Probable IGG4 related ophthalmic disease presenting with uveitis.

We present a case of an uncommon presentation of IgG4-related ophthalmic disease (ROD). A 58-year-old female presented with unilateral acute anterior uveitis of the right eye, which progressed to scleritis with the development of an associated orbital mass despite treatment with oral glucocorticoid. Initial histopathology of an orbital biopsy was non-diagnostic and continued progression of the disease lead to complete loss of vision in the right eye. The development of uveitis in the previously unaffected left eye led to the decision for enucleation of the right globe and further orbital biopsy. Histopathology revealed features supporting IgG4-related ophthalmic disease. Oral glucocorticoid therapy failed to induce remission, and rituximab therapy was initiated, leading to a rapid resolution in her symptoms. Other cases with a similar presentation report a poor visual prognosis, highlighting the need for prompt diagnosis and treatment of uveitis associated with signs of orbital or scleral involvement.

The Management of Orbital Roof Fractures and Defects: A Review.

PURPOSE: To explore the anatomy, etiopathogenesis, diagnosis and classification, current evidence on intervention and the surgical management of orbital roof fractures and defects (ORFD) for oculoplastic surgeons presented with such cases. METHODS: A review of the current literature through the MEDLINE database using the following search terms: "orbital roof fracture (+treatment/management)," "orbital roof defect (+treatment/management)," "orbital roof erosion (+treatment/management)," "orbital roof repair," "orbital roof," "orbital fracture," "pediatric orbital roof (defect/fracture/erosion)," "orbital anatomy," and "orbital roof anatomy" was conducted. As relatively little has been published on this topic, inclusion criteria were broad and peer-reviewed articles judged to be of clinical importance, relevant to the aims of this review, were included. Non-English abstracts were also included if relevant. Year of publication was not a strict exclusion criterion, and older articles were judged for their suitability based on clinical importance and relevance to current practice. Additional references were obtained from citations in key articles and recommendations from the coauthors based on their areas of expertise. RESULTS: The etiopathogenesis of ORFD varies. Classification systems have been formulated to guide management decisions and can range from conservative management to complex neurosurgery. Eyelid approaches have also been described. This review provides a summary of the evidence for each and a management framework oculoplastic surgeons can use when presented with ORFD. CONCLUSION: Oculoplastic surgeons can be involved, either alone or as part of a multidisciplinary team, in the management of ORFD, and for some, conduct orbital approach reconstructive surgery.

Balancing immunosuppression and infection: recurrent enterovirus encephalitis in SLE.

A young woman with systemic lupus erythematosus (SLE) developed recurrent enterovirus meningoencephalitis while taking prednisolone, azathioprine and rituximab. After reducing the immunosuppression, she developed a central nervous system (CNS) flare of SLE, with enterovirus still present in the cerebrospinal fluid (CSF). There are no evidence-based specific treatments for enterovirus encephalitis, but she responded well to intravenous immunoglobulin alongside pulsed methylprednisolone and rituximab. This case highlights the difficulties in managing people with co-existing infective and autoimmune conditions, especially if each affects the CNS. A viral infection and SLE flare can resemble one another clinically, although here the radiological differentiation of CNS lupus versus enterovirus encephalitis helped to guide the diagnosis.

A case of bilateral sensorineural hearing loss from Langerhans cell histiocytosis.

Langerhans cell histiocytosis is a rare disorder, with resultant bilateral sensorineural hearing loss unreported in adults. A 42-year-old man presented with 4 months of right-sided tinnitus and hearing loss treated initially as otitis media with effusion. He re-presented 5 months later with progressive bilateral hearing loss--sensorineural (>100 dB) on pure tone audiogram. CT showed bilateral petrous temporal bone and calvarial lesions. Biopsy confirmed diagnosis of Langerhans cell histiocytosis and chemotherapy was started. Though uncommon, Langerhans cell histiocytosis should be considered among the differentials of persistent otological symptoms, as its progressive nature can cause bilateral irreversible sensorineural hearing loss.

Simultaneous PET-MRI Studies of the Concordance of Atrophy and Hypometabolism in Syndromic Variants of Alzheimer's Disease and Frontotemporal Dementia: An Extended Case Series.

