DNA methylation-based classification of glioneuronal tumours synergises with histology and radiology to refine accurate molecular stratification.

AIMS: Glioneuronal tumours (GNTs) are poorly distinguished by their histology and lack robust diagnostic indicators. Previously, we showed that common GNTs comprise two molecularly distinct groups, correlating poorly with histology. To refine diagnosis, we constructed a methylation-based model for GNT classification, subsequently evaluating standards for molecular stratification by methylation, histology and radiology. METHODS: We comprehensively analysed methylation, radiology and histology for 83 GNT samples: a training cohort of 49, previously classified into molecularly defined groups by genomic profiles, plus a validation cohort of 34. We identified histological and radiological correlates to molecular classification and constructed a methylation-based support vector machine (SVM) model for prediction. Subsequently, we contrasted methylation, radiological and histological classifications in validation GNTs. RESULTS: By methylation clustering, all training and 23/34 validation GNTs segregated into two groups, the remaining 11 clustering alongside control cortex. Histological review identified prominent astrocytic/oligodendrocyte-like components, dysplastic neurons and a specific glioneuronal element as discriminators between groups. However, these were present in only a subset of tumours. Radiological review identified location, margin definition, enhancement and T2 FLAIR-rim sign as discriminators. When validation GNTs were classified by SVM, 22/23 classified correctly, comparing favourably against histology and radiology that resolved 17/22 and 15/21, respectively, where data were available for comparison. CONCLUSIONS: Diagnostic criteria inadequately reflect glioneuronal tumour biology, leaving a proportion unresolvable. In the largest cohort of molecularly defined glioneuronal tumours, we develop molecular, histological and radiological approaches for biologically meaningful classification and demonstrate almost all cases are resolvable, emphasising the importance of an integrated diagnostic approach.

Sedaghatian spondylometaphyseal dysplasia in two siblings.

Sedaghatian type spondylometaphyseal dysplasia (SSMD) is a rare skeletal dysplasia with only 24 reported cases to date. Despite the limited literature available, evidence suggests this is a multi-system disorder, with neurological and cardiovascular abnormalities reported in addition to the skeletal features. We report a new family with two affected siblings and detailed phenotypic description of the affected proband. Diagnosis in the neonatal period led to retrospective genetic diagnosis of a previous affected pregnancy that was terminated due to severe ventriculomegaly. We suggest that a diagnosis of SSMD should be considered when shortened long bones are found in combination with significant brain abnormalities.

Abdominal arterial lesions associated with antiphospholipid antibodies: a comparative cross-sectional magnetic resonance angiography study.

OBJECTIVE: Case reports and small case series suggest that stenotic lesions of the renal, coeliac and mesenteric arteries may occur in the antiphospholipid syndrome (APS) resulting in clinical consequences such as hypertension and abdominal angina. The objective was to determine the prevalence of stenotic lesions in arteries arising from the middle aorta in patients with antiphospholipid antibodies (aPL) compared with healthy, hypertensive and atherosclerotic controls. METHODS: In a cross-sectional comparative radiological study using magnetic resonance angiography (MRA), we assessed five groups of subjects for the prevalence of stenotic lesions in arteries arising from the middle aorta: APS/aPL positive, healthy renal donors, patients with hypertension, patients with atherosclerosis defined radiologically and patients with systemic lupus erythematosus and vasculitis who were negative for aPL. All subjects underwent MRA in suspended respiration and images were assessed by two senior radiologists blinded to the clinical details. RESULTS: In the atherosclerosis group, vascular stenotic lesions were more prevalent (71%) than in any other group (P ≤0.000002). The prevalence of all stenotic lesions in aPL positive patients (33%) was significantly higher than in the renal donors (18%) and hypertensive patients (19%) (P ≤0.009). Renal artery stenosis was significantly more prevalent in aPL positive patients than in renal donors (P ≤0.0006) but similar to the prevalence in hypertensive patients. Coeliac and/or mesenteric lesions were significantly more common in aPL positive patients vs hypertensive patients (P ≤0.001). Stenoses did not correlate with traditional risk factors. CONCLUSION: Arterial stenotic lesions in arteries arising from the middle aorta were highly prevalent in atherosclerotic subjects and were more common in aPL-positive patients than in hypertensive patients and healthy renal donors.

Cerebral microhaemorrhage in COVID-19: a critical illness related phenomenon?

