Dysregulation of the immune system in Aicardi-Goutières syndrome: another example in a TREX1-mutated patient.

Aicardi-Goutières syndrome (AGS) is a rare genetic encephalopathy characterized by neurological and extraneurological involvement. A clinical overlap between AGS and systemic lupus erythematosus (SLE) has been reported. We describe an AGS patient who developed autoimmune manifestations: thyroiditis, cANCA positivity, antiphospholipid antibodies and cerebral ischemia. This first description of antiphospholipid syndrome in a TREX1-mutated patient further expands the clinical spectrum of AGS. Although the clinical overlap with SLE may indicate common pathogenic mechanisms, the autoimmune manifestations in AGS are so extensive that we suggest they should be considered a clinical feature of the disease, rather than a sign of coexistent SLE.

COL4A1 mutations associated with a characteristic pattern of intracranial calcification.

Intracranial calcification (ICC) is a relatively common radiological finding in children undergoing investigation for neurological disorders. Many causes are recognised, and ICC is often regarded as a non-specific sign.From an ongoing study of ICC, we identified 5 patients with characteristic radiological features, in whom a mutation in the COL4A1 gene was found.All patients had CT and MR imaging. MR images demonstrated features of periventricular leukomalacia with irregular dilatation of the lateral ventricles with or without porencephaly, loss of hemispheric white matter volume, and high signal on T2 and FLAIR sequences within periventricular and deep white matter. Calcification was apparent on MR in 4 patients. CT scans demonstrated spot and linear calcification in the subependymal region and around areas of porencephaly. Calcification was also visible in the deep cerebral white matter and basal ganglia. 1 patient showed calcification in the central pons.ICC occurs in COL4A1-related disease. The radiological features are distinct from other conditions demonstrating recognisable patterns of ICC, such as congenital cytomegalovirus infection and Aicardi-Goutiéres syndrome. In the absence of a known risk factor for periventricular leukomalacia, the presence of these radio-logical findings should suggest the possibility of COL4A1-related disease.

The Aicardi-Goutières syndrome. Molecular and clinical features of RNAse deficiency and microRNA overload.

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.

Aicardi-Goutieres syndrome: neuroradiologic findings and follow-up.

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.

Aicardi-Goutieres 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.

Speech Reorganization after an AVM Bleed Cured by Embolization. A Case Report and Review of the Literature.

SUMMARY: Intracerebral arteriovenous malformations (AVMs) are defined as the direct communication of arteries to abnormal veins without interposing capillaries. Although AVMs can have various clinical presentations due to their dynamic nature, the most common presenting sign is intracerebral hemorrhage. Whenever an AVM is discovered, the therapeutic choice is often not obvious and it is influenced not only by the hemodynamic features of the AVM, but also by considerations of the extent of intervention-related morbidity and mortality. A patient with a left frontal AVM is described. He bled three years after gamma knife radiosurgery and developed aphasia. The complete obliteration of the AVM was later achieved by embolization. Functional compensatory brain reorganization and plasticity is discussed, since our patient presented with a fast recovery from aphasia and unexpected contralateral redistribution of the speech function and with preference for his second spoken language.

Recovery of visual functions after early acquired occipital damage.

Plasticity of visual systems after early brain damage has been extensively studied in animal models but poorly documented in children after visual pathway lesions. This report describes the visual recovery of a male child who had a bilateral occipital lobe infarction at the age of 2 years 6 months, 10 days after colon resection for Hirschsprung disease. In the acute phase he had severe visual impairment without visual response. Some weeks later he could perceive movement. Since then, progressive recovery of his visual acuity and oculomotor abilities has been accompanied by a progressive reduction of the visual field defect. At 6 years 8 months, visual recognition acuity was 10/10 in both eyes and neuro-ophthalmological examination was normal, except for persistence of the visual field defect in the upper hemifield and a selective impairment of higher visual functions (recognition of object presented in a hard-to-decode way [e.g. overlapping figures], or use of complex visuospatial skills). The functional recovery observed in this patient confirms the adaptive plasticity of developing visual systems after early brain lesions. It suggests that in humans, as in animal models, processes related to cerebral plasticity may take place years after a brain lesion has been sustained.

Aicardi-Goutières syndrome presenting atypically as a sub-acute leukoencephalopathy.

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.

[Frequency of neuropsychiatric signs and symptoms in patients with viral encephalitis]. / Frecuencia de signos y síntomas neuropsiquiátricos en pacientes con encefalitis viral.

