Diffuse White Matter Hyperintensities Research Articles

Mitochondrial neurogastrointestinal encephalopathy: a case report

BackgroundMitochondrial neurogastrointestinal encephalopathy (MNGIE) is an autosomal recessive disease associated with alterations in mitochondrial DNA (mtDNA). The typical age of onset of MNGIE is between the first and second decade of life. Diagnosis requires the presence of several key clinical features: sensorimotor neuropathy, external ophthalmoplegia, ocular ptosis, leukoencephalopathy, and gastrointestinal (GI) dysmotility. Unfortunately, MNGIE diagnosis is very challenging, and patients often undergo multiple diagnostic and surgical operations that are unnecessary.Case presentationThis case is of a 51-year-old male presenting with a 2-year history of limb weakness, GI problems and cachexia. There was also a 1-year history of progressive ptosis and ophthalmoplegia. The patient’s uncle and brother had both died from GI-related issues prior to the age of 40. On physical examination, ocular motility was impaired in all directions and there was atrophy and reduction in power in both lower and upper extremities. FLAIR and T2-weighted sequences of brain MRI demonstrated diffuse cerebral white matter hyperintensity (leukoencephalopathy). On discharge, the patient was referred for genetic consultation for bone marrow transplantation and had regular follow-up with a gastroenterology specialist.ConclusionIn patients presenting with chronic progressive ophthalmoplegia, severe gastrointestinal complications, sensorimotor neuropathy and white matter lesions on MRI, it is important to consider investigating for MNGIE.

Genotypic and phenotypic heterogeneity among Chinese pediatric genetic white matter disorders

BackgroundThe pediatric genetic white matter disorders are characterized by a broad disease spectrum. Genetic testing is valuable in the diagnosis. However, there are few studies on the clinical and genetic spectrum of Chinese pediatric genetic white matter disorders.MethodsThe participants were enrolled from the cohort of Peking Union Medical College Hospital. They all received history collection, brain MRI and gene sequencing. Their neurologic complaints which were related to white matter disorders occurred before 18. Brain MRI indicated periventricular and/or deep white matter lesions, fazekas grade 2–3.ResultsAmong the 13 subjects, there were 11 males and two females. The average age of onset was 10.0 ± 5.5 years old. The potential genetic variants were found in 84.6% (11/13) subjects. The ABCD1 showed the greatest mutation frequency (30.8%, 4/13). The EIF2B3 A151fs, EIF2B4 c.885 + 2T > G, EIF2B5 R129X and MPV17 Q142X were novel pathogenic/likely pathogenic variants. 100% (4/4) ABCD1 carriers were accompanied by visual impairment, whereas 100% (3/3) EIF2B carriers developed dysuria. 100% (4/4) ABCD1 carriers exhibited diffuse white matter hyperintensities mainly in the posterior cortical regions, while the EIF2B4 and EIF2B5 carriers were accompanied by cystic degeneration.ConclusionThere is genotypic and phenotypic heterogeneity among Chinese subjects with pediatric genetic white matter disorders. The knowledge of these clinical and genetic characteristics facilitates an accurate diagnosis of these diseases.

Basal Ganglia and Brainstem Located Cerebral Microbleeds Contributed to Gait Impairment in Patients with Cerebral Small Vessel Disease.

The mechanism of gait disorder in patients with cerebral small vessel disease (CSVD) remains unclear. Limited studies have compared the effect of cerebral microbleeds (CMBs) and lacunes on gait disturbance in CSVD patients in different anatomical locations. To investigate the relationship of quantitative gait parameters with varied anatomically located MRI imaging markers in patients with CSVD. Quantitative gait tests were performed on 127 symptomatic CSVD patients all with diffuse distributed white matter hyperintensities (WMHs). CMBs and lacunes in regard to anatomical locations and burdens were measured. The correlation between CSVD imaging markers and gait parameters was evaluated using general linear model analysis. Presence of CMBs was significantly associated with stride length (β= -0.098, p = 0.0272) and right step length (β= -0.054, p = 0.0206). Presence of CMBs in basal ganglia (BG) was significantly associated with stride length and step length. Presence of CMBs in brainstem was significantly associated with gait parameters including stride length, step length, step height, and step width. Presence of lacunes in brainstem was significantly associated with gait speed (β= -0.197, p = 0.0365). However, presence of lacunes in the other areas was not associated with worse gait performances. BG and brain stem located CMBs contributed to gait impairment in symptomatic CSVD patients.

