Cerebral hypomyelination associated with biallelic variants of FIG4.

The lipid phosphatase gene FIG4 is responsible for Yunis-Varón syndrome and Charcot-Marie-Tooth disease Type 4J, a peripheral neuropathy. We now describe four families with FIG4 variants and prominent abnormalities of central nervous system (CNS) white matter (leukoencephalopathy), with onset in early childhood, ranging from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Affected individuals inherited biallelic FIG4 variants from heterozygous parents. Cultured fibroblasts exhibit enlarged vacuoles characteristic of FIG4 dysfunction. Two unrelated families segregate the same G > A variant in the +1 position of intron 21 in the homozygous state in one family and compound heterozygous in the other. This mutation in the splice donor site of exon 21 results in read-through from exon 20 into intron 20 and truncation of the final 115 C-terminal amino acids of FIG4, with retention of partial function. The observed CNS white matter disorder in these families is consistent with the myelination defects in the FIG4 null mouse and the known role of FIG4 in oligodendrocyte maturation. The families described here the expanded clinical spectrum of FIG4 deficiency to include leukoencephalopathy.

Whole Exon Deletion in the GFAP Gene Is a Novel Molecular Mechanism Causing Alexander Disease.

Alexander disease (AD) is a leukodystrophy caused by heterozygous mutations in the gene encoding the glial fibrillary acidic protein (GFAP). Currently, de novo heterozygous missense mutations in the GFAP gene are identified in over 95% of patients with AD. However, patients with biopsy-proven AD have been reported in whom no GFAP mutation has been identified. We report identical twin boys presenting in infancy with seizures and developmental delay in whom MR appearances were suggestive of AD with the exception of an unusual, bilateral, arc of calcification at the frontal white-gray junction. Initial mutation screening of the GFAP gene did not identify a mutation. Whole exome sequencing in both brothers revealed a de novo heterozygous in-frame deletion of the whole of exon 5 of the GFAP gene. Mutations in the GFAP gene are thought to result in a toxic effect of mutant GFAP disrupting the formation of the normal intermediate filament network and resulting in Rosenthal fiber formation, which has hitherto not been linked to exonic scale copy number variants in GFAP. Further studies on mutation negative AD patients are warranted to determine whether a similar mechanism underlies their disease.

Imaging assessment of traumatic brain injury.

Traumatic brain injury (TBI) constitutes injury that occurs to the brain as a result of trauma. It should be appreciated as a heterogeneous, dynamic pathophysiological process that starts from the moment of impact and continues over time with sequelae potentially seen many years after the initial event. Primary traumatic brain lesions that may occur at the moment of impact include contusions, haematomas, parenchymal fractures and diffuse axonal injury. The presence of extra-axial intracranial lesions such as epidural and subdural haematomas and subarachnoid haemorrhage must be anticipated as they may contribute greatly to secondary brain insult by provoking brain herniation syndromes, cranial nerve deficits, oedema and ischaemia and infarction. Imaging is fundamental to the management of patients with TBI. CT remains the imaging modality of choice for initial assessment due to its ease of access, rapid acquisition and for its sensitivity for detection of acute haemorrhagic lesions for surgical intervention. MRI is typically reserved for the detection of lesions that may explain clinical symptoms that remain unresolved despite initial CT. This is especially apparent in the setting of diffuse axonal injury, which is poorly discerned on CT. Use of particular MRI sequences may increase the sensitivity of detecting such lesions: diffusion-weighted imaging defining acute infarction, susceptibility-weighted imaging affording exquisite data on microhaemorrhage. Additional advanced MRI techniques such as diffusion tensor imaging and functional MRI may provide important information regarding coexistent structural and functional brain damage. Gaining robust prognostic information for patients following TBI remains a challenge. Advanced MRI sequences are showing potential for biomarkers of disease, but this largely remains at the research level. Various global collaborative research groups have been established in an effort to combine imaging data with clinical and epidemiological information to provide much needed evidence for improvement in the characterisation and classification of TBI and in the identity of the most effective clinical care for this patient cohort. However, analysis of collaborative imaging data is challenging: the diverse spectrum of image acquisition and postprocessing limits reproducibility, and there is a requirement for a robust quality assurance initiative. Future clinical use of advanced neuroimaging should ensure standardised approaches to image acquisition and analysis, which can be used at the individual level, with the expectation that future neuroimaging advances, personalised to the patient, may improve prognostic accuracy and facilitate the development of new therapies.

Pituitary gland duplication syndrome - An international imaging analysis.