BACKGROUND: Simultaneous PET-MRI is used to compare patterns of cerebral hypometabolism and atrophy in six different dementia syndromes. OBJECTIVES: The primary objective was to conduct an initial exploratory study regarding the concordance of atrophy and hypometabolism in syndromic variants of Alzheimer's disease (AD) and frontotemporal dementia (FTD). The secondary objective was to determine the effect of image analysis methods on determination of atrophy and hypometabolism. METHOD: PET and MRI data were acquired simultaneously on 24 subjects with six variants of AD and FTD (n = 4 per group). Atrophy was rated visually and also quantified with measures of cortical thickness. Hypometabolism was rated visually and also quantified using atlas- and SPM-based approaches. Concordance was measured using weighted Cohen's kappa. RESULTS: Atrophy-hypometabolism concordance differed markedly between patient groups; kappa scores ranged from 0.13 (nonfluent/agrammatic variant of primary progressive aphasia, nfvPPA) to 0.49 (posterior cortical variant of AD, PCA). Heterogeneity was also observed within groups; the confidence intervals of kappa scores ranging from 0-0.25 for PCA to 0.29-0.61 for nfvPPA. More widespread MRI and PET changes were identified using quantitative methods than on visual rating. CONCLUSION: The marked differences in concordance identified in this initial study may reflect differences in the molecular pathologies underlying AD and FTD syndromic variants but also operational differences in the methods used to diagnose these syndromes. The superior ability of quantitative methodologies to detect changes on PET and MRI, if confirmed on larger cohorts, may favor their usage over qualitative visual inspection in future clinical diagnostic practice.

Measurements of heterogeneity in gliomas on computed tomography relationship to tumour grade.

To undertake a preliminary study that uses CT texture analysis (CTTA) to quantify heterogeneity in gliomas on contrast-enhanced CT and to assess the relationship between tumour heterogeneity and grade. Retrospective analysis of contrast enhanced CT images was performed in 44 patients with histologically proven cerebral glioma between 2007 and 2010. 11 tumours were low grade (Grade I = 3; Grade II, = 8) and 33 high grade (Grade III = 10, Grade IV = 23). CTTA assessment of tumour heterogeneity was performed using a proprietary software algorithm (TexRAD) that selectively filters and extracts textures at different anatomical scales between filter values 1.0 (fine detail) and 2.5 (coarse features). Heterogeneity was quantified as standard deviation (SD) with or without filtration. Tumour heterogeneity, size and attenuation were correlated with tumour grade. For each parameter, receiver operating characteristics characterised the diagnostic performance for discrimination of high grade from low grade glioma and of grade III tumours from grade IV. Further the CTTA was compared to the radiological diagnosis. Tumour heterogeneity correlated significantly with grade (SD without filtration rs = 0.664, p < 0.001, SD with coarse filtration (rs = 0.714, p < 0.001). Tumour size and attenuation showed only moderate correlations with tumour grade (rs = 0.426, p = 0.004 and rs = 0.447, p = 0.002 respectively). Coarse texture was the best discriminator between high and low grade tumours (AUC 0.832, p < 0.0001) and between grade III and grade IV gliomas (AUC = 0.878 p = 0.0001). Compared to the radiological diagnosis, CTTA further characterised the indetermined cases. By quantifying tumour heterogeneity, CTTA has the potential to provide a marker of tumour grade for patients with cerebral glioma. By differentiating between high and low grade tumours, CTTA could possibly assist clinical management.

Diffuse large B-cell lymphoma: an unusual cause of severe otalgia and facial palsy.

An elderly woman, two months after chemotherapy for diffuse large B-cell lymphoma, presented with left-sided otalgia, discharge and facial nerve palsy. MRI showed an active left mastoid infection with an ear canal lesion, likely to be a cholesteatoma. However, a biopsy of the mass showed recurrent high-grade lymphoma. Following diagnosis, the patient opted for palliative care within the community and consequently passed away a few weeks later.

Magnetic resonance imaging signal hyperintensity of neural tissues in diffuse chronic pain syndromes: a pilot study.

In this pilot study we use T2-weighted magnetic resonance imaging (MRI) to identify possible peripheral nerve inflammation in 4 patients with diffuse chronic pain. In all 4 patients, there was an increase in median and ulnar nerve T2 signal intensity at the wrist (P < 0.05 vs. controls). Positive clinical signs of peripheral nerve mechanosensitivity combined with MRI findings suggest that these patients may have an underlying peripheral nerve pathology.