A Novel c.800G>C Variant of the ITM2B Gene in Familial Korean Dementia.

Mutations in ITM2B have been reported to be associated with several familial dementias, such as Familial British dementia and familial Danish dementia. These are autosomal dominant disorders characterized by progressive dementia with an onset at around the fifth decade of life. We describe a family with cognitive impairment caused by a novel ITM2B p.*267Serext*11 mutation. The probands presented with cognitive impairment and cerebral infarction. MRI revealed diffuse white matter hyperintensity and microbleeds. Amyloid deposition was not observed on amyloid positron emission tomography. Our case suggests that the BRI2 mutation impacts cognition regardless of amyloid-β accumulation.

NOTCH2NLC GGC Repeat Expansion in Patients With Vascular Leukoencephalopathy.

Neuronal intranuclear inclusion disease (NIID), caused by GGC (guanine-guanine-cytosine) repeat expansion in NOTCH2NLC, has several clinical and radiological features akin to cerebral small vessel disease (cSVD). The present study tested the hypothesis that NOTCH2NLC GGC expansion may contribute to cSVD. One hundred and ninety-seven unrelated patients with genetically unsolved vascular leukoencephalopathy without NOTCH3, HTRA1, and mitochondrial m.3243A>G mutations and 730 healthy individuals were screened for NOTCH2NLC GGC repeat expansion using repeat-primed polymerase chain reaction, fragment analysis, Southern blot analysis, or nanopore sequencing with Cas9 (CRISPR associated protein 9)-mediated enrichment. The clinical and neuroimaging features of the patients were compared between individuals with and without NOTCH2NLC GGC repeat expansion. Six of the 197 (3.0%) patients with unsolved vascular leukoencephalopathy and none of the controls carried the GGC repeat expansion (P=0.00009). Skin biopsy of 1 patient revealed eosinophilic, ubiquitin-positive, and p62-positive intranuclear inclusions in the cells of sweat gland and capillary, providing pathologic evidence for the involvement of small vessels in NIID. For the 6 patients, gait disturbance and cognitive decline were common manifestations with a median onset age of 65 (59-69) years. They all had multiple neuroimaging features suggestive of cSVD, including diffuse white matter hyperintensities, lacunes, and enlarged perivascular space in all 6 patients, cerebral microbleeds in 5, and old intracerebral hemorrhage in 4. Four patients had linear hyperintensity in the corticomedullary junction on diffusion-weighted imaging-the characteristic neuroimaging feature of NIID. There was no difference in the severity of cSVD imaging features between the patients with and without the GGC expansion but more pronounced brain atrophy in the patients with the GGC expansion. NOTCH2NLC GGC repeat expansion accounted for 3% of genetically unsolved Taiwanese vascular leukoencephalopathy cases after excluding participants with cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). NIID should be considered in patients manifesting cSVD, especially in those with characteristic neuroimaging feature of NIID.

