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At least 19 recordsLinked to original sources
PubMed2003

MRI in methotrexate-related leukoencephalopathy: Disseminated necrotising leukoencephalopathy in comparison with mild leukoencephalopathy.

We report two fatal cases of methotrexate (MTX)-induced disseminated necrotising leukoencephalopathy (DNL) in which MRI was repeated from the onset. Initial T2-weighted images showed multiple areas of high signal, mainly in deep cerebral white matter, which on follow-up, spread and coalesced to involve the entire white matter. Small irregular low-signal foci on T2-weighted images were seen within the high-signal lesions. Multiple areas of contrast enhancement corresponded to these low-signal foci. The condition of both patients deteriorated and they died. We compared their MRI findings with those of seven patients with mild MTX-related leukoencephalopathy, six of whom were asymptomatic; one had transient neurological symptoms. They showed no contrast enhancement, but rather mild-to-moderate diffuse high signal in deep white matter, which later disappeared. These findings suggest that multiple low-signal foci on T2-weighted images with contrast enhancement may be characteristic of DNL, and that contrast-enhanced imaging is useful to differentiate this condition from mild leukoencephalopathy.

Adolescent↗
PubMed1994

Progressive multifocal leukoencephalopathy complicating Wiskott-Aldrich syndrome. Report of a case and review of the literature of progressive multifocal leukoencephalopathy with other inherited immunodeficiency states.

OBJECTIVE: To describe the occurrence of progressive multifocal leukoencephalopathy (PML) in association with Wiskott-Aldrich syndrome, an X-linked recessive disorder with impairment of both cellular and humoral immunity. DESIGN: A detailed analysis of this patient's clinical illness, immunologic factors, neuroradiographic findings, and brain histopathologic conditions was undertaken. The medical literature on PML complicating congenital immunodeficient states was also reviewed. SETTING: A 1500-bed, university-affiliated, public health hospital. PATIENT: A 15-year-old boy with Wiskott-Aldrich syndrome. His neurologic illness was heralded by dysarthria and right-sided weakness and the diagnosis was established by brain biopsy specimen. Survival from the time of onset of PML was 10 months. CONCLUSION: Although PML typically occurs in the setting of severe acquired cellular immunodeficiency, often as a consequence of acquired immunodeficiency syndrome, organ transplantation, and leukemia and lymphoma, it may rarely accompany inherited immunodeficiency syndromes. The reported childhood cases of PML include three patients, aged 5, 11, and 18 years, with other inherited immunodeficiency syndromes. This patient represents the first time (to our knowledge) that PML has been reported to occur in association with Wiskott-Aldrich syndrome.

Adolescent↗
PubMed2005

Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy.

HAART-induced immune restoration is beneficial for patients with AIDS-related progressive multifocal leukoencephalopathy (PML). However, in rare instances, an immune-reconstitution inflammatory syndrome (IRIS) may cause paradoxical clinical deterioration. We report the neuropathological study of an AIDS patient who presented with progressive cognitive deterioration; CD4(+) count was 117 and the HIV viral load >10(4); imaging showed non-enhancing lesions consistent with PML. Following initiation of HAART, CD4(+) was 300 and HIV viral load <10(3), but his neurological symptoms continued to deteriorate. Imaging revealed an increase in the size and number of lesions and enhancement of all the lesions. A stereotactic biopsy showed severe inflammatory and demyelinating lesions with marked infiltration by macrophages and T lymphocytes in the absence of a detectable infectious agent. Despite high doses of steroids, the patient died 3 months after admission. Autopsy showed two types of lesions: (1) active inflammatory PML changes with abundant JC virus, and intraparenchymal and perivascular infiltration by T lymphocytes, and (2) acute perivenous leukoencephalitis devoid of JC virus. Most lymphocytes were CD8(+) lymphocytes; CD4(+) lymphocytes were virtually absent. Two pathological reactions were associated with the paradoxical clinical deterioration related to dysregulation of the immune response characteristic of IRIS in PML: (1) an accentuation of JCV infection, and (2) a nonspecific acute perivenous leukoencephalitis. We suggest that both these types of lesions are due to an imbalance of CD8(+)/CD4(+) T cells, with massive infiltration of the cerebral parenchyma by CD8(+) cytotoxic T lymphocytes in the absence of sufficient CD4(+) response. Better understanding of the mechanisms of the IRIS may enable prevention or cure of this severe, sometimes fatal complication of HAART.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Increased frequency of JC virus type 2 and of dual infection with JC virus type 1 and 2 in Italian progressive multifocal leukoencephalopathy patients.

