Enfermedad carotídea aterosclerosa y enfermedad de sustancia blanca en sujetos sin historia de infarto cerebral o isquemia cerebral transitoria / Atherosclerotic Carotid Disease and White Matter Disease in Subjects Without a History of Cerebral Infarction or Transient Cerebral Ischemia

Resumen Introducción: La enfermedad carotídea aterosclerosa (ECA) es un factor de riesgo importante para enfermedad vascular cerebral. Objetivo: Analizar la asociación entre factores de riesgo vascular mayores con ECA y leucopatía cerebral en pacientes sin historia de ictus isquémico. Método: Se evaluaron factores de riesgo en sujetos con exploración de carótidas mediante ultrasonografía Doppler dúplex. No se incluyeron casos con historia de infarto cerebral o ataque isquémico transitorio. Los sujetos contaron con resonancia magnética cerebral y se excluyeron aquellos con lesiones isquémicas de grandes vasos. Se construyeron modelos multivariable para la predicción de ECA, estenosis carotídea significativa, carga de ateromas y leucopatía cerebral. Resultados: Se estudiaron 145 sujetos (60.7 % mujeres, edad de 73 años). Se documentó ECA en 54.5 %, estenosis carotídea ≥ 50 % en 9 %, carga de placas de ateroma > 6 en 7.6 % y leucopatía periventricular o subcortical en 28.3 % (20.6 % tenían concurrentemente ECA y leucopatía). Los factores asociados independientemente con ECA fueron edad e hipertensión; con estenosis ≥ 50 %, hipertensión; con cargas de ateromas > 6 placas, edad; con leucopatía, edad, diabetes e hipertensión. La obesidad no se asoció con las variables independientes analizadas. Conclusiones: En los sujetos asintomáticos sin historia de ictus isquémico, la edad y la hipertensión fueron los factores de riesgo más importantes para enfermedad macrovascular. La diabetes mellitus se asoció con enfermedad microvascular. La obesidad por sí sola no fue un determinante mayor de ECA o leucopatía cerebral.

Abstract Introduction: Atherosclerotic carotid artery disease (CAD) is a major risk factor for cerebrovascular disease. Objective: To analyze the association of major vascular risk factors with atherosclerotic CAD and white matter disease (WMD) in patients without a history of ischemic stroke. Method: Risk factors were assessed with carotid examination using Doppler duplex ultrasound. Cases with a history cerebral infarction or transient ischemic attack were not included. Subjects had brain magnetic resonance imaging scans available and those with large-artery ischemic lesions were excluded. Multivariate models were constructed for the prediction of atherosclerotic CAD, significant carotid stenosis, atheroma burden and WMD. Results: One-hundred and forty-five subjects were assessed (60.7% were females, mean age was 73 years). Atherosclerotic CAD was documented in 54.5%, carotid stenosis ≥ 50% in 9.0%, > 6 atheroma plaques in 7.6%, and periventricular or subcortical WMD in 28.3% (20.6% had atherosclerotic CAD and WMD concurrently). Risk factors independently associated with atherosclerotic CAD were age and hypertension; hypertension was associated with ≥ 50% carotid stenosis; age was associated with > 6 atheroma plaques; and age, diabetes and hypertension were associated with WMD. Obesity was not associated with any of the analyzed independent variables. Conclusions: In asymptomatic subjects without a history of ischemic stroke, age and hypertension were the most important risk factors for macrovascular disease. Diabetes mellitus was associated with microvascular disease. Obesity alone was not a major determinant of CAD or WMD.

Asociación entre la mutación homocigota c.318A>T en el exón 2 del gen EIF2B5 y la forma infantil de la leucoencefalopatía con sustancia blanca evanescente / Association between homozygous c.318A>GT mutation in exon 2 of the EIF2B5 gene and the infantile form of vanishing white matter leukoencephalopathy

