The spectrum of magnetic resonance findings in cerebrotendinous xanthomatosis: redefinition and evidence of new markers of disease progression.

Cerebrotendinous xanthomatosis (CTX) is a metabolic disease characterized by systemic signs and neurological impairment, which can be prevented if chenodeoxycholic acid (CDCA) treatment is started early. Despite brain MRI represents an essential diagnostic tool, the spectrum of findings is worth to be reappraised, and follow-up data are needed. We performed clinical evaluation and brain MRI in 38 CTX patients. Sixteen of them who were untreated at baseline examination underwent clinical and MRI follow-up after long-term treatment with CDCA. Brain MRI abnormalities included cortical and cerebellar atrophy, and T2W/FLAIR hyperintensity involving subcortical, periventricular, and cerebellar white matter, the brainstem and the dentate nuclei. Regarding the dentate nuclei, we also observed T1W/FLAIR hypointensity consistent with cerebellar vacuolation and T1W/FLAIR/SW hypointense alterations compatibly with calcification in a subgroup of patients. Long-term follow-up showed that clinical and neuroradiological stability or progression were almost invariably associated. In patients with cerebellar vacuolation at baseline, a worsening over time was observed, while subjects lacking vacuoles were clinically and neuroradiologically stable at follow-up. The brains of CTX patients very often show both supratentorial and infratentorial abnormalities at MRI, the latter being related to clinical disability and including a wide spectrum of dentate nuclei alterations. The presence of cerebellar vacuolation may be regarded as a useful biomarker of disease progression and unsatisfactory response to therapy. On the other hand, the absence of dentate nuclei signal alteration should be considered an indicator of better prognosis.

The role of dentate nuclei in human oculomotor control: insights from cerebrotendinous xanthomatosis.

KEY POINTS: A cerebellar dentate nuclei (DN) contribution to volitional oculomotor control has recently been hypothesized but not fully understood. Cerebrotendinous xanthomatosis (CTX) is a rare neurometabolic disease typically characterized by DN damage. In this study, we compared the ocular movement characteristics of two sets of CTX patients, with and without brain MRI evidence of DN involvement, with a set of healthy subjects. Our results suggest that DN participate in voluntary behaviour, such as the execution of antisaccades, and moreover are involved in controlling the precision of the ocular movement. The saccadic abnormalities related to DN involvement were independent of global and regional brain atrophy. Our study confirms the relevant role of DN in voluntary aspects of oculomotion and delineates specific saccadic abnormalities that could be used to detect the involvement of DN in other cerebellar disorders. ABSTRACT: It is well known that the medial cerebellum controls saccadic speed and accuracy. In contrast, the role of the lateral cerebellum (cerebellar hemispheres and dentate nuclei, DN) is less well understood. Cerebrotendinous xanthomatosis (CTX) is a lipid storage disorder due to mutations in CYP27A1, typically characterized by DN damage. CTX thus provides a unique opportunity to study DN in human oculomotor control. We analysed horizontal and vertical visually guided saccades and horizontal antisaccades of 19 CTX patients. Results were related to the presence/absence of DN involvement and compared with those of healthy subjects. To evaluate the contribution of other areas, abnormal saccadic parameters were compared with global and regional brain volumes. CTX patients executed normally accurate saccades with normal main sequence relationships, indicating that the brainstem and medial cerebellar structures were functionally spared. Patients with CTX executed more frequent multistep saccades and directional errors during the antisaccade task than controls. CTX patients with DN damage showed less precise saccades with longer latencies, and more frequent directional errors, usually not followed by corrections, than either controls or patients without DN involvement. These saccadic abnormalities related to DN involvement but were independent of global and regional brain atrophy. We hypothesize that two different cerebellar networks contribute to the metrics of a movement: the medial cerebellar structures determine accuracy, whereas the lateral cerebellar structures control precision. The lateral cerebellum (hemispheres and DN) also participates in modulating goal directed gaze behaviour, by prioritizing volitional over reflexive movements.

MRI-based assessment of the pineal gland in a large population of children aged 0-5 years and comparison with pineoblastoma: part I, the solid gland.

