Clinical and radiological features of posterior cortical atrophy (PCA) in a GRN mutation carrier: a case report.

BACKGROUND AND PURPOSE: Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome, defined by a distinctive clinical-radiological profile, with Alzheimer's disease (AD) pathology accounting for the majority of cases. The aim of this report was to present the case of a patient with impairment of visual and constructional abilities as initial manifestations. METHOD: The patient underwent a multidimensional assessment, including neuropsychological evaluation, structural and functional imaging and genetic screening. RESULTS: Neurological and neuropsychological assessment showed an impairment of constructive and visuo-spatial skills, associated with dyscalculia, simultanagnosia, optic ataxia and oculomotor apraxia. In accordance with the latest consensus criteria, a diagnosis of PCA was made. Consistent with the clinical findings, structural and functional imaging showed a peculiar pattern of atrophy with primary involvement of right parieto-occipital cortices, whereas cerebrospinal fluid biochemical analysis did not reveal a profile compatible with AD pathology. Genetic screening identified a known pathogenic GRN mutation. CONCLUSION: We present a case of PCA in a GRN mutation carrier in whom a concomitant AD pathological process was excluded. Consequently, although lacking histological data, our case suggests GRN-related pathology causative of PCA. Through this report we provide further evidence for a new neurodegenerative pathway leading to PCA, extending the clinical spectrum of GRN-associated phenotypes.

Functional and radiological outcomes after bridging therapy versus direct thrombectomy in stroke patients with unknown onset: Bridging therapy versus direct thrombectomy in unknown onset stroke patients with 10-point ASPECTS.

BACKGROUND AND PURPOSE: The aim was to assess functional and radiological outcomes after bridging therapy (intravenous thrombolysis plus mechanical thrombectomy) versus direct mechanical thrombectomy (MT) in unknown onset stroke patients. METHODS: A cohort study was conducted on prospectively collected data from unknown onset stroke patients who received endovascular procedures at ≤6 h from symptom recognition or awakening time. RESULTS: Of the 349 patients with a 10-point Alberta Stroke Program Early Computed Tomography Score (ASPECTS), 248 received bridging and 101 received direct MT. Of the 134 patients with 6-9-point ASPECTS, 123 received bridging and 111 received direct MT. Each patient treated with bridging was propensity score matched with a patient treated with direct MT for age, sex, study period, pre-stroke disability, stroke severity, type of stroke onset, symptom recognition to groin time (or awakening to groin time), ASPECTS and procedure time. In the two matched groups with 10-point ASPECTS (n = 73 vs. n = 73), bridging was associated with higher rates of excellent outcome (46.6% vs. 28.8%; odds ratio 2.302, 95% confidence interval 1.010-5.244) and successful recanalization (83.6% vs. 63%; odds ratio 3.028, 95% confidence interval 1.369-6.693) compared with direct MT; no significant association was found between bridging and direct MT with regard to rate of symptomatic intracerebral hemorrhage (0% vs. 1.4%). In the two matched groups with 6-9-point ASPECTS (n = 45 vs. n = 45), no significant associations were found between bridging and direct MT with regard to rates of excellent functional outcome (44.4% vs. 31.1%), successful recanalization (73.3% vs. 76.5%) and symptomatic intracerebral hemorrhage (0% vs. 0%). CONCLUSIONS: Bridging at ≤ 6 h of symptom recognition or awakening time was associated with better functional and radiological outcomes in unknown onset stroke patients with 10-point ASPECTS.

Is aceruloplasminemia treatable? Combining iron chelation and fresh-frozen plasma treatment.

