(What's the story) morning glory? MRI findings in morning glory disc anomaly.

PURPOSE: Morning glory disc anomaly (MGDA) is a rare congenital ophthalmologic disorder. Historically it has been diagnosed fundoscopically, with little in the literature regarding its imaging findings. The purpose of this study is to further characterize the orbital and associated intracranial magnetic resonance imaging (MRI) findings of MGDA in our tertiary pediatric center. METHODS: A retrospective review was performed of fundoscopically-diagnosed cases of MGDA, that had been referred for MRI. All MRI studies were scrutinized for orbital and other intracranial abnormalities known to occur in association with MGDA. RESULTS: 18 of 19 cases of MGDA showed three characteristic MRI findings: funnel-shaped morphology of the posterior optic disc, abnormal soft tissue associated with the retrobulbar optic nerve, and effacement of adjacent subarachnoid spaces. The ipsilateral (intraorbital) optic nerve was larger in one patient and smaller in six. The ipsilateral optic chiasm was larger in two patients and smaller in one. CONCLUSION: This study represents a comprehensive radiological-led investigation into MGDA. It describes the most frequently-encountered MRI findings in MGDA and emphasizes the importance of MRI in this cohort, i.e., in distinguishing MGDA from other posterior globe abnormalities, in assessing the visual pathway, and in screening for associated intracranial abnormalities - skull base/cerebral, vascular, and facial. It hypothesizes neurocristopathy as an underlying cause of MGDA and its associations. Caliber abnormalities of the ipsilateral optic nerve and chiasm are a frequent finding in MGDA. Optic pathway enlargement should not be labeled "glioma". (239/250).

A complicated Chiari type 1 malformation and holocord syrinx as a likely cause for heel pain.

BACKGROUND: Chiari malformations are a rare group of rhomboencephalic abnormalities involving the brain, craniocervical junction and spine. They may manifest in a variety of clinical presentations which relate to the variable involvement of the cerebellum, brainstem, lower cranial nerves, spinal cord and altered CSF flow dynamics. METHOD: We report an unusual case of incidental diagnosis of a type I Chiari malformation with secondary cystic cerebellar tonsillar encephalomalacia and holocord syrinx following investigation of a 5YO girl presenting with heel swelling related to progressive neuropathic osteoarthropathy of the posterior calcaneal body and apophysis. RESULT: The child was treated with decompressive suboccipital craniectomy and C1 laminectomy and tonsillar resection. Cerebellar tonsillar gliosis and cystic degeneration were confirmed on histopathology. Referral for ongoing engagement with occupational and physical therapy. CONCLUSION: Most type I Chiari malformations in the paediatric population are incidental and asymptomatic. Neurological symptoms are typically mild and relate to altered CSF flow dynamics; however, we present a complex case of type I Chiari malformation with an unusual constellation of associated complications.

Neuroimaging manifestations of paediatric histiocytoses.

Histiocytoses are rare multi-system disorders marked by abnormal histiocyte cell proliferation, affecting children with diverse clinical presentations. Classified into five groups in 2016, including Langerhans-related (L), cutaneous (C), malignant (M), Rosai-Dorfman disease (R) and haemophagocytic lymphohistiocytosis (H), newer entities such as ALK-positive histiocytosis have also emerged, heralding the era of molecular (sub)classification. Common entities include Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), Rosai-Dorfman disease (RDD) and haemophagocytic lymphohistiocytosis (HLH). This pictorial essay aids radiologists in recognising and differentiating paediatric histiocytoses based on unique neuroimaging features.

Diffuse paediatric cerebellar glioma: two identical imaging phenotypes of an extremely rare entity with disparate pathology.

Although the posterior fossa is a common location for paediatric brain tumours [1], diffuse glioma isolated to the cerebellum is an extremely rare imaging entity. Only two cases of isolated diffuse paediatric cerebellar glioma have been reported in the English language to the best of our knowledge [2, 3], and only one of these cases had a similar imaging phenotype to our cases [3]. Although somewhat similar to Lhermitte-Duclos (dysplastic gangliocytoma of the cerebellum), the appearances are distinct from other neoplastic entities of the paediatric posterior fossa. Clinical presentation and neurological examination findings are vital however to help differentiate other diffuse pathologies involving the cerebellum such as rhombencephalitis. Presented here are two diffuse cerebellar gliomas in children under the age of 3 with near identical imaging phenotypes demonstrating differing histological and molecular genetic profiles.

Hirayama disease: the importance of flexion imaging.

