A homozygous loss-of-function mutation in inositol monophosphatase 1 (IMPA1) causes severe intellectual disability.

The genetic basis of intellectual disability (ID) is extremely heterogeneous and relatively little is known about the role of autosomal recessive traits. In a field study performed in a highly inbred area of Northeastern Brazil, we identified and investigated a large consanguineous family with nine adult members affected by severe ID associated with disruptive behavior. The Genome-Wide Human SNP Array 6.0 microarray was used to determine regions of homozygosity by descent from three affected and one normal family member. Whole-exome sequencing (WES) was performed in one affected patient using the Nextera Rapid-Capture Exome kit and Illumina HiSeq2500 system to identify the causative mutation. Potentially deleterious variants detected in regions of homozygosity by descent and not present in either 59 723 unrelated individuals from the Exome Aggregation Consortium (Browser) or 1484 Brazilians were subject to further scrutiny and segregation analysis by Sanger sequencing. Homozygosity-by-descent analysis disclosed a 20.7-Mb candidate region at 8q12.3-q21.2 (lod score: 3.11). WES identified a homozygous deleterious variant in inositol monophosphatase 1 (IMPA1) (NM_005536), consisting of a 5-bp duplication (c.489_493dupGGGCT; chr8: 82,583,247; GRCh37/hg19) leading to a frameshift and a premature stop codon (p.Ser165Trpfs*10) that cosegregated with the disease in 26 genotyped family members. The IMPA1 gene product is responsible for the final step of biotransformation of inositol triphosphate and diacylglycerol, two second messengers. Despite its many physiological functions, no clinical phenotype has been assigned to this gene dysfunction to date. Additionally, IMPA1 is the main target of lithium, a drug that is at the forefront of treatment for bipolar disorder.

Cognitive impairment and magnetic resonance imaging correlations in Wilson's disease.

OBJECTIVES: To evaluate the cognitive performance of a group of patients with Wilson's disease (WD) and to correlate the cognitive findings with changes in magnetic resonance imaging (MRI). METHODS: All patients with WD consecutively attended in a Movement Disorders Clinic between September 2006 and October 2007 were invited to participate in the study, together with a group of matched healthy controls. Patients and controls were submitted to comprehensive neuropsychological assessment. MRI was performed in all patients, and abnormalities (high-intensity signal, low-intensity signal and atrophy) were semi-quantitatively rated. Performance of patients and controls in each cognitive test was compared, and correlations between cognitive scores and MRI changes were investigated within the patients' group. RESULTS: Twenty patients with WD (11 men) and 20 controls (nine men) were evaluated. Mean age in the WD and control groups was 30.05 ± 7.25 and 32.15 ± 5.37 years, respectively. Mean schooling years were 11.15 ± 3.73 among WD cases and 10.08 ± 2.62 among controls. Patients with WD performed significantly worse than controls in the Mini-Mental State Examination, Dementia Rating Scale, phonemic verbal fluency (FAS), verb generation, digit span forward, Stroop test, Frontal Assessment Battery and in the Brief Cognitive Screening Battery. A significant correlation emerged between global cognitive impairment and MRI scale (r = 0.535), being higher for high-intensity signal plus atrophy (r = 0.718). CONCLUSION: Patients with WD presented cognitive impairment, especially in executive functions, with good correlation between cognitive abnormalities and MRI changes.

Dandy-Walker Phenotype with Brainstem Involvement: 2 Distinct Subgroups with Different Prognosis.