BACKGROUND: Cerebral microhaemorrhages are increasingly being recognised as a complication of COVID-19. This observational retrospective study aims to further investigate the potential pathophysiology through assessing the pattern of microhaemorrhage and clinical characteristics of patients with COVID-19 and microhaemorrhage. By comparing with similar patterns of microhaemorrhage in other non-COVID-19 disease, this study aims to propose possible common pathogenic mechanisms. METHODS: A retrospective observational case series was performed identifying all patients with COVID-19 complicated by cerebral microhaemorrhage on MRI. The distribution and number of microhaemorrhages were recorded using the microbleed anatomical scale, and patients' baseline characteristics and salient test results were also recorded. RESULTS: Cerebral microhaemorrhages were noted to have a predilection for the corpus callosum, the juxtacortical white matter and brainstem. All patients had a preceding period of critical illness with respiratory failure and severe hypoxia necessitating intubation and mechanical ventilation. DISCUSSION: This study demonstrates a pattern of cerebral microhaemorrhage that is similar to the pattern reported in patients with non-COVID-19 related critical illness and other causes of severe hypoxia. This raises questions regarding whether microhaemorrhage occurs from endothelial dysfunction due the direct effect of SARS-CoV-2 infection or from the secondary effects of critical illness and hypoxia.

Challenges in the Diagnosis of Medulloblastoma Recurrence at an Unusual Site in a Patient With Prader-Willi Syndrome.

Medulloblastoma is the most common malignant pediatric brain tumor. Survival rates range between 50% and 80% depending on histology and other biologic features, metastases, and treatment approach. Prader-Willi syndrome (PWS) is a genetically inherited disorder characterized by dysmorphic features, mental retardation, obesity, and hypogonadism among other features. We describe a 10.5-year-old girl with PWS and previous standard-risk medulloblastoma that relapsed in the pons 3 years after the end of treatment. Diagnosis of relapse was delayed by a preceding varicella infection, an initial clinical/radiologic response to steroids and the unusual location, and was confirmed with a stereotactic biopsy. Second-line therapy was commenced, however, the patient rapidly deteriorated and died. This is the first report of medulloblastoma in a patient with PWS.

Neuroimaging in Sickle Cell Disease: A Review.

Sickle cell disease is the most common hereditary hemoglobinopathy, which results in abnormally shaped and rigid red blood cells. These sickle-shaped red blood cells cause vaso-occlusion and ischemic phenomena that can affect any organ in the body. As a common cause of disability, the neurological manifestations of sickle cell disease are particularly important. Neuroimaging has a crucial role in the diagnosis, management, and prevention of the complications of sickle cell disease. These complications can affect the brain parenchyma, vasculature, and skull and can be ascribed directly or indirectly to a vasculopathy of small and large vessels. Vaso-occlusion can cause ischemic stroke. Ischemic damage in the absence of an acute neurological deficit, and therefore only apparent on neuroimaging, is termed silent cerebral ischemia. Weakening of the arterial walls can cause aneurysms. In its most severe form, a vasculopathy of the terminal internal carotid arteries can progress to moyamoya syndrome, characterized by steno-occlusive disease and the formation of friable collateral arteries. Rupture of aneurysms or friable collateral arteries is a potential cause of intracranial hemorrhage. The skull and vertebrae may be affected by extra-medullary hematopoiesis, due to severe anemia, or iron deposition, due to chronic red blood cell transfusion. Impaired blood supply to bone is associated with osteomyelitis and osteonecrosis. Fat embolization syndrome is a rare complication of osteonecrosis, which may cause devastating neurological impairment. Awareness and early recognition of the diverse manifestations of sickle cell disease on neuroimaging is crucial to ensure optimal treatment in a complex patient cohort.

Congenital lower brachial plexus palsy due to cervical ribs.

Congenital brachial plexus palsy (CBPP) usually occurs secondarily to intrapartum trauma, but this is not always the case. Cervical ribs have previously been reported to increase the risk of CBPP in association with birth trauma. We report the cases of two children (one female, one male) with congenital lower brachial plexus palsy in whom the presence of non-ossified cervical ribs was the only identified risk factor. In the female child magnetic resonance imaging (MRI) of the brain, spinal cord, and brachial plexus revealed no abnormality except for the presence of bilateral cervical ribs at the level of the seventh cervical (C7) vertebra. Chest radiography was normal, which suggested that the cervical ribs identified on the MRI were fibrous bands or cartilaginous ribs rather than ossified ribs. In the male child, MRI of the spine and brachial plexus was normal but he was noted to have bilateral cervical ribs at C7. These were not identifiable on chest radiography and, therefore, are likely to reflect fibrous bands or cartilaginous ribs.