Hirayama disease is a rare cervical myelopathy characterised by asymmetrical upper limb weakness and muscle atrophy in the forearm and hand. MRI of the cervical spine plays an essential role in diagnosis, however, the characteristic findings are often only seen when the patient is imaged with the neck in flexion. We present a case of a 15-year-old male who presented with left forearm and hand weakness with muscle wasting. An MRI of the cervical spine with the neck in a neutral position demonstrated atrophy of the spinal cord with intrinsic signal abnormality between C5 and C7. Further imaging with the patient's neck in flexion demonstrated the hallmark features of Hirayama disease. There was anterior displacement of the thecal sac and spinal cord, and an enlarged, crescent-shaped dorsal epidural space which enhanced following i.v. gadolinium administration. The atrophic segment of cord contacted the posterior vertebral bodies when the neck was in full flexion. This case highlights the importance of imaging patients suspected of having this entity with the neck in full flexion in order to make a diagnosis.

Case report: congenital intraventricular meningioma demonstrated with fetal MRI.

Congenital intracranial meningiomas are rare lesions. We present a case of congenital intraventricular cystic meningioma, initially characterized with fetal MRI and confirmed postnatally with histopathology. To our knowledge, this is the first in vivo description of a congenital meningioma with fetal MRI. The fetal MRI was able to characterize the lesion as an atypical intraventricular mass which was separate from the choroid plexus, differentiating the mass from a choroid plexus neoplasm. An intraventricular location of the meningioma is more commonly described in pediatric than in adult patients. Meningioma should be considered in the differential for an intraventricular congenital lesion, and fetal MRI is advocated for lesion characterization.

Spectrum of neuroimaging findings post-proton beam therapy in a large pediatric cohort.

PURPOSE: Proton beam therapy (PBT) is now well established for the treatment of certain pediatric brain tumors. The intrinsic properties of PBT are known to reduce long-term negative effects of photon radiotherapy (PRT). To better understand the intracranial effects of PBT, we analyzed the longitudinal imaging changes in a cohort of children with brain tumors treated by PBT with clinical and radiotherapy dose correlations. MATERIALS AND METHODS: Retrospective imaging review of 46 patients from our hospital with brain tumors treated by PBT. The imaging findings were correlated with clinical and dose parameters. RESULTS: Imaging changes were assessed by reviewing serial magnetic resonance imaging (MRI) scans following PBT over a follow-up period ranging from 1 month to 7 years. Imaging changes were observed in 23 patients undergoing PBT and categorized as pseudoprogression (10 patients, 43%), white matter changes (6 patients, 23%), parenchymal atrophy (6 patients, 23%), and cerebral large vessel arteriopathy (5 patients, 25%). Three patients had more than one type of imaging change. Clinical symptoms attributable to PBT were observed in 13 (28%) patients. CONCLUSION: In accordance with published literature, we found evidence of varied intracranial imaging changes in pediatric brain tumor patients treated with PBT. There was a higher incidence (10%) of large vessel cerebral arteriopathy in our cohort than previously described in the literature. Twenty-eight percent of patients had clinical sequelae as a result of these changes, particularly in the large vessel arteriopathy subgroup, arguing the need for angiographic and perfusion surveillance to pre-empt any morbidities and offer potential neuro-protection.

Biotinidase deficiency presenting as Neuromyelitis Optica Spectrum Disorder.

Biotinidase deficiency disorder is a rare inherited metabolic disorder with typical neurological manifestations of hypotonia, developmental delay, rashes, seizures, hearing and vision impairment. We present two cases with different and unusual clinical profiles, whose neuroimaging resembled Neuromyelitis Optica Spectrum Disorder. Case 1 was initially treated with immunomodulation with steroids and intravenous immunoglobulins, with partial improvement. However reinvestigation for worsening of symptoms showed more extensive changes on spine magnetic resonance imaging. Raised lactate and alanine levels on repeat cerebrospinal fluid testing resulted in further investigations that revealed a biotinidase deficiency. Case 2 presented mainly with respiratory symptoms: a barium swallow suggested bulbar dysfunction. Neuroimaging of brain and spine was similar to that in case 1 and the child was promptly investigated for and confirmed to have biotinidase deficiency. Both cases responded to biotin supplementation. It is important to be cognisant of atypical neurological presentations of biotinidase deficiency including those that mimic immune mediated neurodemyelination disorders, as biotinidase deficiency is potentially treatable.

Tubulinopathies.

Mutations causing dysfunction of the tubulins and microtubule-associated proteins, otherwise known as tubulinopathies, are a group of recently described entities, that lead to complex brain malformations. An understanding of the fundamental principles of operation of the cytoskeleton and compounds in particular microtubules, actin, and microtubule-associated proteins, can assist in the interpretation of the imaging findings of tubulinopathies. Somewhat consistent morphological imaging patterns have been described in tubulinopathies such as dysmorphic basal ganglia-the hallmark (found in 75% of cases), callosal dysgenesis, cerebellar hypoplasia/dysplasia, and cortical malformations, most notably lissencephaly. Recognizing the common imaging phenotypes present in tubulinopathies can prove invaluable in directing the genetic workup for a patient with brain malformations.