BACKGROUND AND PURPOSE: Although cardinal imaging features for the diagnostic criteria of the Dandy-Walker phenotype have been recently defined, there is a large range of unreported malformations among these patients. The brainstem, in particular, deserves careful attention because malformations in this region have potentially important implications for clinical outcomes. In this article, we offer detailed information on the association of brainstem dysgenesis in a large, multicentric cohort of patients with the Dandy-Walker phenotype, defining different subtypes of involvement and their potential clinical impact. MATERIALS AND METHODS: In this established multicenter cohort of 329 patients with the Dandy-Walker phenotype, we include and retrospectively review the MR imaging studies and clinical records of 73 subjects with additional brainstem malformations. Detailed evaluation of the different patterns of brainstem involvement and their potential clinical implications, along with comparisons between posterior fossa measurements for the diagnosis of the Dandy-Walker phenotype, was performed among the different subgroups of patients with brainstem involvement. RESULTS: There were 2 major forms of brainstem involvement in patients with Dandy-Walker phenotype including the following: 1) the mild form with anteroposterior disproportions of the brainstem structures "only" (57/73; 78%), most frequently with pontine hypoplasia (44/57; 77%), and 2) the severe form with patients with tegmental dysplasia with folding, bumps, and/or clefts (16/73; 22%). Patients with severe forms of brainstem malformation had significantly increased rates of massive ventriculomegaly, additional malformations involving the corpus callosum and gray matter, and interhemispheric cysts. Clinically, patients with the severe form had significantly increased rates of bulbar dysfunction, seizures, and mortality. CONCLUSIONS: Additional brainstem malformations in patients with the Dandy-Walker phenotype can be divided into 2 major subgroups: mild and severe. The severe form, though less prevalent, has characteristic imaging features, including tegmental folding, bumps, and clefts, and is directly associated with a more severe clinical presentation and increased mortality.

Refining the Neuroimaging Definition of the Dandy-Walker Phenotype.

BACKGROUND AND PURPOSE: The traditionally described Dandy-Walker malformation comprises a range of cerebellar and posterior fossa abnormalities with variable clinical severity. We aimed to establish updated imaging criteria for Dandy-Walker malformation on the basis of cerebellar development. MATERIALS AND METHODS: In this multicenter study, retrospective MR imaging examinations from fetuses and children previously diagnosed with Dandy-Walker malformation or vermian hypoplasia were re-evaluated, using the choroid plexus/tela choroidea location and the fastigial recess shape to differentiate Dandy-Walker malformation from vermian hypoplasia. Multiple additional measures of the posterior fossa and cerebellum were also obtained and compared between Dandy-Walker malformation and other diagnoses. RESULTS: Four hundred forty-six examinations were analyzed (174 fetal and 272 postnatal). The most common diagnoses were Dandy-Walker malformation (78%), vermian hypoplasia (14%), vermian hypoplasia with Blake pouch cyst (9%), and Blake pouch cyst (4%). Most measures were significant differentiators of Dandy-Walker malformation from non-Dandy-Walker malformation both pre- and postnatally (P < .01); the tegmentovermian and fastigial recess angles were the most significant quantitative measures. Posterior fossa perimeter and vascular injury evidence were not significant differentiators pre- or postnatally (P > .3). The superior posterior fossa angle, torcular location, and vermian height differentiated groups postnatally (P < .01), but not prenatally (P > .07). CONCLUSIONS: As confirmed by objective measures, the modern Dandy-Walker malformation phenotype is best defined by inferior predominant vermian hypoplasia, an enlarged tegmentovermian angle, inferolateral displacement of the tela choroidea/choroid plexus, an obtuse fastigial recess, and an unpaired caudal lobule. Posterior fossa size and torcular location should be eliminated from the diagnostic criteria. This refined phenotype may help guide future study of the numerous etiologies and varied clinical outcomes.

Multivoxel proton MR spectroscopy in malformations of cortical development.