White Matter Hyperintensities and Poststroke Apathy: A Fully Automated MRI Segmentation Study

Introduction: Poststroke apathy (PSA) is a common neuropsychiatric disorder that may affect up to 30% of stroke patients. Despite the difficulties of investigating this condition (overlapping with depression, heterogeneity of diagnostic criteria, a small number of studies), some recent diffusion tensor imaging studies have suggested that widespread microstructural white matter (WM) disruption plays a key role in the development of PSA. Therefore, we intended to investigate this hypothesis by evaluating the relationship between WM hyperintensities (WMH) and apathy in patients with cerebrovascular disease. Methods: We studied patients with apathy (n = 7), depression (n = 13), comorbid apathy and depression (n = 13), and controls (n = 20), and we investigated the variables associated with the volume of WMH measured by an automated brain MRI segmentation software. Results: The overall prevalence of PSA was 37.7% (pure and comorbid). Patients with apathy presented a higher volume of WMH in comparison to controls. Mini-Mental State Examination (MMSE), NPI-A, and the number of cerebral microbleeds were the only variables associated with WMH. Conversely, NPI-D did not correlate to WMH. Discussion/Conclusion: This is an exploratory study that supports the view of PSA as a distinct syndrome from PSD mediated mainly by diffuse white matter hyperintensities, which suggests that WM disruption is an important pathway to the development of apathy in stroke patients.

Non-lesional late-onset epilepsy in the elderly Japanese patients: Presenting characteristics and seizure outcomes with regard to comorbid dementia

The objective of the present retrospective study was analysis of clinical, radiological, and electrophysiological characteristics of the non-lesional late-onset epilepsy (NLLOE) in the elderly Japanese patients, and comparison of the seizure outcomes in this population with regard to presence of comorbid dementia. The study cohort comprised 89 consecutive patients with NLLOE aged ≥ 65 years. In 49 cases (55%), NLLOE manifested with a single type of seizure. Focal impaired awareness seizures (FIAS) were encountered most often (in 69 patients; 78%). Ten patients (11%) had a history of the status epilepticus. Comorbid dementia was diagnosed in 31 patients (35%). Localized or diffuse white matter hyperintensity was the most common imaging finding (66 cases). Epileptiform discharges in the temporal area represented the most frequent abnormality on interictal EEG (24 cases). Seizure-free status for ≥ 12 months was attained in 46 out of 64 patients (72%), who were followed for ≥ 12 months (range, 12 – 110 months), and 42 of them received monotherapy, mainly with levetiracetam (21 patients), carbamazepine (10 patients), or lacosamide (8 patients). In comparison to their counterparts, the rate of seizure-free status for ≥ 12 months was significantly lower in patients with comorbid dementia (81% vs. 52%; P = 0.0205). In conclusion, the NLLOE among Japanese patients aged ≥ 65 years has variable presenting characteristics, and comorbid dementia is diagnosed in one-third of cases. Seizure-free status for ≥ 12 months may be attained in more than two-thirds of treated patients, but comorbid dementia is associated with significantly worse response to antiseizure therapy.

Experimental models in VCID: What are we aiming for?

Vascular contributions to cognitive impairment and dementia (VCID) encompasses the vascular pathology that is evident in most clinical dementia subtypes, as well as vascular dementia as a primary diagnosis. Underlying causes include hypertensive and diabetic disease as well as genetic risk, including monogenic forms of disease (CADASIL, COL4A1 mutations). The most common cause is microvascular: arteriolosclerosis or simple small vessel disease (SVD). SVD is seen radiologically as subcortical ischaemic foci and diffuse white matter hyperintensities on T2-weighted MRI. Pathologically, SVD means fibrotic thickening of deep penetrating arteries within subcortical white matter and deep grey nuclei, accompanied by diffuse changes in surrounding tissue suggestive of hypoperfusion, oedema and vascular fluid leakage. Behaviourally these lesions are associated with cognitive impairment, particularly in executive functions. Current experimental models reflect some of these aspects of VCID (Hainsworth et al. 2017) and are valuable for mechanistic, exploratory and therapeutic studies (Snyder et al. 2016). In vitro systems and transgenic rodent strains are useful for testing the molecular effects of genetic mutations, either as genetic risk factors (APOE knock-ins) or monogenic disease-relevant mutations (NOTCH3, COL4A1, APP). Larger species such as primates, sheep and pigs have more extensive white matter, amenable to imaging. Chronically hypertensive primates exhibit severe cognitive impairment, but lack pathological and radiological features of clinical SVD (Hainsworth et al. 2017). Primates subjected to global cerebral hypoperfusion (up to 28 days) exhibited diffuse white matter damage, microglial activation and fluid leakage (Hainsworth et al. 2017). Domestic pigs made diabetic by the toxin streptozotocin exhibited elevated circulating inflammatory markers, but no brain pathology. Transgenic large animals relevant to VCID have so far not been reported. We aim for preclinical platforms that report: molecular targets in VCID; behavioural measures relevant to VCID; pathological and radiological features of small vessel disease, especially within white matter.

