White Matter Hypodensity Research Articles

Posterior reversible encephalopathy syndrome as the initial presentation of acute lymphoblastic leukaemia

Posterior reversible encephalopathy syndrome (PRES) is a recognized complication of chemotherapy. However, the development of PRES at presentation of acute lymphoblastic leukemia (ALL) is rare. Here we discuss the uncommon presenting feature of PRES in ALL, and its progression with chemotherapy. A 13-year-old Malay male presented with a one-week history of blurred vision and headache associated with hypertension, hyperkalemia and acute renal failure. CT brain imaging showed symmetrical and bilateral white matter hypodensities at the parietal regions. Brain MRI on T2 and FLAIR images showed patchy areas of high signal intensity at cortical and subcortical region of both parietal and occipital lobes, consistent with PRES. He developed bicytopenia and bone marrow biopsy confirmed pre-B acute lymphoblastic leukemia. He received Phase 1 induction chemotherapy according to the modified UKALL XII protocol but in view of PRES, L-asparaginase and intrathecal methotrexate were delayed until after Day 17 of chemotherapy. No neurological symptoms were observed after chemotherapy. However, during Phase 2 induction chemotherapy with high dose cytarabine and intrathecal methotrexate, he developed accelerated hypertension and status epilepticus requiring mechanical ventilation. Cerebrospinal fluid analysis did not show infection or leukemic infiltration. A repeat brain MRI showed worsening features of the pre-existing PRES, followed by partial resolution on Day 37 of chemotherapy. Subsequent cytotoxic chemotherapies were uneventful except for radiological deterioration of PRES with partial resolution upon hematological recovery. It is important to consider the diagnosis of PRES in a young patient presenting with acute onset of headache and visual disturbances even before the initiation of cytotoxic chemotherapy. In view of the pre-existing PRES, there are risks of further neurological damage and fatal neurological squeal by introducing chemotherapy to treat the leukemia. Therefore it is vital to recognize and treat PRES promptly as early intervention may prevent or reverse the development of encephalopathy.

Reversible Posterior Leucoencephalopathy Syndrome Following Duloxetine: A Case Report and Review of Literature

Reversible Posterior Leucoencephalopathy Syndrome (RPLS) is a disorder characterized by headaches, confusion, and/or decreased level of consciousness, seizures, and visual changes. A 58-year-old female was found unresponsive, with generalized rigidity and urinary incontinence for unknown duration. On presentation, she was febrile, tachycardic, tachypneic, and hypertensive. Neurological exam showed increased muscle tone and brisk deep tendon reflexes. Brain MRI revealed gyriform edema and white matter hypodensities in parieto-occipital regions consistent with RPLS. Discontinuation of duloxetine, one of her home medications, led to resolution of symptoms. We report this case to discuss the syndrome of RPLS and propose the role of duloxetine in causing hypertension and cerebral vasoconstriction leading to RPLS. To our knowledge, this is the first reported case of RPLS resulting from the use of duloxetine. doi:10.4021/jmc98w

Striatal Hypodensities, Not White Matter Hypodensities on CT, Are Associated with Late-Onset Depression in Alzheimer's Disease

This study examined whether there were neuroanatomical differences evident on CT scans of individuals with dementia who differed on depression history. Neuroanatomical variables consisted of visual ratings of frontal lobe deep white matter, subcortical white matter, and subcortical gray matter hypodensities in the CT scans of 182 individuals from the Study of Dementia in Swedish Twins who were diagnosed with dementia and had information on depression history. Compared to individuals with Alzheimer's disease and no depression, individuals with Alzheimer's disease and late-onset depression (first depressive episode at age 60 or over) had a greater number of striatal hypodensities (gray matter hypodensities in the caudate nucleus and lentiform nucleus). There were no significant differences in frontal lobe deep white matter or subcortical white matter. These findings suggest that late-onset depression may be a process that is distinct from the neurodegenerative changes caused by Alzheimer's disease.

