congenital CMV infections is similar to that of PVL and also characterized by axonal losses, lack of myelin deposition due to oligodendrocytic losses, and astrogliosis. Congenital CMV infection and PVL affect the cerebral white matter in the same developmental period when immature oligodendrocytes are particularly vulnerable.

HASH(0x2b3bad5485b0)

Brain injury in premature infants is of enormous public health importance because of the large number of such infants who survive with serious neurodevelopmental disability, including major cognitive deficits and motor disability. This type of brain injury is generally thought to consist primarily of periventricular leukomalacia (PVL), a distinctive form of cerebral white matter injury. Important new work shows that PVL is frequently accompanied by neuronal/axonal disease, affecting the cerebral white matter, thalamus, basal ganglia, cerebral cortex, brain stem, and cerebellum. This constellation of PVL and neuronal/axonal disease is sufficiently distinctive to be termed "encephalopathy of prematurity". The thesis of this Review is that the encephalopathy of prematurity is a complex amalgam of primary destructive disease and secondary maturational and trophic disturbances. This Review integrates the fascinating confluence of new insights into both brain injury and brain development during the human premature period.

We present serial MR findings in a child ultimately diagnosed with the early infantile form of Krabbe disease. MR showed typical features of Krabbe disease including cerebellar and brainstem hyperintensity, periventricular and deep white matter hyperintensity, and cerebral atrophy. In addition, the combination of both enlargement and enhancement of multiple cranial nerves in conjunction with unusual cystic lesions adjacent to the frontal horns of the lateral ventricles was previously unreported and expands the spectrum of imaging findings in early Krabbe disease.

An 8-year-old boy presented with a rare case of germinoma involving the bilateral basal ganglia and cerebral white matter manifesting as precocious puberty. Magnetic resonance (MR) imaging at the initial presentation demonstrated mild hyperintense areas in the bilateral basal ganglia and corpus callosum on T1-weighted images, and a small hyperintense spot in the right internal capsule on T2-weighted images. Human chorionic gonadotropin (hCG) level was elevated in the cerebrospinal fluid (CSF), so we strongly suspected that threre was a hCG-producing germinoma originating in the bilateral basal ganglia. Stereotactic biopsy was performed. Histological examination revealed two-cell pattern germinoma. After three cycles of combination chemotherapy consisting of ifosfamide, cisplatin, and etoposide, followed by whole brain irradiation with a total dose of 24 Gy, the CSF hCG level fell below the detection limit, but MR imaging demonstrated no significant change. Intracranial hCG-producing germinoma should be suspected in patients presenting with precocious puberty and elevated CSF hCG level. Moreover, slight intensity change on MR imaging is important to identify germinoma arising from the basal ganglia in the early stage.

OBJECTIVE To investigate clinical and imaging characteristics of delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) and their relationship to the prognosis. METHODS The clinical, CT and MRI findings in 46 patients with DEACMP were analysed and compared. RESULTS The main manifestations of the disease were mental and extrapyramidal impairment. CT scan showed diffuse low density changes in bilateral cerebral white matter, bilateral or unilateral globus pallidus or basal ganglia areas. The MRI showed necrosis and degeneration of glodus pallidus and cerebral white matter demyelination mainly around the ventricles, with high signal intensity in T(2)-weighted and equal or low signal intensity in T(1)-weighted as well as the lesions in hippocampus and brain stem. There was the sign of encephalatrophy in the late stage. The positive detectable rate of MRI was 82.1%, higher than that of CT, 43.2%. MRI was more sensitive than CT. CONCLUSION The prognosis of the patients is closely related with the age, time of come after DEACMP and the effectiveness of treatment. Both CT and MRI are valuable in the diagnosis and evaluation of the prognosis for DEACMP. MRI is more sensitive than CT in the diagnosis of DEACMP.