Do Measurements of Inner Ear Structures Help in the Diagnosis of Inner Ear Malformations? A Review of Literature.

OBJECTIVE: We conducted an extensive review of the literature relevant to inner ear measurements in normal and malformative conditions to select reproducible methods and normative ranges that may be used in clinical practice. DATA SOURCES AND STUDY SELECTION: A review of the published literature was performed in the English language using PubMed with appropriate keywords. We selected only those articles containing normative values of inner ear structures. DATA EXTRACTION AND DATA SYNTHESIS: The following measurements were identified as reproducible and sensitive for the diagnosis of inner malformations: cochlear height in coronal plane; maximal diameter of bony island of lateral semicircular canal; width of vestibular aqueduct: 1) at midpoint; 2) at operculum in axial plane; cochlear canal and cochlear width in multiplanar reconstructions (MPR)/axial; cochlear length. The following cutoffs for normal inner ears are proposed based on the comparative analysis of the literature: cochlea height: >4.3 mm; lateral semicircular canal bony island: >3 mm; vestibular aqueduct: <0.9 (midpoint) and <1.9 mm (operculum); cochlear canal (axial MPR): >1.4 mm and <2.5 mm; cochlear width (MPR): >5.4 mm. CONCLUSION: Measurements of inner ear structures can help in the interpretation of computed tomography images. They increase the sensitivity in detecting inner ear malformations, especially cochlear hypoplasia now considered more common than previously thought.

Hearing Characteristics of Stroke Patients: Prevalence and Characteristics of Hearing Impairment and Auditory Processing Disorders in Stroke Patients.

BACKGROUND: Stroke survivors may suffer from a range of hearing impairments that may restrict their participation in postacute rehabilitation programs. Hearing impairment may have a significant impact on listening, linguistic skills, and overall communication of the affected stroke patient. However, no studies sought to systematically characterize auditory function of stroke patients in detail, to establish the different types of hearing impairments in this cohort of patients. Such information would be clinically useful in understanding and addressing the hearing needs of stroke survivors. PURPOSE: The present study aimed to characterize and classify the hearing impairments, using a detailed audiological assessment test battery, in order to determine the level of clinical need and inform appropriate rehabilitation for this patient population. RESEARCH DESIGN: A case-control study. STUDY SAMPLE: Forty-two recruited stroke patients who were discharged from a stroke unit and 40 control participants matched for age. DATA COLLECTION AND ANALYSIS: All participants underwent pure-tone audiometry and immittance measurements including acoustic reflex threshold, transient-evoked otoacoustic emissions, auditory-evoked brainstem response, and a central auditory processing assessment battery, performed in a single session. Hearing impairments were classified as peripheral hearing loss (cochlear and neural type), central auditory processing disorder (CAPD), and as a combination of CAPD and peripheral hearing loss. RESULTS: Overall mean hearing thresholds were not significantly different between the control and stroke groups. The most common type of hearing impairment in stroke patients was the combination type, "peripheral and CAPD," in the 61- to 80-yr-old subgroup (in 55%), and auditory processing deficits in 18- to 60-yr-olds (in 40%), which were both significantly higher than in controls. CONCLUSIONS: This is the first study to examine hearing function in detail in stroke patients. Given the importance of hearing for the efficiency of communication, it is essential to identify hearing impairments and differentiate peripheral and central deficits to define an appropriate intervention plan.

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.

Redefining the phenotype of ALSP and AARS2 mutation-related leukodystrophy.

OBJECTIVE: To provide an overview of the phenotype of 2 clinically, radiologically, and pathologically similar leukodystrophies, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and alanyl-transfer RNA synthetase 2 mutation-related leukodystrophy (AARS2-L), and highlight key differentiating features. METHODS: ALSP and AARS2-L cases were identified from the adult-onset leukodystrophy database at our institution. In addition, cases with imaging findings were identified from a literature review. The phenotypic features were determined by combining published cases with those from our database. RESULTS: A combined total of 74 cases of ALSP and 10 cases of AARS2-L with neuroimaging data were identified. The mean age at onset was 42 years in ALSP and 26 years in AARS2-L. Cognitive and motor symptoms were the most common symptoms overall in both. Ovarian failure was exclusive to AARS2-L, present in all known female cases. Both ALSP and AARS2-L showed a confluent, asymmetric, predominantly frontoparietal, periventricular pattern of white matter disease with subcortical U-fiber sparing; pyramidal tract and corpus callosum involvement; and diffusion changes in the white matter which we have termed "deep white matter diffusion dots." Central atrophy and corpus callosal thinning were prominent in ALSP and disproportionately mild in AARS2-L when present. ALSP also occasionally showed ventricular abnormalities and calcifications in the frontal periventricular white matter, features not seen in AARS2-L. AARS2-L demonstrates white matter rarefaction which suppresses on fluid-attenuated inversion recovery MRI sequences, a feature not seen in ALSP. CONCLUSIONS: ALSP and AARS2-L share similar clinical, imaging, and pathologic characteristics with key differentiating features that we have highlighted.