Utilization of dynamic CT perfusion in the study of intracranial meningiomas and their surrounding tissue.

OBJECTIVE: To use CT perfusion (CTP) to assess levels of ischemia in brain areas around intracranial meningiomas. MATERIALS AND METHODS: Fifteen patients with intracranial meningiomas were analysed preoperatively with CTP study. The cerebral blood flow (CBF), cerebral blood volume (CBV) and time to peak (TTP) were measured in the edema, peritumoral edema and in the normal areas of brain. RESULTS: The peritumoral edema measured a mean CBF of 17.36 ml/min/100 ml (median=15.8) and the mean CBF value in the whole edema was 93.86 ml/min/100 ml (median=79.9). The mean CBV measured in the peritumoral edema was 2.7 (median=2.3) and the measured mean CBV of edema was 15 (median=13.2). In the region of the peritumoral edema, the mean CBF and CBV were lower than in the edema bed. Normal brain remote from the edema measured less CBF (mean=28.36 ml/min/100 ml, median=29.7) and CBV (mean=4.1, median=3.8) than the edema. Six patients were noted to have CBF of less than 15 ml/min/100 ml in the perilesional edema. The measured mean CBF and CBV in the normal area of brain were higher than in the peritumoral edema, while the TTP was greater in the perilesional edema (mean=11, median=10.4) when compared with areas of normal brain (mean=9.9, median=9.5) with statistically significant p values. CONCLUSION: The values obtained elucidate the fact that perilesional edematous areas are ischemic. By subset analysis, it may be possible to identify those areas with recoverable tissue from non-recoverable tissue.

Accuracy of dementia diagnosis: a direct comparison between radiologists and a computerized method.

There has been recent interest in the application of machine learning techniques to neuroimaging-based diagnosis. These methods promise fully automated, standard PC-based clinical decisions, unbiased by variable radiological expertise. We recently used support vector machines (SVMs) to separate sporadic Alzheimer's disease from normal ageing and from fronto-temporal lobar degeneration (FTLD). In this study, we compare the results to those obtained by radiologists. A binary diagnostic classification was made by six radiologists with different levels of experience on the same scans and information that had been previously analysed with SVM. SVMs correctly classified 95% (sensitivity/specificity: 95/95) of sporadic Alzheimer's disease and controls into their respective groups. Radiologists correctly classified 65-95% (median 89%; sensitivity/specificity: 88/90) of scans. SVM correctly classified another set of sporadic Alzheimer's disease in 93% (sensitivity/specificity: 100/86) of cases, whereas radiologists ranged between 80% and 90% (median 83%; sensitivity/specificity: 80/85). SVMs were better at separating patients with sporadic Alzheimer's disease from those with FTLD (SVM 89%; sensitivity/specificity: 83/95; compared to radiological range from 63% to 83%; median 71%; sensitivity/specificity: 64/76). Radiologists were always accurate when they reported a high degree of diagnostic confidence. The results show that well-trained neuroradiologists classify typical Alzheimer's disease-associated scans comparable to SVMs. However, SVMs require no expert knowledge and trained SVMs can readily be exchanged between centres for use in diagnostic classification. These results are encouraging and indicate a role for computerized diagnostic methods in clinical practice.

Genetic association and brain morphology studies and the chromosome 8p22 pericentriolar material 1 (PCM1) gene in susceptibility to schizophrenia.