Endothelial dysfunction and cerebral small-vessel disease in brains of older people.

Cerebral small vessel disease (SVD) affects deep penetrating arteries in subcortical white matter and deep grey nuclei, and is a frequent finding at autopsy in brains of older people. SVD is seen as fibrotic thickening of deep penetrating arteries (outer diameter <200 µm), with loss of mural cells and sparing of endothelial cells (Hainsworth et al. 2015). SVD is the underlying cause of most lacunar stroke events, silent focal infarcts and subcortical microbleeds, and is associated with diffuse white matter hyperintensities seen on T2-weighted MRI scans. Brain lesions due to SVD are a major cause of vascular contributions to cognitive impairment and dementia (VCID). In semi-quantitative neuropathological studies of human brain tissue we have examined vascular expression of diverse proteins related to endothelial dysfunction and SVD. We found the antithrombotic protein thrombomodulin localised to small artery endothelia, with more extensive expression in older people with SVD, relative to those without (p=0.012). The inflammation markers ICAM1 and IL-6 were rarely evident in endothelia, and appeared unrelated to SVD. The angiogenic receptor VEGFR2 was robustly expressed in vascular myocytes of small arteries of older people and also those with monogenic SVD (CADASIL), suggesting a role for VEGF signalling in small artery remodelling. The extent of VEGFR2 labelling increased with age (p=0.0026) but not with presence of SVD. The extent of vascular basement membrane collagen-IV, types α1-IV and α2-IV (encoded by COL4A1/COL4A2, genetically associated with SVD) in small arteries was negatively correlated with radiological SVD severity (Spearman's rho: -0.427, p=0.005). Neuropathological studies in human brain tissue yield valuable molecular data on SVD pathology. These are hypothesis-generating for testing of interventions in preclinical models, and future clinical trials. Reference: Hainsworth et al. 2015. Endothelial Cells and Human Cerebral Small Vessel Disease. Brain Pathol. 25;44.

Multiple Dural Arteriovenous Fistulas in the Superior Sagittal Sinus Region with Reversible Parkinsonism and Urinary Incontinence as Rare Presentations: A Case Report

Background: Dural Arteriovenous Fistula (DAVF), characterized by abnormally direct connections between meningeal arteries and meningeal veins or dural venous sinuses, is a rare subtype among the intracranial arteriovenous malformations. Although the clinical manifestations of DAVF are very variable depending on the locations and size of venous drainage, parkinsonism and urinary incontinence are rarely reported. Here, we present a rare case with parkinsonism and urinary incontinence secondary to DAVF. Case Presentation: A 50-year-old man was admitted for a progressively worsening weakness of his left lower limb over a year with urinary incontinence for four months. Neurological examination revealed rigidity and bradykinesia of the left upper limb without an obvious tremor. Magnetic resonance imaging exhibited diffuse white matter hyperintensities in bilateral centrum semiovale. Cranial magnetic resonance venography revealed extensive tortuous venous malformations. Digital subtraction angiography exhibited multiple bilaterally distributed DAVF in the superior sagittal sinus, supplied by bilateral occipital arteries and superficial temporal arteries. In the one year follow-up, the patient with multiple DAVF bilaterally distributed was completely cured after endovascular treatment according to the symptoms and the follow-up imaging results. Conclusion: This report enriches the clinical presentations of DAVF with parkinsonism and urinary incontinence, which is a crucial diagnostic clue to be aware of the possibility. Moreover, these rare symptoms can be relieved by timely endovascular treatment.