To verify the possibility of different role of JC virus genotypes in the etiology of progressive multifocal leukoencephalopathy, we analysed several JC virus isolates amplified from AIDS patients with and without progressive multifocal leukoencephalopathy and healthy controls by nucleotide sequencing. Cerebrospinal fluid (CSF), peripheral blood mononuclear cells (PBMCs) and urine from 52 AIDS patients suffering from various neurological diseases including 21 cases of progressive multifocal leukoencephalopathy, and PBMCs and urine from healthy subjects were evaluated by nested polymerase chain reaction (PCR) for the presence of DNA belonging to the highly conserved large T antigen (LT) of JC virus. The different JC virus subtypes were identified by nucleotide sequence analysis of the virion protein (VP1) genomic region. JC virus DNA was detected in all the CSF samples from the progressive multifocal leukoencephalopathy patients, but not in the CSF from non-progressive multifocal leukoencephalopathy cases, while the frequency of JC virus DNA detection in the PBMCs and urine did not differ among the three groups studied. JC virus type 2 was detected only in progressive multifocal leukoencephalopathy patients, and in particular in 52.4% of their CSF samples. Moreover, in the CSF of 19.0% of the progressive multifocal leukoencephalopathy cases, dual infection with both JC virus types 1 and 2 was found. The data obtained in this study indicate that the unexpected involvement of JC virus type 2, a strain not common in Italy, and the high frequency of dual infection with both JC virus types 1 and 2 in progressive multifocal leukoencephalopathy CSF, can be indications of risk factors for progressive multifocal leukoencephalopathy development.

Acquired Immunodeficiency Syndrome↗
PubMed2004

New insights into progressive multifocal leukoencephalopathy.

PURPOSE OF REVIEW: Progressive multifocal leukoencephalopathy is a deadly demyelinating disease of the central nervous system, which occurs in immunosuppressed individuals. It is caused by a reactivation of the polyomavirus JC, which induces a lytic infection of oligodendrocytes. This review covers recent developments in the clinical and pathological presentations of progressive multifocal leukoencephalopathy, and advances in the understanding of JC virus biology. RECENT FINDINGS: The availability of highly active antiretroviral therapy has changed the clinical spectrum of progressive multifocal leukoencephalopathy in HIV-infected individuals; although the incidence has not diminished, mortality has decreased from 90% to approximately 50% during the first 3 months as a result of recovery of the immune system. More progressive multifocal leukoencephalopathy patients are now negative for JC virus in the cerebrospinal fluid by polymerase chain reaction, which calls for a new consensus terminology. Inflammatory forms of the disease are also becoming more frequent, and are associated with a strong cellular immune response mediated by JC virus-specific CD8 cytotoxic T lymphocytes, which are instrumental in preventing disease progression. SUMMARY: Advances in the understanding of JC virus biology have shed new light on the pathogenesis of progressive multifocal leukoencephalopathy, and on its possible role in cerebellar atrophy in HIV-infected individuals. Findings on the cellular immune response against the virus have direct implications for patient management, and may lead to new forms of immunotherapies for progressive multifocal leukoencephalopathy. An animal model of progressive multifocal leukoencephalopathy in non-human primates will facilitate the development of novel therapeutic strategies.

AIDS-Related Opportunistic Infections↗
PubMed1995

Progressive multifocal leukoencephalopathy: the evolution of a disease once considered rare.