CONTEXT: There is evidence of linkage to a schizophrenia susceptibility locus on chromosome 8p21-22 found by several family linkage studies. OBJECTIVES: To fine map and identify a susceptibility gene for schizophrenia on chromosome 8p22 and to investigate the effect of this genetic susceptibility on an endophenotype of abnormal brain structure using magnetic resonance imaging. DESIGN: Fine mapping and identification of a chromosome 8p22 susceptibility gene was carried out by finding linkage disequilibrium between genetic markers and schizophrenia in multiply affected families, a case-control sample, and a trio sample. Variation in brain morphology associated with pericentriolar material 1 (PCM1) alleles was examined using voxel-based morphometry and statistical parametric mapping with magnetic resonance imaging. Setting and Patients A family sample of 13 large families multiply affected with schizophrenia, 2 schizophrenia case-control samples from the United Kingdom and Scotland, and a sample of schizophrenic trios from the United States containing parents and 1 affected child with schizophrenia. MAIN OUTCOME MEASURES: Tests of transmission disequilibrium between PCM1 locus polymorphisms and schizophrenia using a family sample and tests of allelic association in case-control and trio samples. Voxel-based morphometry using statistical parametric mapping. RESULTS: The family and trio samples both showed significant transmission disequilibrium between marker D85261 in the PCM1 gene locus and schizophrenia. The case-control sample from the United Kingdom also found significant allelic association between PCM1 gene markers and schizophrenia. Voxel-based morphometry of cases who had inherited a PCM1 genetic susceptibility showed a significant relative reduction in the volume of orbitofrontal cortex gray matter in comparison with patients with non-PCM1-associated schizophrenia, who, by contrast, showed gray matter volume reduction in the temporal pole, hippocampus, and inferior temporal cortex. CONCLUSIONS: The PCM1 gene is implicated in susceptibility to schizophrenia and is associated with orbitofrontal gray matter volumetric deficits.

Brain surface reformatted images for fast and easy localization of perirolandic lesions.

OBJECT: The goal of this study was to evaluate a novel form of brain surface representation that allows simple, reliable mapping of the surface neuroanatomy for the preoperative evaluation of the spatial relationship between a focal lesion and the precentral gyrus. METHODS: High-resolution three-dimensional (3D) magnetic resonance (MR) imaging data sets were postprocessed using a curved multiplanar reformatting technique to create brain surface reformatted (BSR) images. These BSR images were reconstructed in less than 5 minutes and demonstrated the entire central sulcus with adjacent surface structures in one view. Two experienced neuroradiologists determined the localization of lesions near the central sulcus in 27 patients on standard MR images in three orthogonal planes and on BSR images. In addition, these observers judged whether the lesions were easy or difficult to localize on standard MR and BSR images, and whether diagnoses based on these methods were certain or doubtful. Anatomical localization based on BSR images was compared with that based on functional MR (fMR) images or intraoperative mapping of motor function. The BSR images yielded a perfect concordance with the fMR images and intraoperative mapping (Cohen kappa 1.0) and optimal diagnostic accuracy in localizing perirolandic lesions (both sensitivity and specificity were 100%). Localization was judged to be easy for 48 of 54 diagnoses based on BSR images compared with 26 of 54 based on standard MR images. Diagnoses were assessed as certain for 52 cases based on BSR images and 34 cases based on standard MR images. CONCLUSIONS: Brain surface reformatted imaging improves the diagnostic accuracy of standard anatomical MR imaging for localizing superficial brain lesions in relation to the precentral gyrus. The complementary use of this technique with standard two-dimensional imaging is supported by the fast and simple postprocessing technique and may provide useful information for preoperative surgical planning.

Dosage-sensitive X-linked locus influences the development of amygdala and orbitofrontal cortex, and fear recognition in humans.

The amygdala, which plays a critical role in emotional learning and social cognition, is structurally and functionally sexually dimorphic in humans. We used magnetic neuroimaging and molecular genetic analyses with healthy subjects and patients possessing X-chromosome anomalies to find dosage-sensitive genes that might influence amygdala development. If such X-linked genes lacked a homologue on the Y-chromosome they would be expressed in one copy in normal 46,XY males and two copies in normal 46,XX females. We showed by means of magnetic neuroimaging that 46,XY males possess significantly increased amygdala volumes relative to normal 46,XX females. However, females with Turner syndrome (45,X) have even larger amygdalae than 46,XY males. This finding implies that haploinsufficiency for one or more X-linked genes influences amygdala development irrespective of a direct or indirect (endocrinological) mechanism involving the Y-chromosome. 45,X females also have increased grey matter volume in the orbitofrontal cortex bilaterally, close to a region implicated in emotional learning. They are as poor as patients with bilateral amygdalectomies in the recognition of fear from facial expressions. We attempted to localize the gene(s) responsible for these deficits in X-monosomy by means of a deletion mapping strategy. We studied female patients possessing structural X-anomalies of the short arm. A genetic locus (no greater than 4.96 Mb in size) at Xp11.3 appears to play a key role in amygdala and orbitofrontal structural and (by implication) functional development. Females with partial X-chromosome deletions, in whom this critical locus is deleted, have normal intelligence. Their fear recognition is as poor as that of 45,X females and their amygdalae are correspondingly enlarged. This 4.96 Mb region contains, among others, the genes for monoamine oxidase A (MAOA) and B (MAOB), which are involved in the oxidative deamination of several neurotransmitters, including dopamine and serotonin. Abnormal activity of these neurotransmitters has been implicated in the aetiology of several neurodevelopmental disorders in which social cognitive deficits are prominent. These associated deficits include a specific lack of fear recognition from facial expressions. We show that the thrombocytic activity of MAOB is proportionate to the number of X-chromosomes, and hypothesize that haploinsufficiency of this enzyme in 45,X females predisposes to their deficits in social cognition.