Spectrum of Neuroimaging Abnormalities in Brain in Patients of Acute-on-Chronic Liver Failure

Acute-on-chronic liver failure (ACLF) is associated with high short-term mortality. There is a paucity of data about the spectrum of neuroimaging abnormalities in the brain in ACLF patients. The present study was aimed to study the prevalence of cerebral edema and other parenchymal changes in MR imaging of the brain in patients with ACLF. In this prospective observational study, MR imaging was done in patients with ACLF (n= 41), and findings were compared with age and sex-matched patients with acute decompensation (AD) (n= 13) and those with cirrhosis but without any decompensation at recruitment (n= 21). Forty-one patients with ACLF (24.4% Grade 1 and Grade 2, 51.2% Grade 3) with 14 (34.1%) having cerebral failure were included in the study. T2-weighted (T2W) diffuse white matter hyperintensities (WMHs) and focal WMHs were seen in 17 (41.4%) and 7 (17%) patients, respectively. T1W basal ganglia hyperintensities in 20 (48.7%), cerebral microbleeds (CMBs) in 6 (14.6%), and 2 (4.8%) patients had cerebral edema. In patients with AD, T2W diffuse WMHs were seen in 3 (23%), T2W focal WMHs in 3 (23%) patients. None of the patients with AD had cerebral edema or CMBs. In compensated cirrhosis patients, T2W diffuse WMHs were present in 7 (33.3%), T2W focal WMHs in 5 (23.8%), while 3 (14.2%) patients had CMBs. T1 weighted hyperintensities in basal ganglia were more common in AD [9 (69.2%)] and compensated cirrhosis [15 (71.4%)] as compared to ACLF patients [20 (48.7%)], P= 0.174. The survival time of 30and 90 days for patients with diffuse T2W WMHs was significantly lesser than patients without T2W WMHs (P=0.007). Cerebral edema is uncommon in ACLF patients, and T2-weighted diffuse white matter hyperintensities may be associated with worse outcomes. However, due to the limited scope of the present study, the same needs to be explored further in larger cohorts.

Teaching NeuroImage: Increasing SPECTations for Ictal SPECT in Epilepsy Surgical Evaluation

We report a 15-year-old boy with chromosome 19p13.3 microdeletion, intellectual disability, colobomas, and drug-resistant epilepsy. He had near daily seizures characterized by eyelid fluttering, behavioral arrest, and unawareness with occasional progression to generalized tonic activity. Brain MRI showed diffuse white matter hyperintensities with a predilection for subcortical U-fibers. Video-EEG monitoring showed multifocal interictal discharges but a consistent ictal onset grossly in the left posterior temporal and occipital regions but with up to 10 seconds of electroclinical delay. Brain PET was unremarkable, but ictal SPECT (figures 1 and 2) revealed a discrete functional lesion in the left ventral occipital cortex. Here, ictal SPECT delineated the 3D borders of the seizure onset zone in the deep occipital cortex. This information can be used to further refine the epileptogenic zone (EZ) in a targeted stereo-EEG investigation to optimize surgical outcome1 and decrease SUDEP risk.2

The pattern of FP-CIT PET in pure white matter hyperintensities–related vascular parkinsonism