We report the case of a patient with hereditary ceruloplasmin deficiency due to a novel gene mutation in ceruloplasmin gene (CP), treated with fresh frozen plasma (FFP) and iron chelation therapy. A 59-year-old man with a past history of diabetes was admitted to our department due to progressive gait difficulties and cognitive impairment. Neurological examination revealed a moderate cognitive decline, with mild extrapyramidal symptoms, ataxia, and myoclonus. Brain T2-weighted MR imaging showed bilateral basal ganglia hypointensity with diffuse iron deposition. Increased serum ferritin, low serum copper concentration, undetectable ceruloplasmin, and normal urinary copper excretion were found. The genetic analysis of the CP (OMIM #604290) reported compound heterozygosity for two mutations, namely c.848G > A and c.2689_2690delCT. Treatment with FFP (500 mL i.v./once a week) and administration of iron chelator (Deferoxamine 1000 mg i.v/die for 5 days, followed by Deferiprone 500 mg/die per os) were undertaken. At the 6-month follow-up, clinical improvement of gait instability, trunk ataxia, and myoclonus was observed; brain MRI scan showed no further progression of basal ganglia T2 hypointensity. This case report suggests that the early initiation of combined treatment with FFP and iron chelation may be useful to reduce the accumulation of iron in the central nervous system and to improve the neurological symptoms.

The brain in late-onset glycogenosis II: a structural and functional MRI study.

BACKGROUND: Late-onset glycogenosis type II (GSD II) is a rare, multisystem disorder mainly affecting limb and respiratory muscles due to acid alpha glucosidase deficiency. Despite evidence at autopsy of glycogen accumulation in the brain, no study exploring brain functions is yet available. OBJECTIVE: Our objective in this study was to assess brain changes in late-onset GSD II. METHODS: Each patient underwent a standardized neuropsychological assessment, regional grey-matter (GM) atrophy, and resting-state functional magnetic resonance imaging (RS-fMRI). Functional connectivity maps of the salience (SN) and default-mode (DMN) networks were considered. A group of age- and gender-matched healthy controls was enrolled for MRI comparisons. P values family-wise error (FWE) cluster level corrected inferior to 0.05 were considered. RESULTS: Nine GSD II patients (age 46.6 ± 8.0; 55% male) were recruited. No significant GM atrophy was found in patients compared with controls (n = 18; age 48.0 ± 9.8,;40% male). Functional connectivity within the SN was selectively reduced in patients, and cingulate gyrus and medial frontal cortex were mainly involved. Accordingly, patients had significant impairment of executive functions (as measured by Wisconsin Card Sorting test), whereas other cognitive domains were within mean normal ranges. CONCLUSIONS: Our findings extend the clinical spectrum of GSD II by indicating that brain changes occur in this muscular disorder. Above all, these results should lead to better examinations of therapeutic approaches and perspectives for the affected patients. Further studies evaluating in depth these issues are warranted.

A challenging diagnosis of reversible "vascular" dementia: Cerebral amyloid angiopathy-related inflammation.

Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare and treatable variant of CAA likely due to an autoimmune response directed toward beta-amyloid deposits. Cognitive and behavioral manifestations are the most common symptoms, followed by focal neurological signs, headache and seizures, associated with characteristics neuroradiological features on brain magnetic resonance imaging (MRI). We describe the clinical course, radiological features and therapeutic approach of two patients with probable CAA-ri with the aim of emphasizing the importance of an early diagnosis of this potentially reversible disease in different neurological settings, such as memory clinics and stroke units.

Joubert syndrome with bilateral polymicrogyria: clinical and neuropathological findings in two brothers.

Joubert syndrome (JS) is characterized by hypotonia, ataxia, developmental delay, and a typical neuroimaging finding, the so-called "molar tooth sign" (MTS). The association of MTS and polymicrogyria (PMG) has been reported as a distinct JS-related disorder (JSRD). So far, five patients have been reported with this phenotype, only two of them being siblings. We report on one additional family, describing a living child with JS and PMG, and the corresponding neuropathological picture in the aborted brother. No mutations were detected in the AHI1 gene, the only so far associated with the JS + PMG phenotype. Moreover, linkage analysis allowed excluding all known gene loci, suggesting further genetic heterogeneity.

Severe brain damage from twin-twin transfusion syndrome treated with serial amnioreductions after 26 weeks: a case to reconsider the gestational age limits of laser therapy.