BACKGROUND AND PURPOSE: Malformations of cortical development (MCD) are traditionally considered as a cause of epilepsy. Our aim was to study patients with focal MCD, by using multivoxel proton MR spectroscopy; we focused not only on the lesion but also on the normal-appearing contralateral side (NACS). Our hypothesis was that the metabolic abnormality extends to the NACS; therefore, it would be inadequate to consider NACS as an internal control. MATERIALS AND METHODS: We studied 16 patients with focal MCD. MR spectroscopy was performed by using a point-resolved spectroscopy sequence technique, including the MCD area and the NACS. In each volume of interest, a smaller volume of interest of 2.25 cm(3) centered on the MCD was selected to study the N-acetylaspartate/creatine (NAA/Cr) ratio. In NACS, this ratio was studied by placing a symmetric voxel in comparison with the smaller MCD volume of interest. A control group (n=30) was also studied to evaluate both white and gray matter by using the same MR spectroscopy protocol. RESULTS: From 16 analyzed volumes of interest with MCD, 9 were composed of gray matter heterotopia and 7 of cortical dysplasia. MR spectroscopy of both MCD lesions and NACS (n=10) showed decreased NAA/Cr compared with that of the control group. NACS in these patients did not present significant differences regarding NAA/Cr in comparison with the affected side. CONCLUSIONS: MR spectroscopy demonstrated abnormal NAA/Cr in both MCD lesions and NACS in patients harboring focal MCD, giving support to the hypothesis that in MCD metabolic abnormalities extend far away from the limits of the lesion, reaching the contralateral side.

The role of conventional MR imaging sequences in the evaluation of neurocysticercosis: impact on characterization of the scolex and lesion burden.

BACKGROUND AND PURPOSE: There are few studies comparing the capacity of lesion detection of conventional MR imaging in neurocysticercosis (NCC). This study was designed to clarify its role in the evaluation of this disease, focusing on the total number of lesions identified and the characterization of the scolex. MATERIALS AND METHODS: MR images from 115 patients were prospectively collected during a 3-year interval, including axial spin-echo (SE) T1-weighted; axial fast SE T2-weighted; axial fluid-attenuated inversion recovery (FLAIR); and gadolinium-enhanced axial, coronal, and sagittal SE T1-weighted sequences. They were compared regarding the potential for detection of NCC lesions and specifically of the scolex. RESULTS: Comparing all sequences, we found that FLAIR images were more sensitive to the detection of the scolex (P < .003), whereas the last gadolinium-enhanced T1-weighted series (coronal or sagittal) identified the highest number of lesions (P < .001). CONCLUSION: When dealing with NCC, optimal MR imaging protocols should include FLAIR images to obtain maximal rates of scolex detection. Special attention should be paid to the last gadolinium-enhanced sequence, which maximizes the quantification of lesion load.

Diffusion tensor imaging in children with periventricular leukomalacia: variability of injuries to white matter tracts.

BACKGROUND AND PURPOSE: Conventional MR imaging shows evidence of brain injury and/or maldevelopment in 70%-90% of children with cerebral palsy (CP), though its capability to identify specific white matter tract injury is limited. The great variability of white matter lesions in CP already demonstrated by postmortem studies is thought to be one of the reasons why response to treatment is so variable. Our hypothesis is that diffusion tensor imaging (DTI) is a suitable technique to provide in vivo characterization of specific white matter tract lesions in children with CP associated with periventricular leukomalacia (PVL). MATERIALS AND METHODS: In this study, 24 children with CP associated with PVL and 35 healthy controls were evaluated with DTI. Criteria for identification of 26 white matter tracts on the basis of 2D DTI color-coded maps were established, and a qualitative scoring system, based on visual inspection of the tracts in comparison with age-matched controls, was used to grade the severity of abnormalities. An ordinal grading system (0=normal, 1=abnormal, 2=severely abnormal or absent) was used to score each white matter tract. RESULTS: There was marked variability in white matter injury pattern in patients with PVL, with the most frequent injury to the retrolenticular part of the internal capsule, posterior thalamic radiation, superior corona radiata, and commissural fibers. CONCLUSION: DTI is a suitable technique for in vivo assessment of specific white matter lesions in patients with PVL and, thus, a potentially valuable diagnostic tool. The tract-specific evaluation revealed a family of tracts that are highly susceptible in PVL, important information that can potentially be used to tailor treatment options in the future.

Inflammatory myofibroblastic tumor of the orbit with associated enhancement of the meninges and multiple cranial nerves.