Novel mutation in ATP-binding domain of ABCD1 gene in adrenoleucodystrophy

gene in Indian population. The diagnosis was basedon clinical symptoms, substantial increase in plasma, verylong-chain fatty acids and typical MRI pattern. MRI of thepatient showed peritrigonal and cerebellar semioval whitematter hypodensities and hyperintense areas (T2/fluid atten-uated inversion recovery) in bilateral cerebral white mat-ter, predominantly in parieto–occipital region. The molecu-lar analysis by direct sequencing of the

Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy

To identify and compare clinical and neuroimaging predictors of primary lobar intracerebral hemorrhage (ICH) recurrence, assessing their relative contributions to recurrent ICH. Subjects were consecutive survivors of primary ICH drawn from a single-center prospective cohort study. Baseline clinical, imaging, and laboratory data were collected. Survivors were followed prospectively for recurrent ICH and intercurrent aspirin and warfarin use, including duration of exposure. Cox proportional hazards models were used to identify predictors of recurrence stratified by ICH location, with aspirin and warfarin exposures as time-dependent variables adjusting for potential confounders. A total of 104 primary lobar ICH survivors were enrolled. Recurrence of lobar ICH was associated with previous ICH before index event (hazard ratio [HR] 7.7, 95% confidence interval [CI] 1.4-15.7), number of lobar microbleeds (HR 2.93 with 2-4 microbleeds present, 95% CI 1.3-4.0; HR = 4.12 when >or=5 microbleeds present, 95% CI 1.6-9.3), and presence of CT-defined white matter hypodensity in the posterior region (HR 4.11, 95% CI 1.01-12.2). Although aspirin after ICH was not associated with lobar ICH recurrence in univariate analyses, in multivariate analyses adjusting for baseline clinical predictors, it independently increased the risk of ICH recurrence (HR 3.95, 95% CI 1.6-8.3, p = 0.021). Recurrence of lobar ICH is associated with previous microbleeds or macrobleeds and posterior CT white matter hypodensity, which may be markers of severity for underlying cerebral amyloid angiopathy. Use of an antiplatelet agent following lobar ICH may also increase recurrence risk.

Ammonia toxicity to the brain: Effects on creatine metabolism and transport and protective roles of creatine

Hyperammonemia can provoke irreversible damage to the developing brain, with the formation of cortical atrophy, ventricular enlargement, demyelination or gray and white matter hypodensities. Among the various pathogenic mechanisms involved, alterations in cerebral energy have been demonstrated. In particular, we could show that ammonia exposure generates a secondary deficiency in creatine in brain cells, by altering the brain expression and activity of the genes allowing creatine synthesis (AGAT and GAMT) and transport (SLC6A8). On the other hand, it is known that creatine administration can exert protective effects in various neurodegenerative processes. We could also show that creatine co-treatment under ammonia exposure can protect developing brain cells from some of the deleterious effects of ammonia, in particular axonal growth impairment. This article focuses on the effects of ammonia exposure on creatine metabolism and transport in developing brain cells, and on the potential neuroprotective properties of creatine in the brain exposed to ammonium.

CNTF protects oligodendrocytes from ammonia toxicity: Intracellular signaling pathways involved

In pediatric patients, hyperammonemia can provoke irreversible damages to developing CNS like cortical atrophy, ventricular enlargement, demyelination or gray and white matter hypodensities which are concordant with alterations of neurons and oligodendrocytes. Cerebral injury triggers endogenous protective mechanisms that can prevent or limit brain damage. Understanding these mechanisms may lead to new therapeutic strategies. We investigated whether ciliary neurotrophic factor (CNTF), a cytokine-like protein expressed by astrocytes and described as an injury-associated survival factor, was up-regulated by ammonia in developing reaggregated 3D brain cell cultures. We showed that CNTF is up-regulated by ammonia exposure, through mediation of p38 MAPK activation in astrocytes. We also observed that SAPK/JNK and Erk1/2 activations in oligodendrocytes and neurons, respectively, also play indirect roles in CNTF synthesis by astrocytes. Co-treatment with exogenous CNTF demonstrated strong protective effects on oligodendrocytes, but not on neurons, against ammonia toxicity. These protective effects involved JAK/STAT, SAPK/JNK and c-jun proteins.