Non-invasive detection and quantification of human foetal brain lactate in utero by magnetic resonance spectroscopy.

OBJECTIVE: To assess the feasibility of foetal cerebral lactate detection and quantification by proton magnetic resonance spectroscopy ((1)H-MRS) in pregnancies at increased risk of cerebral hypoxia, using a clinical 1.5 T magnetic resonance imaging (MRI) system. METHOD: Localised (1)H-MRS was performed in four patients with pregnancies in their third trimester complicated by intrauterine growth restriction (IUGR). A long echo time (TE) of 288 ms was used to maximise detection and conspicuity of the lactate methyl resonance, together with a short TE MRS acquisition to check for the presence of lipid contamination. Individual peaks in the resulting spectra were measured, corrected for relaxation and referenced to the unsuppressed water signal to provide metabolite concentrations. RESULTS: A resonance peak consistent with the presence of lactate was observed in all cases. In one subject, this was confounded by the identification of significant lipid contamination in the short TE MRS acquisition. The range of measured lactate concentrations was 2.0-3.3 mmol/kg and compared well with preterm neonatal MRS studies. CONCLUSION: The non-invasive detection and quantification of foetal cerebral lactate by MRS is achievable on a clinical 1.5 T MRI system.

Vici syndrome associated with sensorineural hearing loss and evidence of neuromuscular involvement on muscle biopsy.

Vici syndrome is a rare, genetically unresolved congenital multisystem disorder comprising agenesis of the corpus callosum, cataracts, immunodeficiency, cardiomyopathy, and hypopigmentation. An associated neuromuscular phenotype has not previously been described in detail. We report on an infant with clinical features suggestive of Vici syndrome and additional sensorineural hearing loss. Muscle biopsy revealed several changes including markedly increased variability in fiber size, increased internal nuclei, and abnormalities on Gomori trichrome and oxidative stains, raising a wide differential diagnosis including neurogenic atrophy, centronuclear myopathy (CNM) or a metabolic (mitochondrial) cytopathy. Respiratory chain enzyme studies, however, were normal and sequencing of common CNM-associated genes did not reveal any mutations. This case expands the clinical spectrum of Vici syndrome and indicates that muscle biopsy ought to be considered in infants presenting with suggestive clinical features. In addition, we suggest that Vici syndrome is considered in the differential diagnosis of infants presenting with congenital callosal agenesis and that additional investigation has to address the possibility of associated ocular, auditory, cardiac, and immunologic involvement when this radiologic finding is present.

White matter abnormalities and dystonic motor disorder associated with mutations in the SLC16A2 gene.

AIM: Mutations in the SLC16A2 gene have been implicated in Allan-Herndon-Dudley syndrome (AHDS), an X-linked learning disability* syndrome associated with thyroid function test (TFT) abnormalities. Delayed myelination is a non-specific finding in individuals with learning disability whose genetic basis is often uncertain. The aim of this study was to describe neuroimaging findings and neurological features in males with SLC16A2 gene mutations. METHOD: We reviewed brain magnetic resonance imaging (MRI) findings and neurological features in a cohort of five males aged between 1 year 6 months and 6 years (median 4y) from four families harbouring SLC16A2 gene mutations. RESULTS: The participants presented aged between 4 and 9 months with initial hypotonia and subsequent spastic paraparesis with dystonic posturing and superimposed paroxysmal dyskinesias. Dystonic cerebral palsy was the most common initial clinical diagnosis, and AHDS was suspected only retrospectively, considering the characteristically abnormal thyroid function tests, with high serum tri-iodothyronine (T(3)), as the most consistent finding. Brain MRI showed absent or markedly delayed myelination in all five participants, prompting the suspicion of Pelizaeus-Merzbacher disease in one patient. INTERPRETATION: Our findings indicate a consistent association between defective neuronal T(3) uptake and delayed myelination. SLC16A2 involvement should be considered in males with learning disability, an associated motor or movement disorder, and evidence of delayed myelination on brain MRI. Although dysmorphic features suggestive of AHDS are not always present, T(3) measurement is a reliable screening test.

Magnetic resonance imaging changes in idiopathic intracranial hypertension in children.