We report a case of monochorionic twin pregnancy complicated by twin-twin transfusion syndrome (TTTS) diagnosed in the late second trimester and treated with two amnioreductions. Three days after the first amniodrainage, the recipient twin developed intracranial ventriculomegaly and, similarly, after a few days, the donor showed signs of brain damage at MRI. We discuss the possible mechanism of brain damage of amnioreductions performed after 26 weeks of gestation in a monochorionic pregnancy with TTTS as a result of a placental 'steal' phenomenon.

Brain magnetic resonance imaging structural changes in a pedigree of asymptomatic progranulin mutation carriers.

Mutations in the progranulin (PGRN) gene have been recently demonstrated as a cause of frontotemporal lobar degeneration (FTLD) with ubiquitin-immunoreactive neuronal inclusion (FTD-U). Neuropathologic, clinical, and neuroimaging features associated with PGRN mutations have been carefully described. No studies on asymptomatic subjects carrying pathogenetic PGRN mutations are available yet. These would be crucial for establishing the timing of brain changes and bringing new insight into disease pathogenesis and disease course. The aim of this study was to evaluate structural brain morphology using diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) in asymptomatic carriers of PGRN delCACT mutation belonging to a four-generation FTLD pedigree (mean age, 37.0 +/- 12.0). The evaluation of the family proband presenting with progressive nonfluent aphasia at 53 years of age, revealed left frontotemporal hypoperfusion and atrophy. VBM analysis of gray and white matter reductions revealed no differences between asymptomatic carriers (n = 7) and controls (n = 15), and between no-carriers (n = 10) and controls (p < 0.001). DTI analysis revealed a reduction in fractional anisotropy in healthy PGRN mutation carriers in the left uncinate fasciculus, connecting the orbito-frontal regions to the temporal pole, and in the left inferior occipitofrontal fasciculus, connecting the parieto-occipital cortex to the dorsolateral frontal cortex (p < 0.001). No significant difference in fractional anisotropy between no-carriers and controls was found. Our data indicate loss of white matter integrity as an early preclinical feature in familial FTD that might antedate the onset of specific neurologic features. Alteration of fiber tracts within the perisylvian language network might represent the early hallmark of subsequent aphasia onset. The study of other pedigrees of asymptomatic PGRN mutation carriers is warranted.

Neurological and neuropsychological features in Parkinsonian patients exposed to neurotoxic metals.

BACKGROUND: Environmental exposure to heavy metals and especially manganese (Mn) took place in Valcamonica, Italy, where a high prevalence of Parkinsonism was observed (age and sex standardized 407/100,000; 95% CI: 393.87-420.12), and the Standardized Morbidity Ratios was associated with environmental Mn levels. METHODS: A cross sectional study compared Parkinsonian patients residents in Valcamonica with patients from Brescia, Italy. Age- and sex-matched healthy individuals were recruited as controls. The protocol included information on clinical, occupational, residential history and life habits, neuro-psychological testing, and assessment of genetic polymorphism. RESULTS: The target group included 65 patients and 52 controls from Valcamonica, 28 patients and 14 controls from Brescia. Age at onset of the disease was lower in women from both areas. After adjusting for age and age at onset, patients from Valcamonica showed more severe motor impairment at the UPDRS scale, higher damage of cognitive and motor functions at MMSE, Token and Trial Making tests. Genetic variables showed a different allelic distribution of DRD4 gene between cases and controls, outside Valcamonica, where a less frequent familiarity for parkinsonism was reported. CONCLUSIONS: Parkinsonian patients with previous exposure to metals showed a more severe neuropsychological phenotype, without detectable contribution from genetic factors.

Subcortical matter in the α-synucleinopathies spectrum: an MRI pilot study.