Leucoencéphalopathie post-anoxique d’apparition retardée

The onset of post-anoxic encephalopathies can be delayed after the acute hypoxic injury. We present the case of a 45-year-old woman who achieved complete recovery from an episode of hypoxia related to a suicide attempt (ingestion of benzodiazepine). Three weeks later she developed a confusional state with akinetic mutism and parkinsonism. Brain CT-scan showed bilateral hemispheric white matter hypodensities. MRI showed extensive bilateral hyperintensities on T2-weighted and Flair sequences within the hemispheric white matter and the globus pallidus. EEG showed diffuse slow activity. All investigations for leukodystrophies were negative. Brain biopsy showed normal cortex and widespread demyelination with axonal sparing in the underlying white matter. The patient experienced a partial clinical recovery. The clinical course and the results of paraclinic investigations were consistent with the diagnosis of delayed post-anoxic leukoencephalopathy.

Biochemical mechanisms of cyclosporine neurotoxicity.

Proper management of chemotoxicity in transplant patients requires detailed knowledge of the biochemical mechanisms underlying immunosuppressant toxicity. Neurotoxicity is one of the most significant clinical side effects of the immunosuppressive undecapeptide cyclosporine, occurring at some degree in up to 60% of transplant patients. The clinical symptoms of cyclosporine-mediated neurotoxicity consist of decreased responsiveness, hallucinations, delusions, seizures, cortical blindness, and stroke-like episodes that mimic those clinical symptoms of mitochondrial encephalopathy. Clinical computed tomography (CT) and magnetic resonance imaging (MRI) studies have revealed a correlation between clinical symptoms of cyclosporine-mediated neurotoxicity and morphological changes in the brain, such as hypodensity of white matter, cerebral edema, metabolic encephalopathy, and hypoxic damages. Paradoxically, in animal models cyclosporine protects the brain from ischemia-reperfusion (I/R) injury. Interestingly, cyclosporine appears to mediate both neurotoxicity (under normoxic conditions) and I/R protection across the same range of drug concentration. Both toxicity and protection might arise from the intersection of cyclosporine with mitochondrial energy metabolism. This review addresses basic biochemical mechanisms of: 1) cyclosporine toxicity in normoxic brain, and 2) its protective effects in the same organ during I/R. The marked and unparallel potential of magnetic resonance spectroscopy (MRS) as a novel quantitative approach to evaluate metabolic drug toxicity is described.

Role of cerebral computerised tomography scans in eclampsia

Eclampsia although a rare occurrence still accounts for a large proportion of maternal deaths worldwide due mainly to intracerebral events. The role of computerised tomography (CT) scans in the detection of cerebral oedema haemorrhage or infarcts both for diagnosis and prognosis is controversial. Moodley et al. (1993) found that the most common CT scan findings associated with eclampsia were transient reversible subcortical white matter hypodensities indicative of oedema and in the absence of clinical signs of central nervous system (CNS) pathology did not alter management. Drislane and Wang (1997) however reported that CT abnormalities in eclamptics were not always benign and reversible and preceded long-term neurological sequelae. In settings in which intensive care unit (ICU) beds are limited a common practice is for the critical care specialist to request a CT scan before ventilation to exclude major intracranial haemorrhage. The aim of our study was to ascertain the impact of the timing of CT scans in cases of complicated eclampsia on management and outcome. (excerpt)

Developmental milestones of vertically HIV infected and seroreverters children: follow up of 83 children.

