Dumbell atypical teratoid/rhabdoid tumour (AT/RT) of the cervical spine.

Spinal Atypical Teratoid/Rhabdoid Tumour (AT/RT) is a highly malignant tumour, and its prognosis is dismal especially for very young patients. In this article, we present the case of a teenage boy with AT/RT in the cervical spine and its multimodality management. A review of the literature on ATRT of the spine is also presented.

Clinical and genetic characterization of leukoencephalopathies in adults.

Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progressive degeneration of cerebral white matter. They are associated with a spectrum of clinical phenotypes dominated by dementia, psychiatric changes, movement disorders and upper motor neuron signs. Mutations in at least 60 genes can lead to leukoencephalopathy with often overlapping clinical and radiological presentations. For these reasons, patients with genetic leukoencephalopathies often endure a long diagnostic odyssey before receiving a definitive diagnosis or may receive no diagnosis at all. In this study, we used focused and whole exome sequencing to evaluate a cohort of undiagnosed adult patients referred to a specialist leukoencephalopathy service. In total, 100 patients were evaluated using focused exome sequencing of 6100 genes. We detected pathogenic or likely pathogenic variants in 26 cases. The most frequently mutated genes were NOTCH3, EIF2B5, AARS2 and CSF1R. We then carried out whole exome sequencing on the remaining negative cases including four family trios, but could not identify any further potentially disease-causing mutations, confirming the equivalence of focused and whole exome sequencing in the diagnosis of genetic leukoencephalopathies. Here we provide an overview of the clinical and genetic features of these disorders in adults.

Malignant meningitis secondary to oesophageal adenocarcinoma presenting with sensorineural hearing loss: a series of three cases and discussion of the literature.

Malignant meningitis may rarely present to the otolaryngologist. We report our experience with 3 patients presenting with sudden, progressive bilateral sensorineural hearing loss secondary to malignant meningitis. The primary tumour in all 3 cases was oesophageal adenocarcinoma. All 3 cases were notable for the rapidity of the patients' clinical deterioration; the interval from presentation to death ranged from 21 to 28 days. We suggest that otolaryngologists should remain vigilant to the possibility of this devastating diagnosis and have a low threshold for further investigation in patients with suspicious features. It is important to note that initial MRI and lumbar puncture may be negative and repeat testing should be undertaken if there is clinical suspicion.

Aicardi-Goutières syndrome harbours abundant systemic and brain-reactive autoantibodies.

OBJECTIVES: Aicardi-Goutières syndrome (AGS) is an autoimmune disorder that shares similarities with systemic lupus erythematous. AGS inflammatory responses specially target the cerebral white matter. However, it remains uncertain why the brain is the most affected organ, and little is known about the presence of autoantibodies in AGS. Here, we aim to profile specific autoantibodies in AGS and to determine whether these autoantibodies target cerebral epitopes. METHODS: Using a multiplex microarray, we assessed the spectrum of serum autoantibodies in 56 genetically confirmed patients with AGS. We investigated the presence of immunoglobulins in AGS brain specimens using immunohistochemistry and studied the reactivity of sera against brain epitopes with proteomics. RESULTS: Serum from patients exhibited high levels of IgGs against nuclear antigens (gP210, Nup62, PCNA, Ro/SSA, Sm/RNP complex, SS-A/SS-B), components of the basement membrane (entactin, laminin), fibrinogen IV and gliadin. Upon testing whether antibodies in AGS could be found in the central nervous system, IgGs were identified to target in vivo endothelial cells in vivo and astrocytes in brain sections of deceased patients with AGS. Using a proteomics approach, we were able to confirm that IgGs in serum samples from AGS patients bind epitopes present in the cerebral white matter. CONCLUSIONS: Patients with AGS produce a broad spectrum of autoantibodies unique from other autoimmune diseases. Some of these autoantibodies target endothelial cells and astrocytes in the brain of the affected patients, perhaps explaining the prominence of neurological disease in the AGS phenotype.

A multimodality assessment of the protective capacity of statin therapy in a mouse model of radiation cardiotoxicity.