BACKGROUND AND PURPOSE: Duplication of the pituitary gland is a rare developmental anomaly. Multiple associated craniofacial malformations have previously been reported with the largest series to date consisting of five patients. In this multi-institutional series of ten patients, we present a detailed review of the imaging features and discuss a possible overarching pathogenesis that would explain most of the detected malformations. MATERIALS AND METHODS: Inclusion criteria for this retrospective imaging review were the presence of a pituitary stalk and gland duplication and the characteristic appearance of the hypothalamic ventral midline. In addition to the clinical presentation, we recorded the imaging findings of ten patients (9 female) through onsite and online reviews. Genetic analysis was available for six patients. RESULTS: The duplicated pituitary stalk and gland showed normal imaging appearances in all patients. Mammillary bodies were clearly identified lateral to the characteristic prominence of the hypothalamic ventral midline. Strands of tissue extending to the anterior dura ("limited ventral myeloschisis") were noted at the medulla oblongata in 10, and at the cervical spinal cord in 7 patients. The medulla oblongata showed a "butterfly" appearance on axial images in 9 patients. Ten patients had cervical segmentation anomalies ("zipper"-like), 9 anterior-posterior brainstem patterning defects (small pons, elongated medulla), and corpus callosum measurements were abnormal in all patients. Three patients each presented with diencephalic-mesencephalic junction abnormalities and 4 with an anterior mesencephalic "cap". An oropharyngeal teratoma was present in four patients. Genetics was normal in three of the six patients studied; the remainder were found to have mutations in EFNB1 and a gene variant of GIT1, two copies of 7. And 8. exon of SMN1 gene, and 2.126 megabase duplication at bands q11.1 and q11.2 of one chromosome 15, respectively. CONCLUSIONS: Duplication of the pituitary gland presents as well-defined craniofacial and cervical spine malformation phenotype. Axial mesoderm duplication generating an excess of Sonic Hedgehog may be the primary embryological driver leading to this condition. ABBREVIATIONS: CFNS＝ Craniofrontonasal Syndrome; DPG＝ Duplication of the Pituitary Gland; SHH＝ Sonic Hedgehog.

Magnetic resonance imaging biomarkers in patients with progressive ataxia: current status and future direction.

A diagnostic challenge commonly encountered in neurology is that of an adult patient presenting with ataxia. The differential is vast and clinical assessment alone may not be sufficient due to considerable overlap between different causes of ataxia. Magnetic resonance (MR)-based biomarkers such as voxel-based morphometry, MR spectroscopy, diffusion-weighted and diffusion-tensor imaging and functional MR imaging are gaining great attention for their potential as indicators of disease. A number of studies have reported correlation with clinical severity and underlying pathophysiology, and in some cases, MR imaging has been shown to allow differentiation of conditions causing ataxia. However, despite recent advances, their sensitivity and specificity vary. In addition, questions remain over their validity and reproducibility, especially when applied in routine clinical practice. This article extensively reviews the current literature regarding MR-based biomarkers for the patient with predominantly adult-onset ataxia. Imaging features characteristic of a particular ataxia are provided and features differentiating ataxia groups and subgroups are discussed. Finally, discussion will turn to the feasibility of applying these biomarkers in routine clinical practice.

Understanding MRI: basic MR physics for physicians.

More frequently hospital clinicians are reviewing images from MR studies of their patients before seeking formal radiological opinion. This practice is driven by a multitude of factors, including an increased demand placed on hospital services, the wide availability of the picture archiving and communication system, time pressures for patient treatment (eg, in the management of acute stroke) and an inherent desire for the clinician to learn. Knowledge of the basic physical principles behind MRI is essential for correct image interpretation. This article, written for the general hospital physician, describes the basic physics of MRI taking into account the machinery, contrast weighting, spin- and gradient-echo techniques and pertinent safety issues. Examples provided are primarily referenced to neuroradiology reflecting the subspecialty for which MR currently has the greatest clinical application.

Magnetic resonance spectroscopy of the brain.

Proton magnetic resonance (MR) spectroscopy of the brain is a non-invasive, in vivo technique that allows investigation into regional chemical environments. Its complementary use with MR imaging sequences provides valuable insights into brain tumour characteristics, progression and response to treatment. Additionally, its sensitivity to brain dysfunction in the presence of apparently normal structural imaging has galvanised interest in its use as a biomarker of neurodegenerative disorders such as Alzheimer's disease. Accordingly, its integration into clinical imaging protocols within many neuroscience centres throughout the world is increasing. This growing attention is encouraging but if the potential of MR spectroscopy is to be realised, fundamental questions need to be addressed, such as reproducibility of the technique and the biochemistry that underpins the neurometabolites measured. Failure to resolve these issues will continue to hinder the extent and accuracy of conclusions that can be drawn from its data. In this review we discuss the issues regarding MR spectroscopy in the brain with particular attention paid to its technique. Key examples of current clinical applications are provided and future directions are discussed.

Recent advances in imaging epilepsy.