Resumen: Introducción: La leucoencefalopatía con sustancia blanca evanescente es una de las leucodistrofias más frecuentes. Generalmente inicia en la infancia y presenta un patrón de herencia autosómica recesiva. El 90% de los casos manifiesta mutaciones en uno de los genes que codifican para las cinco subunidades del factor de iniciación eucariótica 2 (EIF2B5). El diagnóstico se realiza por las manifestaciones clínicas, hallazgos en la resonancia magnética cerebral y estudios moleculares confirmatorios. Caso clínico: Paciente masculino de 13 meses con neurodesarrollo previo normal. Antecedente de internamiento por vómito, hipertermia, irritabilidad y rechazo a la vía oral de 15 días de evolución. Ante la exploración presentó perímetro cefálico y pares craneales normales. Se encontró hipotónico, con reflejos incrementados, sin datos meníngeos ni de cráneo hipertensivo. La tomografía de cráneo mostró hipodensidad generalizada de la sustancia blanca. Egresó sin recuperar deambulación. A los 15 días presentó somnolencia y crisis convulsivas focales después de traumatismo craneoencefálico. En la resonancia magnética se observó hipointensidad generalizada de sustancia blanca. Ante la sospecha de leucoencefalopatía con sustancia blanca evanescente, se solicitó la secuenciación del gen EIF2B5, que reportó mutación homocigota c.318A>T en el exón 2. El paciente requirió múltiples hospitalizaciones por hipertermia y descontrol de crisis convulsivas. Posteriormente mostró deterioro cognitivo, motor y pérdida de la agudeza visual. Falleció a los 6 años por neumonía severa. Conclusiones: Este caso contribuye a conocer el espectro de mutaciones que se presenta en pacientes mexicanos y permite ampliar el fenotipo asociado con esta mutación.

Abstract: Background: Vanishing white matter disease is one of the most frequent leukodystrophies in childhood with an autosomal recessive inheritance. A mutation in one of the genes encoding the five subunits of the eukaryotic initiation factor 2 (EIF2B5) is present in 90% of the cases. The diagnosis can be accomplished by the clinical and neuroradiological findings and molecular tests. Case report: We describe a thirteen-month-old male with previous normal neurodevelopment, who was hospitalized for vomiting, hyperthermia and irritability. On examination, cephalic perimeter and cranial pairs were normal. Hypotonia, increased muscle stretching reflexes, generalized white matter hypodensity on cranial tomography were found. Fifteen days after discharge, he suffered minor head trauma presenting drowsiness and focal seizures. Magnetic resonance showed generalized hypointensity of white matter. Vanishing white matter disease was suspected, and confirmed by sequencing of the EIF2B5 gene, revealing a homozygous c.318A> T mutation in exon 2. Subsequently, visual acuity was lost and cognitive and motor deterioration was evident. The patient died at six years of age due to severe pneumonia. Conclusions: This case contributes to the knowledge of the mutational spectrum present in Mexican patients and allows to extend the phenotype associated to this mutation.

The clinical and genetic features of a case with antenatal form of leukoencephalopathy with vanishing white matter disease / 临床儿科杂志

Objective To explore the clinical features and gene mutations of antenatal form leukoencephalopathy with vanishing white matter disease (VWM).Methods The clinical data and genetic test results in a patient with antenatal form of VWM were retrospectively analyzed.Results A three months old patient was admitted to our hospital with intermittent convulsions commenced from the first month after birth.The baby had low birth weight (1900g) and asphyxia at birth.Developmental retardation and cataracts in both eyes were found on physical examination,and the patient couldn't stare,gaze-following,be amused and raise his head.In addition,he showed hypermyotonia of both lower extremities.Diffused and symmetrical abnormal signals same as that of the cerebrospinal fluid in the cerebral white matter were observed by brain CT and MRI scanning,and the lesions were gradually enlarged.Moreover,a missense mutation (c.1016G＞A) and a frameshift mutation (c.1809delC) in EIF2B5 gene inherited from his parent were detected by DNA sequencing.Conclusions VWM is one of the most prevalently inherited childhood white matter disorders,but the case of antenatal form is very rare.The diagnosis should be based on clinical manifestations and EIF2B genetic analysis.To our knowledge,the frameshift mutation c.1809delC has never been reported to date.

Novel mutations identified in EIF2B5 gene in Kashmiri patients as susceptibility factor for multiple sclerosis.

White matter disease refers to a set of diseases that affect the white matter of the brain and all of which have different consequences on brain function. Most of the studies have shown that it results from the defects during protein synthesis, with the gene defects in EIF2B1–5, encoding the five subunits of eukaryotic translation initiation factor 2B (eIF2B) α, β, γ, δ and ε, respectively. eIF2B plays a crucial role in protein translation and its regulation under different conditions. The previous studies have shown that mutations in five subunits of eIF2B cause white matter disease of the brain and thus EIF2B is the main culprit in development of white matter disease. In this study, the mutational screening of EIF2B5 gene encoding eIF2Bε was performed for the first time in 12 Kashmiri patients, each having a unique white matter disease condition. We found two novel missense mutations in EIF2B5: c.580A>G, p.Thr194Ala and c.611C>T, p.Ala204Val among the patients with demyelinating disease (multiple sclerosis), but no mutation was found in other patients. In conclusion our study suggests involvement of the EIF2B5 gene in MS development, thus suggesting p.Thr194Ala to be a susceptibility factor for the development of multiple sclerosis.