INTRODUCTION: Acute viral encephalitis (AVE) is a frequent condition that usually courses with psychiatric alterations but few systematic studies have been conducted to investigate it. AIMS: To determine the frequency and the progression of the neuropsychiatric symptoms in patients with AVE. PATIENTS AND METHODS: A retrospective study was carried out. AVE was defined as an acute and progressively coursing condition in previously healthy subjects, with clinical signs of diffuse alteration of the central nervous system, abnormal electroencephalogram and/or inflammatory cerebrospinal fluid (CSF). We excluded patients who previously had epilepsy, a positive serodiagnosis for human immunodeficiency virus (HIV), and cases compatible with herpes simplex encephalitis from electroencephalographic or imaging data with focalisation towards temporal, frontal, regions or a positive DNA test for herpes in CSF. Finally, 83 patients were included. The psychiatric signs and symptoms that were produced were recorded during the acute phase and one year after discharge from hospital (sequelae). RESULTS: The psychiatric disorders in the acute phase were psychomotor agitation (67%), drowsiness (55%), disorientation (47%), visual hallucinations (43%) and aggressiveness (34%). One year after hospitalisation, in a sample of 70 patients in a clinical control, we found memory disorders (16%), aggressiveness (9%), aphasia (8%), visual hallucinations (8%), and auditory hallucinations (7%). The mortality rate was 6%. CONCLUSIONS: Neuropsychiatric disorders are very frequent during the acute phase of viral encephalitis, which is relevant for the differential diagnosis in patients who visit emergency departments with behavioural disorders. One year after hospital discharge, the main sequelae are of a neuropsychiatric nature and cognitive impairment is predominant.

Frecuencia de signos y síntomas neuropsiquiátricos en pacientes con encefalitis viral / Frequency of neuropsychiatric signs and symptoms in patients with viral encephalitis

Introducción. La encefalitis viral aguda (EVA) es un padecimiento frecuente que suele cursar con alteraciones psiquiátricas, que han sido estudiadas de forma sistemática. Objetivo. Conocer la frecuencia y la evolución de las manifestaciones neuropsiquiátricas en pacientes con EVA. Pacientes y métodos. Se ha realizado un estudio retrospectivo. Se definió la EVA como un padecimiento agudo y de curso progresivo en sujetos previamente sanos, con signos clínicos de alteración difusa del sistema nervioso central, electroencefalograma anormal y/o líquido cefalorraquídeo (LCR) inflamatorio. Excluimos a los pacientes con epilepsia previa o serología positiva para el virus de la inmunodeficiencia humana (VIH), y los casos compatibles con encefalitis herpética por datos electroencefalográficos o de imagen con focalización hacia las regiones temporales o frontales, o con prueba de ADN positiva para herpes en el LCR. Se incluyeron 83 pacientes. Se registraron los signos y síntomas psiquiátricos manifestados durante la fase aguda y un año después del alta hospitalaria (secuelas). Resultados. Las alteraciones psiquiátricas en la fase aguda fueron: agitación psicomotora (67%), somnolencia (55%), desorientación (47%), alucinaciones visuales (43%) y agresividad (34%). Un año después de la hospitalización, en 70 pacientes en control clínico, encontramos: alteraciones de la memoria (16%), agresividad (9%), afasia (8%), alucinaciones visuales (8%) y alucinaciones auditivas (7%). La mortalidad fue del 6%. Conclusiones. Las alteraciones neuropsiquiátricas son muy frecuentes durante la fase aguda de la encefalitis viral, lo que es relevante para el diagnóstico diferencial de los pacientes que acuden a los servicios de urgencias con alteraciones conductuales. A un año del alta, las principales secuelas son neuropsiquiátricas, y predomina el déficit cognitivo (AU)

Introduction. Acute viral encephalitis (AVE) is a frequent condition that usually courses with psychiatric alterations but few systematic studies have been conducted to investigate it. Aims. To determine the frequency and the progression of the neuropsychiatric symptoms in patients with AVE. Patients and methods. A retrospective study was carried out. AVE was defined as an acute and progressively coursing condition in previously healthy subjects, with clinical signs of diffuse alteration of the central nervous system, abnormal electroencephalogram and/or inflammatory cerebrospinal fluid (CSF). We excluded patients who previously had epilepsy, a positive serodiagnosis for human immunodeficiency virus (HIV), and cases compatible with herpes simplex encephalitis from electroencephalographic or imaging data with focalisation towards temporal, frontal, regions or a positive DNA test for herpes in CSF. Finally, 83 patients were included. The psychiatric signs and symptoms that were produced were recorded during the acute phase and one year after discharge from hospital (sequelae). Results. The psychiatric disorders in the acute phase were psychomotor agitation (67%), drowsiness (55%), disorientation (47%), visual hallucinations (43%) and aggressiveness (34%). One year after hospitalisation, in a sample of 70 patients in a clinical control, we found memory disorders (16%), aggressiveness (9%), aphasia (8%), visual hallucinations (8%), and auditory hallucinations (7%). The mortality rate was 6%. Conclusions. Neuropsychiatric disorders are very frequent during the acute phase of viral encephalitis, which is relevant for the differential diagnosis in patients who visit emergency departments with behavioural disorders. One year after hospital discharge, the main sequelae are of a neuropsychiatric nature and cognitive impairment is predominant (AU)

A model for the organization of a regional bank for musculoskeletal tissues in Italy.