PURPOSE: Despite technological advances in radiotherapy (RT), cardiotoxicity remains a common complication in patients with lung, oesophageal and breast cancers. Statin therapy has been shown to have pleiotropic properties beyond its lipid-lowering effects. Previous murine models have shown statin therapy can reduce short-term functional effects of whole-heart irradiation. In this study, we assessed the efficacy of atorvastatin in protecting against the late effects of radiation exposure on systolic function, cardiac conduction, and atrial natriuretic peptide (ANP) following a clinically relevant partial-heart radiation exposure. MATERIALS AND METHODS: Female, 12-week old, C57BL/6j mice received an image-guided 16 Gy X-ray field to the base of the heart using a small animal radiotherapy research platform (SARRP), with or without atorvastatin from 1 week prior to irradiation until the end of the experiment. The animals were followed for 50 weeks with longitudinal transthoracic echocardiography (TTE) and electrocardiography (ECG) every 10 weeks, and plasma ANP every 20 weeks. RESULTS: At 30-50 weeks, mild left ventricular systolic function impairment observed in the RT control group was less apparent in animals receiving atorvastatin. ECG analysis demonstrated prolongation of components of cardiac conduction related to the heart base at 10 and 30 weeks in the RT control group but not in animals treated with atorvastatin. In contrast to systolic function, conduction disturbances resolved at later time-points with radiation alone. ANP reductions were lower in irradiated animals receiving atorvastatin at 30 and 50 weeks. CONCLUSIONS: Atorvastatin prevents left ventricular systolic dysfunction, and the perturbation of cardiac conduction following partial heart irradiation. If confirmed in clinical studies, these data would support the use of statin therapy for cardioprotection during thoracic radiotherapy.

Insights on Epidemiology, Morbidity and Mortality of Cushing's Disease in Northern Ireland.

Cushing's disease is a rare condition occurring due to an adrenocorticotrophin-producing corticotrophinoma arising from the pituitary gland. The consequent hypercortisolaemia results in multisystem morbidity and mortality. This study aims to report incidence, clinicopathological characteristics, remission outcomes and mortality in a regional pituitary neurosurgical cohort of patients diagnosed with Cushing's disease in Northern Ireland from 2000-2019. Clinical, biochemical and radiological data from a cohort of patients operated for Cushing's disease were retrospectively collected and analysed. Fifty-three patients were identified, resulting in an estimated annual incidence of Cushing's disease of 1.39-1.57 per million population per year. Females accounted for 72% (38/53) of the cohort. The majority (74%, 39/53) of corticotrophinomas were microadenomas and in 44% (17/39) of these no tumour was identified on preoperative magnetic resonance imaging. Histopathological characterisation was similarly difficult, with no tumour being identified in the histopathological specimen in 40% (21/53) of cases. Immediate postoperative remission rates were 53% and 66% when considering serum morning cortisol cut-offs of ≤50nmol/L (1.8µg/dL) and ≤138nmol/L (5µg/dL) respectively in the week following pituitary surgery. Approximately 70% (37/53) of patients achieved longer term remission with a single pituitary surgery. Three patients had recurrent disease. Patients with Cushing's disease had a significantly higher mortality rate compared to the Northern Ireland general population (standardised mortality ratio 8.10, 95% confidence interval 3.3 - 16.7, p<0.001). Annual incidence of Cushing's disease in Northern Ireland is consistent with other Northern European cohorts. Functioning corticotrophinomas are a clinically, radiologically and histopathologically elusive disease with increased mortality compared to the general population.

Bilateral non-contiguous atypical papillary glioneuronal tumor: case report.

Papillary glioneuronal tumor (PGNT) was first described as a distinct clinic-pathological entity by Komori et al. in 1998. Since then it has been included as a mixed neuronal-glial tumor in the revised WHO (2007) classification of central nervous system tumors. On brain imaging, it appears as a demarcated, solid to cystic, contrast-enhancing mass usually located in the temporal lobe. Histologically, it is considered a biphasic tumor characterized by small cuboidal GFAP-positive astrocytes around hyalinised blood vessels and synaptophysin-positive interpapillary collections of neurocytes, large neurons and intermediate-sized "ganglioid cells". Although they are generally regarded as benign WHO Grade I tumors, recent reports have described more pathologically aggressive features. To date, these reports have all been single lesions.

Empirical treatment with parenteral acyclovir in a child with herpes simplex virus hepatitis and acute lymphoblastic leukemia.

Introduction: Hepatitis secondary to Herpes Simplex Virus (HSV) infection is a complication that often leads to fatal hepatic failure. Early treatment with the anti-viral drug, acyclovir, is life-saving. In view of the non-specific nature of the signs and symptoms associated with HSV hepatitis, diagnosis is often made late during the course of the disease; a factor that largely contributes to the high mortality rate of this treatable disease complication. There is thus a growing consensus in the field to initiate empirical treatment with acyclovir once suspicion of HSV hepatitis is raised even before reaching a conclusive diagnosis. Presentation of case: We present clinical evidence on the benefit of starting empirical acyclovir treatment on the outcome of patients suffering from HSV hepatitis. We report two cases of HSV hepatitis in children with cancer. One case presented with fulminant hepatitis which was fatal and the diagnosis was only reached post mortem. In the second case, there was enough suspicion of HSV hepatitis to start early empirical acyclovir therapy. The diagnosis was confirmed 48 hours following the initiation of treatment and the early intervention with anti-virals proved to be life-saving. Discussion: In both cases above, the following symptoms were shared; fever, elevated transaminase levels and mucositis without clear cutaneous lesions. HSV hepatitis should thus be considered in the differential diagnosis of immuonocomprimised patients exhibiting the above symptoms. Conclusion: Due to the frequent delay in HSV diagnosis and the safety of acyclovir, we recommend empirically administering acyclovir in patients suspected of HSV hepatitis.