ObjectivesTo determine whether vascular parkinsonism (VaP) patients with visually normal dopamine transporter (DAT) scans have presynaptic dopaminergic depletion. MethodsWe enrolled 23 VaP patients who had parkinsonism, relevant diffuse subcortical white matter hyperintensities (WMH), and visually normal DAT scans, 23 Parkinson's disease (PD) patients, and 31 control subjects. By quantitatively analyzing 18F–N-(3-fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane (18F-FP-CIT) positron emission tomography, we compared the pattern of striatal DAT availability among groups. The discriminatory power of striatal DAT availability to differentiate VaP patients from control subjects or PD patients was assessed using receiver operating characteristics (ROC) analyses. Additionally, correlation analysis was performed to determine whether WMH severity or Unified Parkinson Disease Rating Scale Part III (UPDRS-III) score is related to presynaptic dopaminergic depletion in VaP. ResultsVaP patients exhibited decreased DAT availability in all striatal subregions, including posterior putamen, compared to control subjects. VaP patients and control subjects had similar patterns of anteroposterior and ventrodorsal DAT gradients in caudate and putamen level, but VaP patients exhibited significantly different patterns at putamen level, relative to PD patients. The severity of periventricular WMH was significantly correlated with all substriatal DAT availability in VaP, but not with UPDRS-III scores. The ROC analysis showed that DAT availability in caudate and posterior putamen had a fair discriminatory power when differentiating VaP patients from control subjects. ConclusionsThis study demonstrates that VaP patients with WMH exhibited diffusely decreased DAT availability without any specific regional gradients of DAT patterns distinct from either control subjects or PD patients.

Symptomatic cerebrospinal fluid escape.

: Cerebrospinal fluid (CSF) viral escape is defined by detectable HIV-RNA in CSF despite undetectable or lower-than-CSF level in plasma of patients receiving combination antiretroviral therapy (cART). This condition may occasionally be associated with neurological problems, consisting of new and progressive cognitive decline and/or focal symptoms and signs, defining the 'symptomatic CSF escape'. Brain MRI usually shows diffuse white matter hyperintensities that recall the presentation of HIV encephalopathy in the precART era. However, patients develop symptomatic CSF escape with relatively high CD4 cell counts and suppressed or low systemic virus replication. In addition, the frequent CSF pleocytosis and the pathological demonstration of CD8 T-cell brain infiltrates in some cases of symptomatic escape indicate that inflammation is an important component in the pathogenesis of this condition. Low nadir CD4 cells are common, likely reflecting the establishment of a HIV reservoir in the central nervous system (CNS). CSF escape seems to result from reactivation of CNS infection when cART potency is lowered, because of low patient's adherence, drug resistance, or use of drug combinations that are poorly effective in the CNS and cART optimization is key to revert escape and neurological disease in the great majority of cases.

New insights in radiation-induced leukoencephalopathy: a prospective cross-sectional study.

Radiation-induced leukoencephalopathy (RIL) is the most threatening delayed complication of cerebral radiotherapy (RT) and remains roughly defined by cognitive dysfunction associated with diffuse FLAIR MRI white matter hyperintensities after brain irradiation. We documented clinical, neuropsychological, and radiological aspects of RI in order to refine diagnostic criteria. Patients referred to our center for deterioration in cognitive complaint at least 6months after completing a focal or whole brain RT underwent a systematic cross-sectional assessment including clinical examination, neuropsychological tests, and a standardized MRI protocol. Patients with progressive tumor were excluded. Forty patients were prospectively enrolled. Of these, 26 had received a focal RT, median dose of 53Gy (range 50 to 60), and 14 had received a whole brain RT, median dose of 30Gy. Cognitive complaints, gait apraxia, and urinary troubles were reported in 100, 67, and 38% of cases, respectively. On neuropsychological examination, patients displayed a global and severe cognitive decline through a subcortical frontal mode. The cognitive changes observed were not hippocampic, but related to executive dysfunction. On MRI, 68% of the patients had extensive FLAIR hyperintensities with anterior predominance, 87% had brain atrophy, and 21% had intraparenchymal cysts. T2*-weighted MRI showed small asignal areas in 53% of the patients. These abnormalities are evocative of cerebral small vessel disease. Fractional anisotropy in the corpus callosum correlated with the cognitive evaluation. No differentiation in terms of cognitive and MRI features could be made between patients treated with focal brain RT (glioma) and patients treated with WBRT (for brain metastases or PCNSL). RIL can be defined by clinical symptoms (subcortical frontal decline, gait apraxia, urinary incontinence) and MRI criteria (cortico-subcortical atrophy, spread FLAIR HI, T2* asignals). This condition mimics a diffuse progressive cerebral small vessel disease triggered by RT, independent of RT protocol.