To evaluate the usefulness of neuroimaging in children with idiopathic intracranial hypertension, brain magnetic resonance imaging (MRI) scans of children with idiopathic intracranial hypertension and age-matched controls were reviewed. Compared with controls, patients with idiopathic intracranial hypertension had flattening of the posterior sclera in 61% versus 40% of cases, distension of perioptic subarachnoid space in 65% versus 35%, intraocular protrusion of pre-laminar optic nerve in 17% versus 0%, tortuosity of optic nerve in 30% versus 5%, and an empty sella in 26% versus 5% of cases. The presence of 3 or more of the MRI features is 95% specific in predicting idiopathic intracranial hypertension. The observed general anesthetic effect on these neuroimaging features are also minimized when multiple features are taken into account. Magnetic resonance imaging features can assist in suspecting the diagnosis of idiopathic intracranial hypertension in children, provided caution is applied when interpreting imaging performed under a general anesthesia.

Cutaneous signs are important in the diagnosis of the rare neoplasia syndrome Carney complex.

We describe a 15-year-old boy who presented with a stroke. Brain MRI imaging showed thalamic and multiple cerebral infarcts. An echocardiogram revealed multiple atrial masses, which were resected. Histological examination confirmed multiple atrial myxomas. Further clinical examination of the patient revealed subtle buccal and peri-oral lentigenes. The diagnosis of Carney complex was made clinically. The patient was subsequently diagnosed with testicular seminomas and a cutaneous angiomyxoma. Genetic investigation revealed a pathological mutation in the PRKAR1A gene. We review the reported manifestations and presentations of Carney complex, along with current diagnostic guidelines. We emphasise the importance of recognising the cutaneous manifestations of this rare autosomal dominantly inherited neoplasia syndrome.

Magnetic resonance renal angiography and venography: an analysis of 111 consecutive scans before donor nephrectomy.

OBJECTIVE: To determine the accuracy of magnetic resonance imaging (MRI) renal angiography in predicting vascular anatomy before donor nephrectomy, to determine the significance of missed vessels and to ascertain whether vessels are missed because of technical limitations or errors in interpretation. PATIENTS AND METHODS: In all, 111 consecutive living donations were assessed; the anatomy on MRI before donation was compared with that at nephrectomy. The significance of additional arteries and veins was recorded at the time of donation, with extra vessels either anastomosed or sacrificed. Finally, the scans in which extra vessels had not been identified were re-examined to establish whether these could be identified retrospectively. RESULTS: In all, 93 kidneys had a single renal artery and 18 had two. All lower pole arteries were anastomosed and all upper pole arteries were sacrificed. Nine arteries were identified before surgery (five were to the lower pole), and nine were missed (four to the lower pole). There were 13 kidneys with more than one vein. Four of these were seen on MRI. However, an extra vein was anastomosed in only one case. On review of the imaging, three arteries were missed because of human error and six due to technical limitations. Of the nine missed veins, only three were easily identified retrospectively. Overall, using MRI as a preoperative investigation for the 111 consecutive cases, the surgeon encountered a previously unidentified accessory artery in nine (8%), and this required anastomosis in four (4%). CONCLUSION: MR angiography has the advantage over computed tomography (CT) of having virtually no side-effects, and if the small possibility is accepted of missing extra vessels because of technical limitation or interpretation, it is a good investigation. However, in light of the failure to visualize all arteries transplanted, we have started to use multi-slice (16-channel) CT to see if its improved spatial resolution alters the results.

Hypertrophic pachymeningitis and undifferentiated connective tissue disease: a case report and review of the literature.

A 63-year-old man with hypertrophic pachymeningitis (HP) and an undifferentiated connective tissue disease is described. Combined therapy with prednisolone and azathioprine improved his symptoms. The association between an undifferentiated connective tissue disease and HP is discussed.

Neurocysticercosis masquerading as a cerebral infarct.

The differential diagnosis of acute focal neurologic deficit in childhood is diverse. We report the case of a child presenting with an acute hemiparesis persisting for longer than 24 hours following a focal seizure. The clinical history, examination findings, and results of cranial magnetic resonance imaging (MRI) were initially interpreted as consistent with an arterial ischemic cerebral infarction. Follow-up cranial MRI performed 9 months later revealed changes indicative of neurocysticercosis. Review of original neuroimaging resulted in a revision of the diagnosis to neurocysticercosis. The clinical history, together with neuroimaging findings, is highly compatible with a diagnosis of neurocysticercosis but unusual because it occurred in a child resident in a nonendemic area who had never traveled to an endemic area and whose diet excluded pork. The case reported raises two important issues. The first is the need to carefully consider the differential diagnosis of acute hemiparesis, including unusual causes. Second, it raises awareness of the potential for neurocysticercosis to occur in low-risk patients in nonendemic areas.