Progressive multifocal leukoencephalopathy, a formerly rare disease that chiefly occurred in persons with underlying lymphoma and chronic lymphocytic leukemia, is now seen with increasing frequency in the era of acquired immunodeficiency syndrome. Progressive multifocal leukoencephalopathy is currently estimated to arise in 5% of all human immunodeficiency virus-infected individuals. The clinical features of the disorder in patients with acquired immunodeficiency syndrome do not appear to be significantly different from progressive multifocal leukoencephalopathy occurring in association with other immunosuppressive disorders. Radiographically, the appearance of HIV dementia on magnetic resonance imaging is sometimes confused with that of progressive multifocal leukoencephalopathy. Among the characteristics that are helpful in distinguishing between the two disorders are the presence of focal findings, the rate of disease progression, the specific magnetic resonance imaging attributes, including the location of the lesions, and certain cerebrospinal fluid parameters, including surrogate markers for human immunodeficiency virus dementia and the presence of myelin basic protein. The remarkable increase in the burden of progressive multifocal leukoencephalopathy has provided a vital impetus for its study, particularly with respect to diagnosis and therapy. Establishing an unequivocal diagnosis of progressive multifocal leukoencephalopathy currently requires brain biopsy. The application of polymerase chain reaction for JC virus amplification to cerebrospinal fluid samples suggests that it may provide an alternative means of diagnosis. Recent in vitro studies of cytosine arabinoside and camptothecin suggest that they, or similar agents, may prove useful in the treatment of this illness and well-designed clinical trials are underway.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Quantitative MRI assessment of leukoencephalopathy.

Quantitative MRI assessment of leukoencephalopathy is difficult because the MRI properties of leukoencephalopathy significantly overlap those of normal tissue. This report describes the use of an automated procedure for longitudinal measurement of tissue volume and relaxation times to quantify leukoencephalopathy. Images derived by using this procedure in patients undergoing therapy for acute lymphoblastic leukemia (ALL) are presented. Five examinations from each of five volunteers (25 examinations) were used to test the reproducibility of quantitated baseline and subsequent, normal-appearing images; the coefficients of variation were less than 2% for gray and white matter. Regions of leukoencephalopathy in patients were assessed by comparison with manual segmentation. Two radiologists manually segmented images from 15 randomly chosen MRI examinations that exhibited leukoencephalopathy. Kappa analyses showed that the two radiologists' interpretations were concordant (kappa = 0.70) and that each radiologist's interpretations agreed with the results of the automated procedure (kappa = 0.57 and 0.55). The clinical application of this method was illustrated by analysis of images from sequential MR examinations of two patients who developed leukoencephalopathy during treatment for ALL. The ultimate goal is to use these quantitative MR imaging measures to better understand therapy-induced neurotoxicity, which can be limited or even reversed with some combination of therapy adjustments and pharmacological and neurobehavioral interventions.

Adult↗
PubMed1995

Leukoencephalopathy associated with intra-arterial ACNU in patients with gliomas.

Thirty cases of gliomas treated by surgery, radiotherapy and intra-arterial (IA) ACNU were reviewed with a focus on the late side-effect known as leukoencephalopathy. All cases were classified into three groups; remission (10 cases), regrowth (15 cases) and leukoencephalopathy (5 cases) from their outcome. The average total doses of IA ACNU were 49.8 mg/sqm body surface area in the remission group, 157.3 mg/sqm in the regrowth group and 203.1 mg/sqm in the leukoencephalopathy group. There were significant differences in the total IA ACNU doses between the remission group and both regrowth and leukoencephalopathy groups, while no significant differences were noticed in the dose of radiation given. There was a correlation between the total dose of IA ACNU and the occurrence of leukoencephalopathy. An autopsy of a typical case of leukoencephalopathy revealed various degrees of myelin breakdown and thickening of arterial walls, which probably manifested progressive dementia accompanied by urinary incontinence and gait disturbance.

Adolescent↗
PubMed1999

Leukoencephalopathy in childhood acute lymphoblastic leukemia with t(1;19).