The national and local need for human tissues to be used in transplants is a high one, and constantly growing. Human, scientific and financial resources involved in guaranteeing safe and high-quality tissues as defined by the national guidelines for musculoskeletal tissue banks are considerable. For this reason we need to find adequate solutions to the problem of guaranteeing sufficient availability of tissues with the lowest cost possible for supply. The Piedmont Region Musculoskeletal Tissue Bank, which is located in an Azienda Ospedaliera, has been organized to guarantee the quality of its tissues via biological validation and scientific-clinical coordination; it makes use of the collaboration of removal centers that send tissues taken from the central bank for certification and identifies several centers for preservation; it collaborates with a bank of national importance for tissue processing. The publication of regulations and tariffs based on cost analysis improves the procedures.

The integration of vascular surgical techniques with oncological surgical protocols in the treatment of soft tissue sarcomas of the limbs.

Soft tissue tumors, involving the vascular bundle, require a particular surgical approach: oncological and vascular surgical techniques must be integrated in order to perform a limb-saving surgery with adequate margins. Thirty-six soft tissue sarcomas of the thigh and popliteal region were treated from June 1999 to September 2002. Nineteen cases involving the vascular bundle were analysed and placed in two groups according to imaging and clinical information: Group A, 14 patients, with tumors close to femoral vessels without adventitial infiltration, and Group B, 5 patients, with vascular infiltration. Group A was treated with vascular blunt dissection performing adventitial excision. Group B was treated with vascular "en-bloc" resection and reconstruction. Imaging and clinical information together with surgical techniques, strategies and complications were analysed in order to plan the surgical approach in neoplastic vascular bundle involvement.

Echocolor Power Doppler with contrast medium to evaluate vascularization in lesions of the soft tissues of the limbs.

PURPOSE: Echocolor Power Doppler with contrast medium forms a non-invasive vascular image; the purpose of the study is to evaluate the effectiveness in differentiating benign and malignant tumors in the soft tissues of the limbs. MATERIAL AND METHOD: Echocolor Power Doppler with contrast medium was used to study 80 patients with swelling in the soft tissues of the limbs: there were 54 benign lesions, 22 sarcomas, and 4 aggressive desmoid fibromatoses. RESULTS: Were identified 4 patterns of wash-in and wash-out curves that could be correlated to the histological diagnosis: type I was present in 85% of benign lesions, type III in 91% of malignant lesions and in 3.7% of the benign ones, type II in aggressive fibromatoses, anomalous type in 4 benign lesions and 2 sarcomas; the curve was absent in 2 benign lesions. CONCLUSIONS: Power Doppler Echocolor with contrast medium can become a useful method to be associated with traditional imaging methods in the differential diagnosis of swelling of the soft tissues of the limbs.

CT evaluation pre- and post-percutaneous ablation by radiofrequency of osteoid osteoma. Preliminary experience.

PURPOSE: Evaluation of bone remanagement after treatment by thermoablation of osteoid osteoma (OO) by CT scan. MATERIAL AND METHOD: Nine cases of OO (8 in the limbs, 1 in the pelvis) following biopsy were treated by CT-guided thermoablation. Clinical results, complications, density of tissues treated by CT scan (pre-postop, 6, 12 months) are evaluated. RESULTS: Absence of complications, regression of pain over 2 weeks, resumption of sports activity in 1 month. Bone density after treatment increases but even after 1 year it is much lower than normal levels. CONCLUSIONS: Bone remodeling after thermoablation of OO requires much time, the process is still visible 12 months later by CT scan. CT scan is an adequate method, not only for diagnosis and treatment, but also for follow-up, capable of evaluating in time the changes in density of the site of the lesion, which is useful for a comparison in case of postoperative pain of doubtful origin.

Rescue percutaneous coronary intervention immediately following coronary artery bypass grafting.

Perioperative graft failure after coronary artery bypass graft (CABG) can result in acute myocardial infarction with dire clinical consequences. We report a case of rescue percutaneous coronary intervention immediately after unsuccessful CABG. This approach salvaged the patient from cardiogenic shock and should be recognized as a viable alternative to immediate reoperation for certain patients.