Around 30 000 people are diagnosed with epilepsy every year in the UK. While many of these respond well to antiepileptic drugs, 20-30% have seizures that are resistant to best medical treatment. For these patients it is important to identify any structural abnormalities responsible for generating seizure activity that may be amenable to surgical resection. There are many imaging modalities available to investigate epilepsy including computed tomography (CT), nuclear medicine and magnetic resonance imaging (MRI). Additional techniques are available in specific circumstances including single positron emission CT, diffusion imaging, MR spectroscopy, perfusion imaging and functional MRI. Clearly with so many options, a targeted approach is required to reach a diagnosis efficiently. In this article, each modality is discussed along with the imaging options for the common causes of focal seizure activity.

Should we be moving to a national standardized non-gadolinium MR imaging protocol for the surveillance of vestibular schwannomas?

OBJECTIVES:: To examine whether the model of Getting It Right First Time (GIRFT) could be relevant to the surveillance of non-operated vestibular schwannomas (vs) by testing the following hypotheses: (1) in the UK there is a great variation in the imaging protocol for the follow-up of vs; (2) high-resolution, T 2 weighted MRI (HRT 2W-MRI) has an equivalent accuracy to gadolinium-enhanced T 1 weighted MRI (Gd-MRI) in the assessment of vs size and; (3) imaging with HRT 2W-MRI rather than Gd-MRI could offer financial savings. METHODS:: Two neuroradiologists independently performed measurements of 50 vs imaged with HRT 2W-MRI and Gd-MRI. Differences in mean tumour measurements between HRT 2W-MRI and Gd-MRI were determined, as were intra- and interobserver concordance. Level of agreement was measured using Bland-Altman plots. Consultant neuroradiologists within 30 adult neurosurgical units in the UK were contacted via email and asked to provide the MRI protocol used for the surveillance of non-operated vs in their institution. The financial difference between scanning with HRT 2W-MRI and Gd-MRI was determined within Leeds Teaching Hospitals NHS Trust. RESULTS:: There was no statistically significant difference in the mean diameter of vs size, measured on HRT 2W-MRI and Gd-MRI (p = 0.28 & p = 0.74 for observers 1 and 2 respectively). Inter- and intraobserver concordance were excellent (Interclass correlation coefficient = 0.99, Interclass correlation coefficient ≥ 0.98 respectively). Differences between the two sequences were within limits of agreement. 26 of 30 UK neuroscience centres (87 % response rate) provided imaging protocols. 16 of the 26 (62%) centres use Gd-MRI for the surveillance of vs. HRT 2-MRI is £36.91 cheaper per patient than Gd-MRI. CONCLUSION:: Variation exits across UK centres in the imaging surveillance of non-operated vs. HRT 2W-MRI and Gd-MRI have equivalent accuracy when measuring vs. Imaging with HRT 2W-MRI rather than Gd-MRI offers potential financial savings. ADVANCES IN KNOWLEDGE:: This study highlights the potential health and economic benefits of a national standardized imaging protocol for the surveillance of non-operated vs.

Medulloblastoma in childhood: revisiting intrathecal therapy in infants and children.

INTRODUCTION: Intrathecal chemotherapy is being explored in medulloblastoma in pre-school children as part of brain-sparing strategies and as an alternative to unacceptably neurotoxic cranio-spinal radiotherapy. The range of drugs suitable for this route of administration is restricted by the lack of research evidence of pharmacological suitability and efficacy of other drugs in medulloblastoma. METHODS: Ideal clinical, biological, physicochemical and pharmaceutical properties for intrathecal administration were defined through literature review of pharmaceutical texts, Medline, Embase and consulting the manufacturers. A total of 126 chemotherapy agents were assessed against these criteria by searching the academic domain of pharmaceutical texts, computer databases and consultation with manufacturers. RESULTS: Of the 126 candidate drugs, 99 were rejected because of documentation of their irritant nature, neurotoxicity and requirement for hepatic activation in standard pharmaceutical texts. Fifty were rejected for a single identifiable reason including, neurotoxicity (n = 24), irritant (n = 15), needs enzyme activation (n = 5), clinical evidence of intrathecal neurotoxicity (n = 4) and no evidence of tumour-specific efficacy (n = 2). Where two reasons were cited the justifications were: neurotoxic and irritant (n = 3) and needs activation and systemic administration results in equivalent concentration (n = 1). Twenty-seven drugs remained of which 12 were selected as eligible for further clinical investigation, and 15 were selected for further pre-clinical investigation. CONCLUSIONS: The pre-determined criteria were not applicable, in their entirety, in the majority of drugs, due to lack of information in the academic domain, emphasising the importance of a more open approach for sharing basic drug information. The prioritised list of 12 candidate drugs for clinical trial and 15 for pre-clinical investigation justify that a concerted research effort in this area of practice is made.