To clarify the incidence of leukoencephalopathy in patients with t(1;19) and their clinical characteristics, we studied 239 acute lymphoblastic leukemia (ALL) cases. The 1;19 translocation was found in 20 (8.5%) of the 239 children with ALL. Leukoencephalopathy occurred in 2 (10%) patients with t(1;19) during the early first remission and in one case with t(1;19) at the time of central nervous system (CNS) relapse. Leukoencephalopathy was not found during the early first remission in patients lacking t(1;19), but did develop in 4 patients lacking t(1;19) at the time of CNS relapse. There were no differences in age, sex, leukocyte count, platelet count or serum lactate dehydrogenase level between t(1;19) patients with and without leukoencephalopathy. Our results suggest the incidence of leukoencephalopathy in patients with t(1;19) during the early first remission to be 10%, but we can not predict which patients will develop leukoencephalopathy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Relationship between lobar intracerebral hemorrhage and leukoencephalopathy associated with cerebral amyloid angiopathy: clinicopathological study of 64 Japanese patients.

Cerebral amyloid angiopathy (CAA) has two major clinical manifestations: intracerebral hemorrhages and ischemic lesions. Among these, the lobar type of intracerebral hemorrhage (ICH) is a well-known clinical manifestation, while the CAA-related diffuse deep white matter degeneration known as leukoencephalopathy is thought to be rare. The characteristics of CAA-related leukoencephalopathy are still incompletely understood, and the relationship between lobar ICH and leukoencephalopathy in patients with CAA has not been properly clarified. The main purpose of this study is to elucidate the clinical and histopathological features of CAA-related lobar ICH and leukoencephalopathy in order to determine whether the degree of deep white matter degeneration parallels the severity of CAA-associated vasculopathies that lead to vascular wall rupture. We studied 64 Japanese patients with histopathologically proven amyloid beta protein (A beta) type CAA presenting with lobar ICH (52 biopsy and 12 autopsy). In this study, a total of 106 hematomas were observed. CAA-related cerebral hemorrhages tend to occur recurrently and multifocally. Multiple simultaneous labor hemorrhages occasionally developed (9.4%). CAA-related ICH in the sixth decade was not rare (14.1%). Although most patients suffered relapsing and/or multiple severe ICH, no patient in our series presented with diffuse leukoencephalopathy. In conclusion, A beta type cerebrovascular amyloid deposition causes recurrent, multifocal, and often multiple simultaneous ICH even in relatively younger elderly patients, but rarely produces diffuse leukoencephalopathy. This suggests that CAA-associated vasculopathies that cause vascular wall rupture do not always lead to ischemic deep white matter degeneration, and that there may be another unknown pathogenetic mechanism producing the latter CAA-related white matter lesion.

Aged↗
PubMedDate not supplied

Toxic leukoencephalopathy.

The white matter of the brain is vulnerable to a wide variety of toxins. Leukoencephalopathy is being increasingly recognized in a number of different patient populations. The detection of early and subtle toxin effects has been facilitated by the advent of magnetic resonance imaging, which offers better resolution of white matter than other neuroimaging methods. Neuropathologic features of leukoencephalopathy are also becoming more completely elucidated. Injury to white matter has been described from cranial irradiation and cancer chemotherapeutic drugs, and from a number of other therapeutic agents, drugs of abuse, and environmental toxins. Many patients have reversible leukoencephalopathy, whereas others experience a progressive and irreversible course. Leukoencephalopathy is associated with neurobehavioral manifestations that may be subtle or devastating, and the syndrome of white matter dementia may result. The pathogenesis of toxic leukoencephalopathy remains largely unknown, and treatment is limited in most cases to prevention by avoidance or minimization of the toxin exposure. However, the prognosis for this syndrome may be relatively favorable because of the frequent sparing of axons even when myelin is affected. Toxic leukoencephalopathy is an emerging clinical disorder that presents the opportunity for improving clinical outcomes in a number of patient groups and for achieving a deeper understanding of the role of white matter in cognitive and emotional function.

Air Pollutants↗
PubMed2006

Multiple sclerosis, natalizumab therapy, and progressive multifocal leukoencephalopathy.