15. Prevalence of cerebral edema and other structural changes in acute on chronic liver failure

Background and Aims: Acute on chronic liver failure (ACLF) is associated with high short-term mortality. There is paucity of data on prevalence of cerebral edema and other structural changes of brain in ACLF patients. Present prospective study was designed to study the prevalence of cerebral edema and other changes on MR imaging of brain in patients with ACLF. Methods: In this prospective study from July 2016 to December 2017, we included patients with ACLF, acute decompensation (AD) and compensated cirrhosis. Study patients underwent MRI brain and findings were evaluated. Results: A total of 75 patients, ACLF (n = 41), AD (n = 21) and compensated cirrhosis (n = 14) were included. In ACLF patients T2W diffuse white matter hyperintensities (WMHs) were seen in 17 (41.4%), T2W focal WMHs in 7 (17%), T1W basal ganglia hyperintensities in 20 (48.7%), cerebral microbleeds (CMBs) in 6 (14.6%) and 2 (4.8%) patients had cerebral edema. In AD patients T2W diffuse WMHs seen in 3 (23%), T2W focal WMHs in 3 (23%), T1W basal ganglia hyperintensities in 9 (69.2%). while no patients had cerebral edema or CMBs. In compensated cirrhosis T2W diffuse WMHs seen in 7 (33.3%), T2W focal WMHs in 5 (23.8%), T1W basal ganglia hyperintensities in 15 (71.4%), 2 (11.8%) patients had CMBs. MR spectroscopy was done in total 32 patients, but changes were not significant among ACLF, AD and CLD patients. 30 and 90 days survival for patients with diffuse T2W WMHs was significantly lesser than patients without T2W WMHs (P = 0.007). Conclusions: Cerebral edema is uncommon in ACLF patients. T2 weighted diffuse white matter hyperintensities may have prognostic value in acute on chronic liver failure patients. The authors have none to declare.

Systematic Review of Cysteine-Sparing NOTCH3 Missense Mutations in Patients with Clinical Suspicion of CADASIL.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by mutations in the NOTCH3 gene, affecting the number of cysteines in the extracellular domain of the receptor, causing protein misfolding and receptor aggregation. The pathogenic role of cysteine-sparing NOTCH3 missense mutations in patients with typical clinical CADASIL syndrome is unknown. The aim of this article is to describe these mutations to clarify if any could be potentially pathogenic. Articles on cysteine-sparing NOTCH3 missense mutations in patients with clinical suspicion of CADASIL were reviewed. Mutations were considered potentially pathogenic if patients had: (a) typical clinical CADASIL syndrome; (b) diffuse white matter hyperintensities; (c) the 33 NOTCH3 exons analyzed; (d) mutations that were not polymorphisms; and (e) Granular osmiophilic material (GOM) deposits in the skin biopsy. Twenty-five different mutations were listed. Four fulfill the above criteria: p.R61W; p.R75P; p.D80G; and p.R213K. Patients carrying these mutations had typical clinical CADASIL syndrome and diffuse white matter hyperintensities, mostly without anterior temporal pole involvement. Cysteine-sparing NOTCH3 missense mutations are associated with typical clinical CADASIL syndrome and typical magnetic resonance imaging (MRI) findings, although with less involvement of the anterior temporal lobe. Hence, these mutations should be further studied to confirm their pathological role in CADASIL.