Neurodevelopmental Outcomes of VLBW Infants with Diffuse Excessive High Signal Intensity (DEHSI) in the White Matter of the Brain MR Imaging around a Near Term-equivalent Age

PURPOSE: The aim of this study was to investigate the relationship between diffuse excessive high signal intensity (DEHSI) in the white matter of the brain MRI and neurodevelopmental abnormalities in VLBW infants. METHODS: The T1- and T2-weighted MR images of the brain around a near term-equivalent age in 167 VLBW infants were evaluated for the white matter lesions. The presence of DEHSI was determined and classified into four grades on the extent of DEHSI. The relationship between the grade of DEHSI and neurodevelopmental abnormalities was investigated in 94 infants who were assessed for neurodevelopmental outcomes by using a neurologic examination and neurodevelopmental assessment (BSID-II) at 18-24 months of corrected age. RESULTS: DEHSI was the most commonly observed white matter lesion (68.3%) in the MR imaging of the brain around a near term-equivalent age. Gestational age and birth weight tended to increase with increasing grade of DEHSI (P=0.060, P=0.001, respectively). There was no significant relationship between the grade of DEHSI and neurodevelopmental outcomes at 18??4 months of corrected age (P>0.05). Periventricular cysts and ventriculomegaly in the brain MRI were significant risk factors for neurodevelopmental abnormalities (P<0.05). CONCLUSION: DEHSI, most commonly seen in the white matter of the brain MRI around a near term-equivalent age in VLBW infants, did not seem to be related to the neurodevelopmental abnormalities at 18-24 months of corrected age.

Effect of Dexamethasone in the Development of O1 or O4 Immunoreactive Oligodendrocyte of the Neonatal Rat / 체질인류학회지

White matter disease (WMD) study, which underlies the subsequent progress of cerebral palsy as well as cognitive impairment of premature and/or low birth weight infants, has been focused either on the hypoxia-ischemia damage or cytokine-induced brain damage related with maternal or fetal inflammation. Also, dexamethasone (DEXA) may increase the risk of neuropsychological problem including adverse cognitive and behavioral outcome in preterm infants. Thus, we hypothesized that perinatal DEXA would damage and trigger the death of developing oligodendrocytes (OL) progenitors, and subsequently disturb myelination. In this study, DEXA was administered to neonatal rats for 3 consecutive days subcutaneously between postnatal day 1 (P1) and P3. By using immunofluorescent staining of stage specific OL progenitor markers such as O4 and O1, the morphological changes of OL progenitors were examined and the apoptosis of OL progenitors were visualized by TUNEL staining. Results depicted that relative number of O1 immunoreactive (IR) cells were less to that of O4 IR cells. Multipolar O1 IR cells with short dendritic processes were observed in both control and DEXA group at P3. In the total O1 immunoreactive cells, the relative percentages of apoptosis cells were calculated at P3 as 8.7% in control, 23.0% in DEXA group. The relative percentages of apoptosis in the total O4 immunoreactive cells were measured at P3 as 3.0% in control and 13.5% in DEXA group. OL progenitors' apoptosis may contribute to the overall reduction of immature OLs in cerebral white matter. Therefore, specific stages of OL maturation could clinically be an important factor in determining the susceptibility to DEXA. To elucidate the disease mechanism of the white matter disease, further investigation may be needed whether OL progenitors' decrease by the DEXA administration affects to the myelin formation as developmental stages.

Acute Marchiafava-Bignami Disease With Typical White Matter Involvement on Diffusion Weighted MRI

Marchiafava-Bignami disease (MBD) is characterized by cerebral white matter lesions associated with chronic alcoholism. Premortem diagnosis of MBD is usually based on history and clinical manifestations. We report a case of acute MBD in which diffusion-weighted MRI (DWI) showed high signal intensities along the white matter including the corpus callosum. DWI may be useful in premortem diagnosis of acute MBD.