PURPOSE OF REVIEW: Multiple sclerosis affects many people, often in early adulthood, and causes significant disability. Natalizumab is a novel agent to be evaluated for multiple sclerosis and Crohn's disease that has demonstrated unique efficacy but has unfortunately been implicated in three cases of progressive multifocal leukoencephalopathy. This review covers the mechanism of action of natalizumab and efficacy for multiple sclerosis, the three cases of natalizumab-associated progressive multifocal leukoencephalopathy, our understanding of progressive multifocal leukoencephalopathy, and the mechanisms that may account for these events. RECENT FINDINGS: Natalizumab, an anti-alpha4-integrin antibody, binds to T-cell surface receptors to prevent migration from the circulation into the brain tissue. Phase II and III trials have been completed and demonstrate previously unseen efficacy in preventing relapses and disease progression. The cases of progressive multifocal leukoencephalopathy, two fatal and one disabling, resulted in the voluntary suspension of natalizumab and bring this entire class of agents into doubt. It is important to determine what led to the development of progressive multifocal leukoencephalopathy in the natalizumab-associated cases and to advance understanding and continue to develop therapies for the treatment of multiple sclerosis. SUMMARY: With ongoing safety evaluations, natalizumab is being reevaluated by the US Food and Drug Administration for possible reapproval and return to the market. If natalizumab is reapproved, challenging questions and issues will remain in treating patients with multiple sclerosis.

Adult↗
PubMedDate not supplied

Leukoencephalopathy in patients with ischemic stroke.

Thirty-one (16 women, 15 men; mean age 68 years) of 1,000 consecutive patients with an ischemic stroke investigated systematically with computed tomography (CT), Doppler, electrocardiography (ECG), and biological tests had a diffuse hypodensity of the cerebral hemispheric white matter on CT, a sign indicative of leukoencephalopathy. In 25 of the 31 patients, the acute infarct was deep. Leukoencephalopathy was more frequent in patients with a deep infarct (8%) than in patients in whom the cortex was involved (0.8%) (p less than 0.01). A history of progressive intellectual impairment (23%) and the finding of a mild or moderate impairment, or severe dementia (84%) were more frequent in study patients (p less than 0.05) than in 31 sex- and age-matched controls with an acute infarct of same size and topography but without leukoencephalopathy. A history of hypertension (81%) and high blood pressure on admission (166 +/- 19/96 +/- 12 mm Hg) were the most common risk factors and were more frequent in study patients (p less than 0.05) than in controls. On the other hand, study patients had a greater than or equal to 50% stenosis or occlusion of the carotid artery (13%) less often than controls (35%) (p less than 0.05). Diabetes (23%), elevated blood cholesterol (13%), hematocrit greater than 45% (23%), smoking (32%), and myocardial ischemia by history or ECG (45%) did not differ. These findings suggest that hypertension may be more strongly associated with leukoencephalopathy than with deep infarcts. In acute stroke patients, leukoencephalopathy on CT should not be considered a fortuitous finding.

Aged↗
PubMed1997

[Progressive multifocal leukoencephalopathy: virological and neuropathological aspects].

Progressive multifocal leukoencephalopathy is a subacute demyelinating disease of the central nervous system due to an opportunistic infection by a polyomavirus, most often JC virus, which predominantly infects oligodendrocytes. Progressive multifocal leukoencephalopathy used to be a rare condition, usually complicating lymphoproliferative diseases. Since the onset of the AIDS epidemic, its incidence has considerably increased and HIV infection has become, by far, the main risk factor for the disease. In AIDS patients, progressive leukoencephalopathy frequently shows atypical clinical and pathological features. The development of malignant glial tumors, within demyelinating regions, in patients with progressive multifocal leukoencephalopathy, has been reported in exceptional cases. The course of progressive multifocal leukoencephalopathy is invariably fatal. The diagnosis can only be made with certainty by histopathological examination of the brain, on cerebral biopsy or at postmortem. However, neuroradiological features may be extremely suggestive in many cases and PCR seems to be a reliable technique for demonstrating viral genome in the CSF. A few antiviral treatments have been proposed, however their efficacy is difficult to assess due to the low prevalence of the disease and the occurrence of rare cases with spontaneously prolonged survival.