Dystrophin Exon 29 Nonsense Mutations Cause a Variably Mild Phenotype.

BACKGROUND: Nonsense mutations in the dystrophin gene usually result in a severe Duchenne muscular dystrophy phenotype. FINDINGS: We describe a 7-year-old boy with a rare pathogenic mutation in exon 29 c.3940C>T p.(Arg1314Ter) resulting in exon skipping, in turn rescuing the phenotype from a severe Duchenne type to a milder Becker muscular dystrophy type. No adults have been described with this mutation to date. CONCLUSIONS: Exon skipping of exon 29 results in a higher level of functional dystrophin. Some cases of muscular dystrophy may still require muscle biopsy to determine optimal management and pharmaceutical treatment options.

A 'second truncation' in TTN causes early onset recessive muscular dystrophy.

Mutations in the gene encoding the giant skeletal muscle protein titin are associated with a variety of muscle disorders, including recessive congenital myopathies ±cardiomyopathy, limb girdle muscular dystrophy (LGMD) and late onset dominant distal myopathy. Heterozygous truncating mutations have also been linked to dilated cardiomyopathy. The phenotypic spectrum of titinopathies is emerging and expanding, as next generation sequencing techniques make this large gene amenable to sequencing. We undertook whole exome sequencing in four individuals with LGMD. An essential splice site mutation, previously reported in dilated cardiomyopathy, was identified in all families in combination with a second truncating mutation. Affected individuals presented with childhood onset proximal weakness associated with joint contractures and elevated CK. Cardiac dysfunction was present in two individuals. Muscle biopsy showed increased internal nuclei and immunoblotting identified reduction or absence of calpain-3 and demonstrated a marked reduction of C-terminal titin fragments. We confirm the co-occurrence of cardiac and skeletal myopathies associated with recessive truncating titin mutations. Compound heterozygosity of a truncating mutation previously associated with dilated cardiomyopathy and a 'second truncation' in TTN was identified as causative in our skeletal myopathy patients. These findings add to the complexity of interpretation and genetic counselling for titin mutations.

Complete right ventricular obstruction caused by a giant cardiac myxoid sarcoma.

Myxoid sarcoma is a very rare variant of primary malignant sarcoma of the heart, which presents like a myxoma. We describe the case of 21-year-old man with a giant myxoid sarcoma occupying most of the right ventricle. He underwent emergency surgery to resect the tumor and replace the tricuspid valve which was infiltrated. Chemotherapy and radiotherapy were given postoperatively.

Ascending aorta thrombus: A diagnostic and treatment dilemma.

Due to its position, a mass lesion in the ascending aorta poses a diagnostic and treatment dilemma. We describe the management of a symptomatic mass in the ascending aorta in a 35-year-old man who presented with a cerebrovascular accident.

Constrictive pericarditis and rheumatoid nodules with severe aortic incompetence.

The case of a female patient presenting with constrictive rheumatoid pericarditis and aortic incompetence secondary to valvular rheumatoid nodules is described along with a review of the literature with the aim to highlight this rare cause of aortic insufficiency.

Rare case of primary spinal ependymomatosis occurring in a 26-year-old man: a case report.

INTRODUCTION: The authors report a rare case of primary spinal ependymomatosis in a young adult man. Multiple primary ependymomatous lesions were seen on magnetic resonance imaging and no anaplasia was identified on the surgical-pathological analysis. The aetio-pathological mechanism and surgical significance of this rare occurrence is discussed. CASE PRESENTATION: A 26-year-old man of Polish origin presented with a ten-day history of pain in the left leg and lower back. This was followed by difficulty in urinating and a decrease in sensation in both legs. Examination revealed pyramidal signs and mild weakness in both lower limbs. He had early sphincter involvement requiring catheterization. Magnetic resonance imaging of the brain was normal. However, that of the spinal cord revealed multiple intradural spinal lesions, both intra- and extramedullary, extending from the cervical cord down to the cauda equina roots. T12-L1 laminectomy was performed. Multiple intradural, extra- and intra-medullary tumors were seen. After the operation, the patient deteriorated with a sensory level at T4. Post-operative cranio-spinal radiotherapy was administered but there was no clinical improvement in the lower limbs. CONCLUSION: Primary spinal ependymomatosis is a rare phenomenon involving multiple spinal segments in the absence of a primary intracranial tumor. Radical excision is unrealistic in this condition. Biopsy followed by radiotherapy is the preferred method of treatment.