Changes in cerebral morphology consequent to peripheral autonomic denervation.

Pure autonomic failure (PAF) is characterized by an acquired, selective, peripheral denervation of the autonomic nervous system. Patients with PAF fail to generate bodily states of arousal via the autonomic nervous system in response to physical or cognitive effort. We used voxel-based morphometry to test the hypothesis that changes in the morphology of brain regions involved in autonomic control would arise as a consequence to the longstanding absence of peripheral autonomic responses in PAF patients. Optimized voxel-based morphometry of structural magnetic resonance scans was used to test for regional differences in grey and white matter in 15 PAF patients and matched controls. There were no group differences observed in global measures of grey matter, white matter, or cerebrospinal fluid (CSF). We identified morphometric differences reflecting regional decreases in grey matter volume and concentration in anterior cingulate and insular cortices in PAF patients relative to controls. Morphometric differences in brainstem and subcortical regions did not reach statistical significance. Our findings suggest that peripheral autonomic denervation is associated with grey matter loss in cortical regions encompassing areas that we have previously shown are functionally involved in generation and representation of bodily states of autonomic arousal. The nature of these changes cannot be determined from morphometric analysis alone, but we suggest that they reflect experience-dependent change consequent upon loss of afferent input to brain regions involved in representation of autonomic states.

Navigation expertise and the human hippocampus: a structural brain imaging analysis.

Grey matter volume in the posterior hippocampus of London taxi drivers is greater than in age-matched controls, and the size of this increase correlates positively with time spent taxi driving (E.A. Maguire et al., 2000. Proc Natl Acad Sci USA 97: 4398-4403). This change suggests that increased posterior hippocampal grey matter volume is acquired in response to increased taxi driving experience, perhaps reflecting their detailed representation of the city. However, an alternate hypothesis is that the difference in hippocampal volume is instead associated with innate navigational expertise, leading to an increased likelihood of becoming a taxi driver. To investigate this possibility, we used structural brain imaging and voxel-based morphometry (VBM) to examine a group of subjects who were not taxi drivers. Despite this group showing a wide range of navigational expertise, there was no association between expertise and posterior hippocampal grey matter volume (or, indeed, grey matter volume throughout the brain). This failure to find an association between hippocampal volume and navigational expertise thus suggests that structural differences in the human hippocampus reflect the detail and/or duration of use of the spatial representation acquired, and not innate navigational expertise per se.

Dementia and ageing.

Sophisticated imaging techniques are required to characterise the complex dynamic neuro-anatomical changes that occur over time in health and disease. With the advent of potential therapies for the treatment of degenerative dementias, imaging strategies need to enable early diagnosis and facilitate monitoring of disease progression in treatment trials. This chapter highlights some of the innovative structural and functional imaging techniques that have impacted on the clinical management of Alzheimer's disease.

Voxel-based morphometry in hypocretin-deficient narcolepsy.