Inflammatory myofibroblastic tumor (IMT), Tolosa-Hunt syndrome (THS), and idiopathic hypertrophic pachymeningitis (IHP) seem to be part of a spectrum of disorders that have diverse locations but similar histologic and imaging findings. We report a case of a 50-year-old man presenting with multiple progressive cranial nerves palsies with leptomeningeal cranial nerve enhancement on MRI (II, V1-V3, and X), orbital and infraorbital masses, prominence within the left cavernous sinus, and diffuse dural enhancement. Biopsies of the orbital lesion and infraorbital nerve revealed IMT. The patient's lesions, symptoms, and dural enhancement quickly improved with steroid administration and nearly resolved over multiple subsequent scans over the next few months. This case illustrates a rare case of pseudotumor mimicking a more aggressive appearance that would usually portend a case of malignancy. There is a potential association of IMT, THS, and IHP, which may have existed in a concomitant fashion in this patient. The case also describes the unique finding of enhancement of the cisternal segments of multiple cranial nerves (simulating leptomeningeal malignant involvement), which may be related to inflammatory perineural edema or ischemic neuropathy.

Reduced diffusion in neurocysticercosis: circumstances of appearance and possible natural history implications.

BACKGROUND AND PURPOSE: Few studies discuss DWI findings in patients with NCC, and their conclusions are variable and contradictory. The aim of our study was to describe DWI findings of a cohort of patients with NCC, emphasizing the frequency of reduced diffusion. MATERIALS AND METHODS: This retrospective study included 48 patients with NCC. Two neuroradiologists analyzed MR images regarding location, number, and stage of NCC lesions. On the basis of visual analysis, they defined, by consensus, the presence of high signal within NCC lesions on DWI and measured their ADC values when feasible. RESULTS: The total number of lesions was 342: parenchymal (263), subarachnoid (65), and intraventricular (14); 83 were DWI hyperintense. The first pattern was a small eccentric hyperintense dot/curvilinear structure on DWI (representing the scolex) noted in intraparenchymal lesions in vesicular (41 lesions, 29%) and colloidal vesicular (18 lesions, 19%) stages, in 14 (22%) subarachnoid lesions, and 2 (14%) intraventricular lesions; rADC calculations were hampered by the intrinsic small dimensions of this finding. The second pattern was the presence of total/subtotal DWI hyperintensity in intraparenchymal lesions, 5 in the colloidal vesicular stage (5%) and 1 in the granular nodular phase (3%). Two subarachnoid lesions also showed the same presentation; in this second pattern, reduced diffusion was present in different degrees, measured by rADC calculations. CONCLUSIONS: DWI may identify the scolex, increasing diagnostic confidence for NCC. Total/subtotal DWI hyperintensity, related to the stage of the lesion, though uncommon, allows including NCC as a consideration in the differential diagnosis of lesions with reduced diffusion and ring enhancement.

Correlation between carotid bifurcation calcium burden on non-enhanced CT and percentage stenosis, as confirmed by digital subtraction angiography.

OBJECTIVES: Previous evidence supports a direct relationship between the calcium burden (volume) on post-contrast CT with the percent internal carotid artery (ICA) stenosis at the carotid bifurcation. We sought to further investigate this relationship by comparing non-enhanced CT (NECT) and digital subtraction angiography (DSA). METHODS: 50 patients (aged 41-82 years) were retrospectively identified who had undergone cervical NECT and DSA. A 64-multidetector array CT (MDCT) scanner was utilised and the images reviewed using preset window widths/levels (30/300) optimised to calcium, with the volumes measured via three-dimensional reconstructive software. Stenosis measurements were performed on DSA and luminal diameter stenoses >40% were considered "significant". Volume thresholds of 0.01, 0.03, 0.06, 0.09 and 0.12 cm(3) were utilised and Pearson'S correlation coefficient (r) was calculated to correlate the calcium volume with percent stenosis. RESULTS: Of 100 carotid bifurcations, 88 were available and of these 7 were significantly stenotic. The NECT calcium volume moderately correlated with percent stenosis on DSA r=0.53 (p<0.01). A moderate-strong correlation was found between the square root of calcium volume on NECT with percent stenosis on DSA (r=0.60, p<0.01). Via a receiver operating characteristic curve, 0.06 cm(3) was determined to be the best threshold (sensitivity 100%, specificity 90.1%, negative predictive value 100% and positive predictive value 46.7%) for detecting significant stenoses. CONCLUSION: This preliminary investigation confirms a correlation between carotid bifurcation calcium volume and percent ICA stenosis and is promising for the optimal threshold for stenosis detection. Future studies could utilise calcium volumes to create a "score" that could predict high grade stenosis.