The aim of the study was to detect neurological abnormalities in human immunodeficiency virus (HIV) infected children. This was achieved by a prospective evaluation, from November/1995 to April/2000, of 43 HIV infected children (group I) and 40 HIV seroreverters children (group II) through neurological exam and neurodevelopmental tests: Denver Developmental Screening Test (DDST) and Clinical Adaptive Test/Clinical Linguistic and Auditory Milestone Scale (CAT/CLAMS). A control group (III), of 67 children, were evaluated by CAT/CLAMS. Hyperactivity, irritability and hypotonia were the findings on neurological examination, without statistical differences between group I and II. On CAT/CLAMS, the group I developmental quotient (DQ) was significantly lower than the other groups. The same occurred in DDST, with group I presenting significantly more failures than group II. Nineteen HIV children of group I had brain computed tomographic scan, with abnormalities in three of them (basal ganglia calcification, white matter hypodensity and asymmetry of lateral ventricles). We conclude that in HIV infected children a neurodevelopment delay occur early in the disease, and it can be detected by screening tests.

Risk factors for cerebral hypoperfusion, mild cognitive impairment, and dementia

Putative risk factors accelerating mild cognitive decline and dementia were correlated with repeated measures of cerebral atrophy, CT, densitometry, perfusions, and cognitive testing among neurologically and cognitively normative aging volunteers. A total of 224 normative subjects at increased risk for cognitive decline were admitted to the study. Mean entry age was 59.5 ± 15.8 years. Mean follow-up is 5.8 ± 3.3 years. At follow-up, 22 developed mild cognitive impairment (41 CCSE ≥ −3), 19 became demented—8 with Vascular type (VAD), 11 with Alzheimer’s type (DAT)—and 183 remain cognitively unchanged. Cerebral atrophy, tissue densities, and perfusions were measured by Xe-CT. After age 60, cerebral atrophy, ventricular enlargement, and polio- and leuko-araiosis geometrically increased as perfusions declined. Risk factors accelerating perfusional decline, cerebral atrophy, polio-araiosis, and leuko-araiosis were: transient ischemic attacks (TIAs), hypertension, smoking, hyperlipidemia, and male gender. At age 71.5 ± 11.9, mild cognitive impairment began accelerated by TIAs, hypertension and heart disease. Leuko-araiosis began before cognitive decline. TIAs, hypertension, and hyperlipidemia correlated with VAD. Excessive cortical perfusional decrease, gray and white matter hypodensities, and cerebral atrophy correlate with cognitive decline.

Laminin- α2 (merosin), β-dystroglycan, α-sarcoglycan (adhalin), and dystrophin expression in congenital muscular dystrophies: An immunohistochemical study

Muscle biopsies of 13 congenital muscular dystrophy (CMD) patients were investigated for the expression of laminin- α 2 (merosin), β-dystroglycan, α-sarcoglycan (adhalin) and dystrophin. Expression of these proteins was normal in six out of eight patients with pure-CMD, in three non-Japanese patients clinically resembling Fukuyama-CMD (F-CMD), and in two patients with Walker–Warburg syndrome (WWS). The two ‘pure’-CMD patients with white matter hypodensity showed severely decreased laminin- α 2 expression and normal expression of the other proteins. Our findings in the non-Japanese patients, clinically resembling F-CMD, are different from those in Japanese cases with F-CMD in the literature. Consequently, our patients suffer from WWS or from another yet undetermined form of CMD.