STUDY OBJECTIVES: Recent studies suggest that narcolepsy is caused by degeneration of hypocretin (orexin) producing neurons. To find evidence for this hypothesis, we aimed to detect structural changes in the hypothalamus and/or hypocretin projection areas of patients with narcolepsy. DESIGN: We used voxel-based morphometry (VBM), an unbiased MRI morphometric method with a high sensitivity for subtle changes in gray and white matter volumes. SETTING: Image acquisition was carried out in the department of Radiology at Leiden University Medical Center; image post-processing was performed in the Wellcome Department of Cognitive Neurology, London. PARTICIPANTS: Fifteen narcoleptic patients were studied, all having cataplexy and typical findings on Multiple Sleep Latency Testing. All patients were HLA-DQB1*0602 positive and hypocretin-1 deficient. The control group consisted of 15 age and sex matched healthy subjects. MEASUREMENTS AND RESULTS: We found no differences in global gray or white matter volumes between patients and controls. Furthermore, regional gray or white matter volumes in the hypothalamus and hypocretin projection areas did not differ between patients and controls. CONCLUSIONS: VBM failed to show structural changes in the brains of patients with narcolepsy. This suggests that narcolepsy either is associated with microscopic changes undetectable by VBM or that functional abnormalities of hypocretin neurons are not associated with structural correlates.

Age effects on the neural correlates of successful memory encoding.

Event-related functional MRI (fMRI) was used to investigate the neural correlates of memory encoding as a function of age. While fMRI data were obtained, 14 younger (mean age 21 years) and 14 older subjects (mean age 68 years) made animacy decisions about words. Recognition memory for these words was tested at two delays such that older subjects' performance at the short delay was comparable to that of the young subjects at the long delay. This allowed age-associated changes in the neural correlates of encoding to be dissociated from the correlates of differential recognition performance. Activity in left inferior prefrontal cortex and the left hippocampal formation was greater for subsequently recognized words in both age groups, consistent with the findings of previous studies in young adults. In the prefrontal cortex, these 'subsequent memory effects' were, however, left-lateralized in the younger group but bilateral in the older subjects. In addition, for the younger group only, greater activity for remembered words was observed in anterior inferior temporal cortex, as were reversed effects ('subsequent forgetting' effects) in anterior prefrontal regions. The data indicate that older subjects engage much of the same neural circuitry as younger subjects when encoding new memories. However, the findings also point to age-related differences in both prefrontal and temporal activity during successful episodic encoding.

Automatic differentiation of anatomical patterns in the human brain: validation with studies of degenerative dementias.

We compared voxel-based morphometry (VBM) with independent accurate region-of-interest (ROI) measurements of temporal lobe structures in order to validate the usefulness of this fully automated and unbiased technique in Alzheimer's disease (AD) and semantic dementia (SD). In AD, ROI analyses appear more sensitive to volume loss in the amygdalae, whereas VBM analyses appear more sensitive to right middle temporal gyrus and regional hippocampal volume loss. In SD, ROI analyses appear more sensitive to left middle and inferior temporal gyrus volume loss, whereas VBM appears more sensitive to regional hippocampal volume loss. In addition the significance of volume reductions was generally less in VBM owing to more stringent corrections for multiple comparisons. In conclusion, the automated technique detects a general trend of atrophy similar to that of expertly labeled ROI measurements in AD and SD, although there are discrepancies in the ranking of severity and in the significance of volume reductions that are more marked in AD.

Cortical and subcortical gray matter abnormalities in schizophrenia determined through structural magnetic resonance imaging with optimized volumetric voxel-based morphometry.

OBJECTIVE: Structural neuroimaging studies have suggested an association between schizophrenia and abnormalities in brain morphology such as ventricular enlargement and differences in gray matter distribution. Less consistently reported are findings of regional abnormalities such as selective differences in thalamic volume. The authors applied an unbiased technique to test for differences in cerebral morphometry between patients with schizophrenia and matched comparison subjects. METHOD: T(1)-weighted images from 20 schizophrenic patients and matched comparison subjects were processed by using optimized automated voxel-based morphometry within multiple linear regression analyses. RESULTS: Global differences in gray matter volume were seen between the schizophrenic and comparison subjects, with selective regional gray matter differences noted in the mediodorsal thalamus and across cortical regions, including the ventral and medial prefrontal cortices. Within the schizophrenic subjects, a relationship was observed between gray matter volume loss in the medial prefrontal cortex and a positive family history of schizophrenia. There was no significant difference between patients and comparison subjects in rates of proportional gray matter reduction with age. CONCLUSIONS: These observations confirm an association between thalamocortical morphometric abnormalities and schizophrenia, consistent with theoretical models of primary pathoetiological dysfunction in filtering, integration, and information transfer processes in patients with schizophrenia.