Analysis of Mutations in AARS2 in a Series of CSF1R-Negative Patients With Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia.

IMPORTANCE: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a frequent cause of adult-onset leukodystrophy known to be caused by autosomal dominant mutations in the CSF1R (colony-stimulating factor 1) gene. The discovery that CSF1R mutations cause ALSP led to more accurate prognosis and genetic counseling for these patients in addition to increased interest in microglia as a target in neurodegeneration. However, it has been known since the discovery of the CSF1R gene that there are patients with typical clinical and radiologic evidence of ALSP who do not carry pathogenic CSF1R mutations. These patients include those in whom the pathognomonic features of axonal spheroids and pigmented microglia have been found. Achieving a genetic diagnosis in these patients is important to our understanding of this disorder. OBJECTIVE: To genetically characterize a group of patients with typical features of ALSP who do not carry CSF1R mutations. DESIGN, SETTINGS, AND PARTICIPANTS: In this case series study, 5 patients from 4 families were identified with clinical, radiologic, or pathologic features of ALSP in whom CSF1R mutations had been excluded previously by sequencing. Data were collected between May 2014 and September 2015 and analyzed between September 2015 and February 2016. MAIN OUTCOMES AND MEASURES: Focused exome sequencing was used to identify candidate variants. Family studies, long-range polymerase chain reaction with cloning, and complementary DNA sequencing were used to confirm pathogenicity. RESULTS: Of these 5 patients, 4 were men (80%); mean age at onset of ALSP was 29 years (range, 15-44 years). Biallelic mutations in the alanyl-transfer (t)RNA synthetase 2 (AARS2) gene were found in all 5 patients. Frameshifting and splice site mutations were common, found in 4 of 5 patients, and sequencing of complementary DNA from affected patients confirmed that the variants were loss of function. All patients presented in adulthood with prominent cognitive, neuropsychiatric, and upper motor neuron signs. Magnetic resonance imaging in all patients demonstrated a symmetric leukoencephalopathy with punctate regions of restricted diffusion, typical of ALSP. In 1 patient, brain biopsy demonstrated axonal spheroids and pigmented microglia, which are the pathognomonic signs of ALSP. CONCLUSIONS AND RELEVANCE: This work indicates that mutations in the tRNA synthetase AARS2 gene cause a recessive form of ALSP. The CSF1R and AARS2 proteins have different cellular functions but overlap in a final common pathway of neurodegeneration. This work points to novel targets for research and will lead to improved diagnostic rates in patients with adult-onset leukoencephalopathy.

Population-based observational study of claudication in older men: the Health in Men Study.

OBJECTIVES: To assess the prevalence of and risk factors for claudication and its association with subsequent cardiovascular events. DESIGN, SETTING AND PARTICIPANTS: Observational cohort study of 12 203 Western Australian men aged 65 years and over, recruited from 1996 to 1999, and followed up from 2001 to 2004. MAIN OUTCOME MEASURES: Prevalence of claudication and incidence of peripheral arterial disease (PAD); risk factors for claudication and its association with subsequent cardiovascular events. RESULTS: The prevalence of claudication was 5.3% (638 of 11 970 men). At follow-up, after exclusion of 148 men with claudication at baseline and 76 with missing data at follow-up, the crude average annual incidence of new PAD (claudication or procedure for PAD) was 0.85% (95% CI, 0.72%-0.96%). The risk factors for prevalent claudication and incident PAD were similar, with age, smoking, hypertension, diabetes and history of cardiovascular disease dominating. Of the men with claudication at baseline, nearly half (47.5%; 303 of 638) were not taking aspirin. At follow-up, 42.5% (82 of 193) of the men with incident PAD were not taking aspirin. Claudication at baseline was associated with twice the risk of cardiovascular death (hazard ratio, 2.00; 95% CI, 1.52-2.64). There was a J-shaped relationship between aortic diameter, and both prevalent claudication and subsequent cardiovascular events. CONCLUSIONS: Among older men, claudication is prevalent and is associated with factors that can still be modified in older age, including smoking, exercise and diet. Relatively few men with claudication or at risk of PAD use aspirin. Claudication is a significant predictor of cardiovascular outcome.