α-Synucleinopathies, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB), are characterized by α-synuclein accumulation from brainstem structures to the neocortex. PD and DLB are clinically distinguishable, while discrimination between Parkinson Disease Dementia (PDD) and DLB can be subtle and based on the temporal relationship between motor and cognitive symptoms. To explore patterns of subcortical atrophy in PD, PDD and DLB, and assess specific differences between PD and PDD, and between DLB and PDD. 16 PD, 11 PDD and 16 DLB patients were recruited and underwent 1.5 Tesla structural MRI scanning. Segmentation of subcortical structures was performed with a well-validated, fully-automated tool, and volume and shape for each structure were compared between groups. PDD and DLB patients showed global subcortical atrophy compared to PD patients. Greater hippocampal atrophy was the specific trait that distinguished PDD from PD, while greater atrophy of the pallidi discriminated DLB from PDD. Vertex analysis revealed specific shape differences in both structures. Our results suggest that automated, time-sparing, subcortical volumetry may provide diagnostically useful information in α-synucleinopathies. Future studies on larger samples and with iron-sensitive MRI contrasts are needed.

Gadolinium-pentetic acid magnetic resonance imaging in patients with relapsing remitting multiple sclerosis.

Ten patients with relapsing-remitting multiple sclerosis have been studied by serial gadolinium-pentetic acid magnetic resonance imaging (MRI) every 14 days for 3 months. At the end of the follow-up, seven relapses occurred in six patients; no therapy was administered during the study. Ninety-three enhancing lesions were collected in eight patients. With regard to the duration of the enhancement, 32 lesions were detected in only one MRI scan and 32 were found in more MRI scans (most of the lesions occurring in two serial examinations). Four old lesions increased their size with delayed enhancement. Correlation was found between the relapses and the gadolinium-pentetic acid-enhancing areas only for one brain-stem and two cervical spinal cord lesions. Gadolinium-pentetic acid MRI provides useful information about activity of the disease that cannot be obtained clinically even if the dynamic of the lesions may be undervalued in old plaques.

The effect of imprecise repositioning on lesion volume measurements in patients with multiple sclerosis.

In this study, we evaluated the effect of imprecision in patient repositioning encountered in real life on multiple sclerosis (MS) lesion volumes measured from MRIs. We also evaluated two putative methods for reducing the variability in these lesion volume measurements: first, a reduction of slice thickness (from the conventional 5 mm to 3 mm) and second, the application of a new repositioning technique based on the use of head immobilization shells. We evaluated the errors in lesion volume by scanning 10 patients a total of four times using the two slice thicknesses and two repositioning methods (conventional and using a head immobilization shell). The mean absolute percentage difference between two corresponding scans was 6.8% (range, 1.24 to 11%) using conventional slice thickness and repositioning, 4.1% (range, 0.7 to 5.56%) using conventional slice thickness and head immobilization shells, 2.6% (range, 0.8 to 6.66%) using the conventional repositioning technique and 3-mm slice thickness, and 1.4% (range, 0.2 to 6.14%) using slice thickness of 3 mm and head immobilization shells. These mean absolute differences were significantly different (p = 0.0008). Our results indicate that the effect of repositioning errors of the order of those that can be encountered in the daily life situation of clinical trials affects significantly lesion load measurements in MS and that the combined use of thinner slices and more accurate repositioning techniques can markedly improve the reproducibility of such measurements.

Three-dimensional MR myelography of traumatic injuries of the brachial plexus.

PURPOSE: To determine the diagnostic accuracy of three-dimensional MR myelography in the evaluation of traumatic injuries of the brachial plexus. METHODS: Twenty patients with clinical and electromyographic evidence of traumatic brachial plexopathy were examined with three-dimensional MR myelography, conventional cervical myelography, and CT myelography 1 to 9 months after trauma. Three-dimensional MR myelography was performed on a 1.5-T MR unit with a constructive interference in steady state (CISS) technique. For each patient, maximum intensity myelographic projections and multiplanar reconstruction reformatted 1-mm axial sections were obtained from the same 3-D data set. Three-dimensional MR myelographic findings were compared with findings at cervical myelography and CT myelography. Surgical findings were available for comparison in 13 patients. RESULTS: Three-dimensional MR myelography enabled detection of meningoceles with avulsed or intact nerve roots, partial or complete radicular avulsions without disruption of the thecal sac, dural sleeve abnormalities, and dural scars. Assuming cervical myelography and CT myelography as the standards of reference, 3-D MR myelography showed 89% sensitivity, 95% specificity, and 92% diagnostic accuracy in the evaluation of nerve root integrity. CONCLUSION: Three-dimensional MR myelography can show the majority of traumatic lesions that involve the proximal portion of the brachial plexus in a single rapid examination. On the basis of our findings, we propose this technique as a screening examination for patients with traumatic brachial plexus palsy.