INTRODUCTION: Differentiation between normal solid (non-cystic) pineal glands and pineal pathologies on brain MRI is difficult. The aim of this study was to assess the size of the solid pineal gland in children (0-5 years) and compare the findings with published pineoblastoma cases. METHODS: We retrospectively analyzed the size (width, height, planimetric area) of solid pineal glands in 184 non-retinoblastoma patients (73 female, 111 male) aged 0-5 years on MRI. The effect of age and gender on gland size was evaluated. Linear regression analysis was performed to analyze the relation between size and age. Ninety-nine percent prediction intervals around the mean were added to construct a normal size range per age, with the upper bound of the predictive interval as the parameter of interest as a cutoff for normalcy. RESULTS: There was no significant interaction of gender and age for all the three pineal gland parameters (width, height, and area). Linear regression analysis gave 99 % upper prediction bounds of 7.9, 4.8, and 25.4 mm(2), respectively, for width, height, and area. The slopes (size increase per month) of each parameter were 0.046, 0.023, and 0.202, respectively. Ninety-three percent (95 % CI 66-100 %) of asymptomatic solid pineoblastomas were larger in size than the 99 % upper bound. CONCLUSION: This study establishes norms for solid pineal gland size in non-retinoblastoma children aged 0-5 years. Knowledge of the size of the normal pineal gland is helpful for detection of pineal gland abnormalities, particularly pineoblastoma.

MRI helps depict clinically undetectable risk factors in advanced stage retinoblastomas.

This study compared high-resolution MRI with histology in advanced stage retinoblastomas in which ophthalmoscopy and ultrasonography did not give an exhaustive depiction of the tumour and/or its extension. MRI of orbits and head in 28 retinoblastoma patients (28 eyes) treated with primary enucleation were evaluated. Iris neoangiogenesis, infiltrations of optic nerve, choroid, anterior segment and sclera suspected at MR and histology were compared. Abnormal anterior segment enhancement (AASE) was also correlated with histologically proven infiltrations. Brain images were also evaluated. Significant values were obtained for: prelaminar optic nerve (ON) sensitivity (0.88), positive predictive value (PPV) (0.75) and negative predictive value (NPV) (0.71); post-laminar ON sensitivity (0.50), specificity (0.83), PPV (0.50) and NPV (0.83); overall choroid sensitivity (0.82), and massive choroid NPV (0.69); scleral specificity (1), and NPV (1). AASE correlated with iris neoangiogenesis in 14 out of 19 eyes, and showed significant values for: overall ON PPV (0.65), prelaminar ON sensitivity (0.65), and PPV (0.61), post-laminar ON NPV (0.64); overall choroid sensitivity (0.77), PPV (0.59) and NPV (0.73); scleral NPV (0.83); anterior segment sensitivity (1), and NPV (1). Odds ratios (OR) and accuracy were significant in scleral and prelaminar optic nerve infiltration. Brain examination was unremarkable in all cases. High-resolution MRI may add important findings to clinical evaluation of advanced stage retinoblastomas.

Hereditary diffuse leukoencephalopathy with axonal spheroids: three patients with stroke-like presentation carrying new mutations in the CSF1R gene.

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant disorder characterized by white matter neurodegeneration, progressive cognitive decline, and motor symptoms. Histologically, it is characterized by axonal swellings ("spheroids"). To date, over 20 different mutations affecting the tyrosine kinase domain of the protein have been identified in the colony stimulating factor 1 receptor (CSF1R) gene. Our goal is to describe three unrelated Italian patients affected by HDLS and carrying new CSF1R mutations, thus expanding the mutational spectrum and phenotypic presentation. CSF1R gene analysis was performed in 15 patients (age range 25-83 years) with undefined leukoencephalopathy and progressive cognitive decline. In three patients (two males and one female, aged 58, 37, and 48 years, respectively), new heterozygous missense mutations affecting the protein tyrosine kinase domain of the CSF1R gene were detected. In all of these patients, behavioural and cognitive changes were preceded by an ischemic stroke-like episode. A positive family history was present in only one case.

Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease.