Brain computerized tomography after hyperbaric oxygen therapy for carbon monoxide poisoning: Pracyk JB, Stolp BW, Fife CE, et al. Undersea and Hyperbaric Medicine, 1995; 22(1):1–7

The role of brain computerized tomography (CT) imaging in predicting clinical outcome was investigated in patients receiving hyperbaric oxygen therapy for serious carbon monoxide (CO) poisoning. From a series of 48 consecutive patients suffering loss of consciousness from CO exposures, the records of 40 selected patients were evaluated to determine how their CT findings correlated with clinical outcome. A neuroradiologist blinded to patient outcome confirmed the radiographic findings. CT abnormalities consisted of globus pallidus hypodensities (nine patients), subcortical white matter hypodensities (four), cerebral cortical lesions (one), cerebral edema (one), hippocampal lesions (one), and complete loss of gray-white differentiation (one). Of the patients with globus pallidus lesions, 44% manifested incomplete recovery, whereas white matter lesions reflected a 74% incidence of morbidity. Age, duration of CO exposure, and interval between CO exposure and treatment did not significantly relate to clinical outcome. The blood carboxyhemoglobin levels correlated with clinical prognosis (P < 0.05) and, importantly, CT results significantly predicted clinical outcome (P < 0.05). A normal scan correlated highly with a complete recovery, whereas an abnormal scan predicted incomplete recovery or death, despite prior HBO therapy. The current study establishes prognostic validity for brain CT imaging for evaluating clinical outcome after HBO therapy for CO poisoning.

Congenital muscular dystrophy with cerebral white matter hypodensity. Correlation of clinical features and merosin deficiency

We report clinical and pathological findings in 9 children affected by congenital muscular dystrophy with normal or borderline intelligence and hypodensity of cerebral white matter (CMD-HWM), also frequently called ‘occidental or western form of cerebro-muscular dystrophy’ (OCMD). Our patients have uniform, distinct, clinical presentation that includes: normal or subnormal intelligence, severe, slowly progressive motor disability, high rate of facial involvement and dysmorphic aspect, increased creatine kinase levels and variable degrees of abnormal, radiographic, cerebral white matter pattern. By comparing our cases with previous reports we suggest that this subtype of CMD is not uncommon in Brazil and it is represented by a particularly severe and homogeneous clinical picture with important motor disability. The immunohistochemical staining for merosin, performed on the muscle biopsy of 6 among 9 patients, showed that all are merosin negative.

White matter abnormalities in congenital muscular dystrophy

Central nervous system (CNS) characteristics were examined in seventeen patients with autosomal recessive classic or “pure” congenital muscular dystrophy (CMD). In three patients, neuroradiological examination (CT/MRI) indicated hypodense white matter areas. Two out of these three patients had epilepsy (seizures and epileptic discharges on their EEG). Only two of the remaining patients had epileptic EEG discharges, but without clinical seizures. By comparing our results to data in the literature, we could conclude that the classic or “pure” form of CMD can be subdivided into two subtypes, i.e. those with and those without white matter hypodensities. A mild form of epilepsy or an epileptic predisposition on EEG can be part of the subtype with white matter hypodensities.

Divergence of Central Nervous System Involvement in 2 Italian Sisters with Congenital Muscular Dystrophy: A Clinical and Neuroradiological Follow-Up

We report the clinical and neuroradiological follow-up of 2 Italian sisters, 10 and 6 years of age, affected by congenital muscular dystrophy (CMD) with divergent CNS involvement. In both, CMD was diagnosed by finding dystrophic alterations in muscle biopsy and muscular deficit at birth. The elder sister suffered also from marked intellectual deficit and epilepsy, as usually reported in children with Fukuyama CMD. In the same patient, at 2 years of age, CT scan showed severe hypodensity of cerebral white matter and severe ventricular dilatation of occipital horns. At 8 years of age, MRI also showed clearcut pachygyria mainly in the parietal and occipital lobes. MRI and CT scan at the same age showed improvement of the leukoencephalopathy and unchanged ventricular dilatation, as reported for patients with Fukuyama CMD. Unlike Japanese cases, however, she showed no progression in her muscular deficit and her muscle immunostaining of laminin M chain (merosin) was normal. The younger sister had normal mental development, never experienced epileptic fits and had always normal EEG. However, as often seen in classical CMD, her CT scan showed moderate hypomyelination of cerebral white matter and mild dilatation of lateral ventricles. MRI did not show any other brain abnormalities. Sequential CT scan at 2, 4 and 6 years of age showed improvement of the leukoencephalopathy. Her muscular deficit had a stationary clinical course. Her immunostaining of muscle merosin was moderately reduced. The finding of Fukuyama-like and classical CMD in 2 sisters indicates the possibility that different forms of CMD may be different expressions of the same genetic disease.