Brain magnetic resonance imaging and manganese exposure.

Due to its paramagnetic properties, manganese (Mn) can be effectively visualized by MRI. Mn accumulates selectively in the globus pallidus of basal ganglia, where it can produce high signals at brain magnetic resonance. These hyperintensities are bilateral, symmetrical, and visible in T1-weighted magnetic resonance imaging of different manganese overload conditions. A review of the literature shows identical findings in manganese exposed workers, hepatopatic patients, and patients undergoing total parenteral nutrition with excessive amount of manganese. Two indicators of exposure and hyperintensity were considered, represented respectively by the concentration of Mn in total blood (MnB), and the pallidal index (PI). These two indicators show a positive association, which indicates a possible continuum from normality to clinical stages both in workers occupationally exposed to Mn and in patients suffering from chronic liver disease. Since both MnB and PI show a high degree of variability, further research should be focused on the identification of more accurate indicators.

Motor evoked potentials and disability in secondary progressive multiple sclerosis.

BACKGROUND: To investigate the mechanisms underlying disability in multiple sclerosis (MS), 40 patients with the relapsing-remitting form of the disease and 13 patients with secondary progressive MS underwent multimodal evoked potential (EP), motor evoked potential (MEP), and spinal motor conduction time evaluation. Clinical disability was evaluated by the expanded disability status scale (EDSS) and functional system scales. In secondary progressive MS patients, magnetic resonance imaging (MRI) was used to obtain a semiquantitATive estimate of the total lesion load of the brain. RESULTS: Spinal motor conduction time was significantly longer in secondary progressive MS patients than controls (p < 0.001) and relapsing-remitting MS patients (p < 0.05), but did not differ between relapsing-remitting patients and controls. Spinal motor conduction times also correlated directly with EDSS scores (p < 0.001) and pyramidal functional system scores (p < 0.001). Brain lesion load (4960.3 +/- 3719.0 mm2) and the total number of lesions (67.7 +/- 37.0) in secondary progressive MS did not correlate with disability scores. For the following EPs, the frequencies of abnormalities were significantly higher in secondary progressive MS patients than relapsing-remitting patients: visual evoked potentials (p < 0.05), somatosensory evoked potentials and upper limb motor evoked potentials (p < 0.01), and brainstem auditory evoked potentials, lower limb somatosensory evoked potentials and lower limb motor evoked potentials (p < 0.001). CONCLUSIONS: These findings suggest that disability in secondary progressive MS patients is mainly due to progressive involvement of corticospinal tract in the spinal cord.

Ruptured cerebral aneurysms operated on with only MRA. Reports of two cases.

Two cases of ruptured aneurysms of anterior communicating artery were reported. The aneuryms were showed only by means of MR angiography and operated on without conventional angiography, since patients' allergy to drugs and medium contrast. The MRA showed precisely the sites of the aneurysm and the directions of the sac, but underestimated the size of the sac. In spite of the lack of angiograms induced a great caution during the dissection of the aneurysm and made necessary a larger operative field, anyway clipping of the aneurysm's neck was performed without great difficulties.

Comparison between computed tomography and magnetic resonance imaging in the postoperative evaluation of acromegalic patients.