Manganese is essential for several metabolic pathways but becomes toxic in excessive amounts. Manganese levels in the body are therefore tightly regulated, but the responsible protein(s) remain incompletely known. We studied two consanguineous families with neurologic disorders including juvenile-onset dystonia, adult-onset parkinsonism, severe hypermanganesemia, polycythemia, and chronic hepatic disease, including steatosis and cirrhosis. We localized the genetic defect by homozygosity mapping and then identified two different homozygous frameshift SLC30A10 mutations, segregating with disease. SLC30A10 is highly expressed in the liver and brain, including in the basal ganglia. Its encoded protein belongs to a large family of membrane transporters, mediating the efflux of divalent cations from the cytosol. We show the localization of SLC30A10 in normal human liver and nervous system, and its depletion in liver from one affected individual. Our in silico analyses suggest that SLC30A10 possesses substrate specificity different from its closest (zinc-transporting) homologs. We also show that the expression of SLC30A10 and the levels of the encoded protein are markedly induced by manganese in vitro. The phenotype associated with SLC30A10 mutations is broad, including neurologic, hepatic, and hematologic disturbances. Intrafamilial phenotypic variability is also present. Chelation therapy can normalize the manganesemia, leading to marked clinical improvements. In conclusion, we show that SLC30A10 mutations cause a treatable recessive disease with pleomorphic phenotype, and provide compelling evidence that SLC30A10 plays a pivotal role in manganese transport. This work has broad implications for understanding of the manganese biology and pathophysiology in multiple human organs.

Myelodysplasia presenting as thoracic spinal epidural extramedullary hematopoiesis: a rare treatable cause of spinal cord myelopathy.

We present clinical, magnetic resonance imaging, and pathological findings of a 61-year-old patient with an otherwise asymptomatic myelodysplastic syndrome presenting with progressive paraparesis from epidural thoracic spinal extramedullary hematopoiesis. Surgical spinal cord decompression resulted in complete clinical remission.

Contrast-enhanced magnetic resonance imaging of fibrovascular tissue ingrowth within synthetic hydroxyapatite orbital implants in children.

PURPOSE: To assess the usefulness of magnetic resonance imaging (MRI) in assessing fibrovascularization progression into synthetic hydroxyapatite (HA) implants inserted in anophthalmic sockets of children submitted to enucleation. METHODS: We studied 23 HA orbital implants in 23 children who underwent enucleation for retinoblastoma. Each patient was examined by MRI within to 9 to 69 weeks after implant insertion (mean 34 weeks, median 30 weeks). No patient had received chemotherapy or radiotherapy at MRI examination. From each T1-weighted, fat-suppressed enhanced axial examination, the image depicting the center of the implant was identified. Enhancement was evaluated using a 5-point scale. Additionally, possible associated orbital and intracranial pathologies and implant migration or extrusion were evaluated. RESULTS: All patients showed areas of enhancement of the implant consistent with the presence of fibrovascular ingrowth. There was no grade 1 enhancement in our series. Grade 2 was observed in 1 patient (4.34%), grade 3 in 7 patients (30.43%), grade 4 in 11 patients (47.82%), and grade 5 in 4 patients (17.39%). During follow-up there were no cases of clinically evident orbital infection, implant migration, or implant extrusion. No second tumor, optic nerve invasion, orbital extension, tumor relapse, or leptomeningeal brain seeding were noted. CONCLUSIONS: In this series, enhanced MRI showed satisfactory fibrovascular ingrowth of orbital implants since the 13th week after HA spheres insertion, with a trend towards progressive enhancement during the following weeks. The data also confirm the advice to wait at least 5-6 months after enucleation to perform drilling and peg placement.

Safety of intravenous thrombolysis in ischemic stroke caused by left atrial myxoma.

Intravenous thrombolytic treatment represents the gold standard for acute ischemic stroke treatment. However there is some concern to perform this treatment in patients with known cardiac myxomas for the risk of haemorragic complications. Here we described a 63-year-old patient with ischemic stroke due to embolization of atrial myxoma and treated with intravenous recombinant tissue plasminogen activator alteplase. The patient did not show improvement after treatment; 25 days later a brain CT showed an asymptomatic small hemorrhagic infarction, probably due to the large size of ischemic lesion. The lack of response might be explained by the embolization of a large tumor fragment. One-year after cardiac surgery clinical follow-up did not reveal new neurological signs nor symptoms. This case report suggests that systemic thrombolysis is a safe procedure also in patient with atrial myxoma. The efficacy of therapy seems to be related to embolus composition.

Intracranial involvement in plasmacytomas and multiple myeloma: a pictorial essay.