AIDS-Related Opportunistic Infections↗
PubMed2005

Late magnetic resonance imaging features of leukoencephalopathy in children with central nervous system tumours following high-dose methotrexate and neuraxis radiation therapy.

High-dose methotrexate (HDMTX) is used increasingly to treat children with central nervous system (CNS) tumours. Although the neuro-imaging features of leukoencephalopathy associated with systemic or intrathecal methotrexate administered after cranial radiation have been well described, the extent to which the sequencing of HDMTX prior to cranial radiation in infants and children predisposes to late neuroradiological features of leukoencephalopathy is unknown. This report describes the National Cancer Institute (NCI) toxicity grade of leukoencephalopathy based on magnetic resonance imaging (MRI) findings in all patients who survived 4 or more years after treatment on an earlier phase II study. These patients, with newly diagnosed CNS embryonal tumours, were in the age range 3.5-14.2 years (median 6.9 years) at diagnosis, and received four courses of pre-irradiation combination chemotherapy, including HDMTX 8 g/m(2). Following completion of the 'up-front' phase II study, all patients received conventionally fractionated whole brain doses of 36-50.4 Gy. The radiation dose and treatment volumes were determined individually according to the primary tumour location and results of extent of disease evaluations. The most recent MRI brain scans, obtained 4.0-10.5 years (median 6.5 years) after radiation therapy and comprising a minimum of T1, T1 following gadolinium and T2 sequences, were reviewed centrally to assess the neuroradiological grade of leukoencephalopathy, based on the NCI Common Terminology Criteria for Adverse Events, v3.0. Grade I changes (mild increase in subarachnoid space, and/or mild ventriculomegaly, and/or small/focal T2 hyperintensities) were evident in 8 of the 12 patients and grade II changes (moderate increase in subarachnoid space and/or moderate ventriculomegaly, and/or focal T2 hyperintensities extending to the centrum ovale) were found in the remaining 4. In conclusion, treatment with multiple courses of HDMTX prior to 36-50.4 Gy cranial radiation did not result in moderate to severe MRI features of leukoencephalopathy. Future studies in paediatric neuro-oncology patients, involving HDMTX combined with prospective neuropsychological evaluations appear justified.

Adolescent↗
PubMed2000

Familial occipital calcifications, hemorrhagic strokes, leukoencephalopathy, dementia, and external carotid dysplasia.

OBJECTIVE: To describe a new familial association of late-onset dementia, patchy leukoencephalopathy, intracerebral hemorrhages, bilateral occipital calcifications (BOC), and external carotid artery dysplasia (ECAD). METHODS: At age 62, the proband, who was of Spanish descent, had left temporal hemorrhage in a background of progressive mental deterioration. Neuroimaging revealed fine tram-line BOC, extensive leukoencephalopathy, and bilateral ECAD. Biologic screening for celiac disease was negative. Skin biopsy with ultrastructural study revealed heretofore unreported changes in the basal lamina of capillaries, with multilayered appearance and round-shaped microcalcifications. Of 19 next-of-kin who survived beyond 60 years of age, six had brain disorders; four of the six presented at least three components of the syndrome. The proband's mother had died at age 83 with profound dementia; one sister, who was diagnosed with dementia with BOC and leukoencephalopathy at age 67, died 2 years later from intracerebral hemorrhage; a brother had an occipital hemorrhage at age 58, at which time BOC and leukoencephalopathy were discovered; and another brother died after a minor stroke at age 70 with dementia, leukoaraiosis, BOC, and ECAD. A proband's cousin also had an unexplained ischemic stroke at age 55, but without other features of the entity. In no subject was there evidence of seizures, facial angioma, or intracranial vascular malformation, and arterial hypertension was neither constant nor severe. CONCLUSION: These clinical, neuroradiologic, and histologic features suggest a new familial cerebrovascular entity with widespread microvascular calcifications and autosomal (presumably dominant) inheritance. We suggest the acronym FOCHS-LADD, for familial occipital calcifications, hemorrhagic strokes, leukoencephalopathy, arterial dysplasia, and dementia.

Aged↗