A novel frameshift mutation in two siblings with merosin-deficient congenital muscular dystrophy

Introduction: Merosin-deficient congenital muscular dystrophy (MDC1A #607855) is an autosomal recessive disorder characterized by muscle weakness and hypotonia at birth that due to mutations in the laminin α2 (LAMA2) gene mapped to the 6q22-23 chromosomal location. Case reports: We present two siblings with elevated serum creatine kinase level, delayed motor milestones, muscle weakness and contractures of the lower limbs. The older sibling was 3 years old. She had proximal muscle weakness power of grade 3/5. Her deep tendon reflexes were absent. She had contractures on her lower limbs. Her intellectual and speech development was normal. The electromyogram showed a myopathic process. We suspected the diagnose of MDC1A and magnetic resonance imaging (MRI) revealed diffuse white matter hyperintensity supporting the diagnose. Immunohistochemical studies on the muscle biopsy showed dystrophic pattern and a completely negative reaction for merosin. The 20 months old patient was the younger sister of the first case. She had similar clinical features like her sister. Sequencing of two siblings revealed a novel homozygous frameshift mutation p.N55Mfs*16 (c.163_163delA) within the LAMA2 gene. Discussion: This mutation is leading to a premature stop codon and no reported in the literatüre. This study emphasize that in individual with congenital hypotonia, muscle weakness, elevated serum creatine kinase level and white matter abnormalities MDC1A should be kept in mind.

Delayed leukoencephalopathy of non-small cell lung cancer patients with brain metastases underwent whole brain radiation therapy.

To explore the incidence, MR imaging findings, dynamic developing process of delayed leukoencephalopathy (DLE) in non-small cell lung cancer (NSCLC) patients with brain metastases patients who undergone whole brain radiation (WBRT) therapy, we retrospectively reviewed 48 NSCLC patients who underwent WBRT for brain metastases from January 2010 through June 2015 and had evaluable magnetic resonance imaging after treatment. The DLE were graded using a scale to evaluate T2-FLAIR (fluid attenuated image recovery) images: grade 1 = little or no white matter hyperintensity, grade 2 = limited periventricular hyperintensity and grade 3 = diffuse white matter hyperintensity. 48 NSCLC patients with brain metastases were enrolled. The median age of these patients was 55.7 years (range 33-75 years). The median follow-up was 12 months. The characteristic MR imaging of DLE in those patients was bilaterally diffuse white matter T2 hyperintensity around the periventricular areas without enhancement, sparing from U-fiber, callosum and gray matter structure. The incidence of DLE developed 6.25% (3/48), 30.00% (12/40), 48.39% (15/31), 61.90% (13/21), 85.71% (6/7), 100% (3/3) in those patients who were followed up for 3, 6, 9, 12, 24, 36 months, respectively. Through increased understanding of it, it may be possible to help clinicians develop further therapeutic strategies to maximize benefit while limiting potential long term toxicities. These data supplement existing reports regarding the late effects of WBRT in NSCLC patients with brain metastasis.

Atypical vanishing white matter disease with microcephaly and hepatosplenomegaly provoked after diphtheria pertussis tetanus vaccination

Vanishing white matter (VWM) disease is a rare leukoencephalopathy. Normal development in early childhood with regression of milestones after trauma or infection is typical clinical presentation. We are reporting a child with atypical VWM disease. A 1.5-year-old female child presented with fever followed by altered sensorium and convulsions following first booster dose of diphtheria pertussis tetanus vaccination. Her development was normal till 1 yr of age. Her weight and head size were below 3 standard deviations. She had hepatosplenomegaly. Her routine investigations including cerebrospinal fluid examination were normal. Magnetic resonance imaging (MRI) of brain shows diffuse white matter signals changes (hyperintensity on T2-weighted and hypointensity on T1-weighted images) involving the subcortical “U” fibers sparing basal ganglia. MRI shows diffuse white matter hyperintensity on T2-weighted images with areas of low signal on fluid-attenuated inversion recovery, close to the signal of cerebrospinal fluid. Based on MRI findings we diagnosed as VWM disease.