INTRODUCTION: The purpose of this pictorial essay is to increase awareness of the clinical presentation, neuroradiological findings, treatment options, and neuroradiological follow-up of plasmacytomas and multiple myeloma with intracranial growth. METHODS: This pictorial essay reviews the clinical features and neuroradiological findings in seven patients (four women, three men; age range at diagnosis 62-82 years) followed in two institutions. Six patients, one with IgG-kappa plasmacytoma, and five with IgG-kappa (n = 3), IgG-lambda (n = 1), and nonsecretory (n = 1) multiple myeloma, had been seen over a period of 9 years in one institution, and the other patient with IgG-kappa plasmacytoma had been seen over a period of 3.5 years in the other. RESULTS: Intracranial involvement is rare, most frequently resulting from osseous lesions in the cranial vault, skull base, nose, or paranasal sinuses. Primary dural or leptomeningeal involvement is rarer. Some typical findings of a dural and/or osseous plasmacytoma include iso- to hyperdensity on CT scan, T1 equal to high signal intensity and T2 markedly hypointense signal on MRI, and high vascularity possibly documented on intraarterial digital subtraction angiography. However, the neuroradiological findings generally lack specificity, since they are generally no different from those of meningioma, metastasis, lymphoma, dural sarcoma, plasma cell granuloma, infectious meningitis, and leptomeningeal carcinomatosis. CONCLUSION: The spectrum of clinical and neuroradiological evaluation shows that intracranial involvement from plasmacytoma and multiple myeloma must be taken into account in the differential diagnosis of cranial osseous and meningeal disease.

Regional cerebral blood flow in childhood autism: a SPET study with SPM evaluation.

AIM: To establish a link between rCBF assessed with Tc-ECD SPET and the clinical manifestation of the disease. METHODS: We performed the study on 11 patients (five girls and six boys; mean age 11.2 years) displaying autistic behaviour and we compared their data with that of an age-matched reference group of eight normal children. A quantitative analysis of rCBF was performed calculating a perfusion index (PI) and an asymmetry index (AI) in each lobe. Images were analysed with statistical parametric mapping software, following the spatial normalization of SPET images for a standard brain. RESULTS: A statistically significant (P=0.003) global reduction of CBF was found in the group of autistic children (PI=1.07+/-0.07) when compared with the reference group (PI=1.25+/-0.12). Moreover, a significant difference was also observed for the right-to-left asymmetry of hemispheric perfusion between the control group and autistic patients (P=0.0085) with a right prevalence greater in autistic (2.90+/-1.68) with respect to normal children (1.12+/-0.49). Our data show a significant decrease of global cerebral perfusion in autistic children in comparison with their normal counterparts and the existence of left-hemispheric dysfunction, especially in the temporo-parietal areas devoted to language and the comprehension of music and sounds. CONCLUSION: We suggest that these abnormal areas are related to the cognitive impairment observed in autistic children, such as language deficits, impairment of cognitive development and object representation, and abnormal perception and responses to sensory stimuli. Tc-ECD SPET seems to be sensitive in revealing brain blood flow alterations and left-to-right asymmetries, when neuroradiological patterns are normal.

Retinoblastoma: Abnormal gadolinium enhancement of anterior segment of eyes at MR imaging with clinical and histopathologic correlation.

PURPOSE: To evaluate abnormal gadolinium enhancement of the anterior segment of eyes harboring retinoblastoma at magnetic resonance (MR) imaging and correlate this finding with clinical and histopathologic information. MATERIALS AND METHODS: Three neuroradiologists examined 46 eyes with 34 retinoblastomas in 25 children on gadolinium-enhanced T1-weighted orbital MR images obtained shortly after contrast material injection for evidence of abnormally high signal intensity in the anterior segment. Twenty-two of the 34 affected eyes were enucleated, and six of these 22 eyes were treated with preenucleation adjuvant therapy. Thus, correlation of the clinical, MR imaging, and histopathologic findings in 16 eyes was performed. Statistical analysis was performed with nonparametric methods (Fisher exact test). P <.05 indicated a statistically significant difference. RESULTS: Fourteen of the 34 affected eyes showed abnormal gadolinium enhancement of the anterior segment. Regarding the 16 eyes evaluated for statistical analysis, a significant correlation (P =.011) between abnormal gadolinium enhancement of the anterior segment and histopathologically documented optic nerve infiltration was noted. A trend toward an association between abnormal enhancement and elevated intraocular pressure (P =.215), tumor growth beyond the equator at MR imaging (P =.125), and histopathologically proved iris neoangiogenesis (P =.182) also was noted. Histopathologic evidence of optic nerve and/or choroid infiltration correlated significantly (P =.001; sensitivity, 100% [nine of nine eyes]; specificity, 86% [six of seven eyes]) with abnormal enhancement. CONCLUSION: Abnormal gadolinium enhancement of the anterior segments of eyes harboring retinoblastoma seems to indicate more aggressive tumor behavior.