Spectrum of cognitive impairment in neurocysticercosis: differences according to disease phase.

OBJECTIVES: Cognitive decline related to neurocysticercosis (NC) remains poorly characterized and underdiagnosed. In a cross-sectional study with a prospective phase, we evaluated cognitive decline in patients with strictly calcified form (C-NC), the epidemiologically largest subgroup of NC, and investigated whether there is a spectrum of cognitive abnormalities in the disease. METHODS: Forty treatment-naive patients with C-NC aged 37.6 ± 11.3 years and fulfilling criteria for definitive C-NC were submitted to a comprehensive cognitive and functional evaluation and were compared with 40 patients with active NC (A-NC) and 40 healthy controls (HC) matched for age and education. Patients with dementia were reassessed after 24 months. RESULTS: Patients with C-NC presented 9.4 ± 3.1 altered test scores out of the 30 from the cognitive battery when compared to HC. No patient with C-NC had dementia and 10 patients (25%) presented cognitive impairment-no dementia (CIND). The A-NC group had 5 patients (12.5%) with dementia and 11 patients (27.5%) with CIND. On follow-up, 3 out of 5 patients with A-NC with dementia previously still presented cystic lesions with scolex on MRI and still had dementia. One patient died and the remaining patient no longer fulfilled criteria for either dementia or CIND, presenting exclusively calcified lesions on neuroimaging. CONCLUSIONS: Independently of its phase, NC leads to a spectrum of cognitive abnormalities, ranging from impairment in a single domain, to CIND and, occasionally, to dementia. These findings are more conspicuous during active vesicular phase and less prominent in calcified stages.

MR spectroscopy detects lipid peaks in cerebrotendinous xanthomatosis.

CTX is a rare lipid-storage disease. Novel MRS findings from 3 patients, using a short TE, were the presence of lipid peaks at 0.9 and 1.3 ppm in the depth of the cerebellar hemisphere; this might represent an additional marker of disease that is CNS-specific and noninvasive. A decrease in NAA concentration was also detected and attributed to neuroaxonal damage. One patient presented an increase in mIns concentration, pointing to gliosis and astrocytic proliferation.

Non-alcoholic Wernicke's encephalopathy: broadening the clinicoradiological spectrum.

Wernicke's encephalopathy (WE) is a serious neurological disorder secondary to thiamine deficiency. Improved recognition by radiologists and allied health providers of the different clinical settings and imaging findings associated with this emergency can optimise the management of this condition and help prevent its severe consequences. The aim of this study is to illustrate the broad clinicoradiological spectrum of non-alcoholic WE, while emphasising atypical MRI findings.

An Atlas of Infectious and Parasitic Diseases of the Central Nervous System. A Cooperative Study of SILAN (Sociedad Iberolatinoamericana de Neurorradiologia).

Infectious diseases of the central nervous system vary in frequency in different locations in America and Europe. What is common in Brazil can be a sporadic presentation in Europe. Cooperative work gathering experiences from neuroradiologists working in various places can be achieved and will help to identify uncommon cases that can present in our daily practice.

Reversible findings of restricted diffusion in 5-fluorouracil neurotoxicity.

A 35-year-old woman presented with neurotoxicity correlated to an i.v. regimen of 5-fluorouracil as episodes of acute confusional state and abnormalities of symmetrically restricted diffusion in the periventricular white matter and corpus callosum. On discontinuing the medication, the areas of severely restricted diffusion had entirely resolved, with minimal residual T2 signal abnormality. In this case, immediate discontinuation of the chemotherapeutic agent apparently reversed the patient's symptoms and findings on MRI. The scant information available in the published literature regarding this phenomenon is reviewed with regard to 5-fluorouracil.