Twelve acromegalic patients who underwent transphenoidal resection of a GH-secreting pituitary adenoma were evaluated postoperatively by Computed Tomography (CT) and Magnetic Resonance (MR). CT and MR findings were compared with surgical and clinical results. MR was more accurate than CT in delineating postoperative abnormalities of the infundibulum, diaphragma sellae and optic chiasm. In three cases MR differentiated packing materials from adenomatous tissue. In cases with biochemical evidence of residual or recurrent tumor, MR clearly demonstrated intra- or extrasellar adenomatous tissue and the spatial relationship between the soft tissue mass and the cavernous sinuses. CT was superior to MR only in demonstrating sellar floor disruption. MR imaging detected the anatomical causes of clinical abnormalities in almost all acromegalic patients with incomplete recovery after surgery. On the basis of MR results it is possible to plan additional surgery, radiation therapy or medical treatment. MR may be the radiological procedure of choice for both surgical treatment planning and postoperative follow-up.

Patterns of brain structural changes in first-contact, antipsychotic drug-naive patients with schizophrenia.

BACKGROUND AND PURPOSE: Previous studies have suggested that structural changes do occur in the brain of patients with schizophrenia compared with healthy control participants. However, findings from such studies are inconclusive, probably because of the different methodologic approaches, the clinical heterogeneity of patient samples, and also the fact that patients enrolled were treated with antipsychotic drugs. The aim of this study was to investigate brain GM volumes and intrinsic structural WM changes in first-contact, antipsychotic drug-naïve patients with schizophrenia. MATERIALS AND METHODS: A total of 43 first-contact, drug-naïve, patients with schizophrenia and 17 age-matched control participants were studied. All participants underwent T1-weighted MR imaging and DTI scans. Voxel-based morphometry and tract-based spatial statistics were used to compare GM volumes and WM DTI metrics between groups. MR imaging measures were correlated with the duration of the untreated psychosis and the clinical positive and negative symptoms. RESULTS: Compared with control participants, patients with schizophrenia showed smaller volumes of the temporal, parietal, and occipital GM, and a pattern of decreased mean diffusivity and increased fractional anisotropy in the brain stem and cerebellum bilaterally, interhemispheric and cortico-cortical connections bilaterally, and right anterior and posterior limb of the internal capsule. In patients, decreased mean diffusivity and increased fractional anisotropy in several brain regions were related to a longer duration of the untreated psychosis and the severity of positive symptoms. CONCLUSIONS: First-contact, drug-naïve, patients with schizophrenia present with volumetric and DTI changes, which correlated with their clinical features. This study increases our knowledge on the neural networks involved in the pathophysiologic mechanisms of schizophrenia.

Intra-arterial or intravenous thrombolysis for acute ischemic stroke? The SYNTHESIS pilot trial.

OBJECTIVE To assess the feasibility, safety and preliminary efficacy of intra-arterial thrombolysis (IAT) compared with standard intravenous thrombolysis (IVT) for acute ischemic stroke. METHODS Eligible patients with ischemic stroke, who were devoid of contraindications, started IVT within 3 h or IAT as soon as possible within 6 h. Patients were randomized within 3 h of onset to receive either intravenous alteplase, in accordance with the current European labeling, or up to 0.9 mg/kg intra-arterial alteplase (maximum 90 mg), over 60 min into the thrombus, if necessary with mechanical clot disruption and/or retrieval. The purpose of the study was to determine the proportion of favorable outcome at 90 days. Safety endpoints included symptomatic intracranial hemorrhage (SICH), death and other serious adverse events. RESULTS 54 patients (25 IAT) were enrolled. Median time from stroke onset to start to treatment was 3 h 15 min for IAT and 2 h 35 min for IVT (p<0.001). Almost twice as many patients on IAT as those on IVT survived without residual disability (12/25 vs 8/29; OR 3.2; 95% CI 0.9 to 11.4; p=0.067). SICH occurred in 2/25 patients on IAT and in 4/29 on IVT (OR 0.5; CI 0.1 to 3.3; p=0.675). Mortality at day 7 was 5/25 (IAT) compared with 4/29 (IVT) (OR 1.6; CI 0.4 to 6.7; p=0.718). There was no significant difference in the rate of other serious adverse events. CONCLUSIONS Rapid initiation of IAT is a safe and feasible alternative to IVT in acute ischemic stroke.