Callosal atrophy in patients with lacunar infarction and extensive leukoaraiosis. An indicator of cognitive impairment.

It is unclear why only some patients with lacunar infarction and radiological evidence of diffuse white matter abnormalities have dementia. The purpose of this study is to investigate the value of callosal atrophy as an indicator of cognitive impairment. We used magnetic resonance imaging to evaluate 11 right-handed male patients with lacunar infarction and extensive white matter hypodensities on computed tomography (8 with dementia and 3 without dementia). The midsagittal corpus callosum area on T1-weighted images was compared with the IQ determined by the Wechsler Adult Intelligence Scale. The relation between these parameters and cerebral oxygen metabolism measured with positron emission tomography was also evaluated in the 8 patients with dementia. All patients showed diffuse high-intensity areas in the bilateral hemispheric white matter on T2-weighted images. Compared with 19 age- and sex-matched right-handed normal control subjects, the patients had a significantly smaller callosal area. The severity of callosal atrophy, which varied from mild to severe, was significantly related to the total IQ. In the 8 demented patients, the total callosal area was significantly correlated with the mean level of oxygen metabolism in the cerebral white matter. In patients with lacunar infarction and diffuse white matter abnormalities, the presence of callosal atrophy may indicate cognitive impairment. Callosal atrophy may reflect the severity and extent of white matter damage associated with a decrease in oxygen metabolism, which may determine the severity of intellectual decline.

Analysis of "pure" congenital muscular dystrophies in thirty-eight cases. How different is the classical type 1 from the occidental type cerebromuscular dystrophy?

Congenital muscular dystrophies (CMD) are heterogenous in clinical and pathologic manifestations. The "pure" classical form includes cases without severe impairment of intellectual development (Type 1), and cases with normal or subnormal IQ which show white matter hypodensity on CT scan examination. This latter group is sometimes called the "occidental type cerebro-muscular dystrophy" (OCMD). In this study we report clinical and pathologic findings in 38 cases with pure CMD. Eighteen of them were classified as Type 1 and 20 as OCMD, following the neuroradiological work-up. Statistical analysis between the two groups were done for: age range, consanguinity, multiple joint contractures, maximal motor capacity, facial involvement, high CK, endomysial fibrosis, adiposis, fiber atrophy and necrosis. CK was significantly higher in the OCMD group. Though not statistically significant, multiple joint contractures and muscle fiber necrosis were seen in more OCMD patients. These parameters denoted severity. The results of electrophysiological tests did not show any statistical differences. In pure CMDs there is evidence for overlap between the two sub-groups. OCMD cases may tend to run a more severe course in the presence of significantly higher CK levels.

Magnetic resonance imaging in cerebrotendinous xanthomatosis: A prospective clinical and neuroradiological study

We describe MRI findings in 13 persons with typical clinical, EEG, CT and biochemical features of cerebrotendinous xanthomatosis (CTX). MRI showed brain ( 13 13 ) and cerebellar ( 12 13 ) atrophy and diffuse white matter hypodensity ( 4 13 ) presumably reflecting sterol infiltration with demyelination. Focal lesions were rare ( 2 13 ). Mass effect, edema or enhancement were not observed. Treatment with chenodeoxycholic acid (CDCA) 750 mg/day orally improved neurological and biochemical abnormalities. MRI appears to be of little value in following improvement after treatment has begun. Otherwise, the MRI studies are very sensitive and useful in diagnosing early incomplete forms of CTX.