Multifocal White Matter Lesions Research Articles

Demyelination as a harbinger of lymphoma: a case report and review of primary central nervous system lymphoma preceded by multifocal sentinel demyelination

BackgroundPrimary central nervous system lymphoma (PCNSL) may rarely be preceded by “sentinel demyelination,” a pathologic entity characterized by histologically confirmed demyelinating inflammatory brain lesions that mimic multiple sclerosis (MS) or acute disseminated encephalomyelitis (ADEM). Interpreting the overlapping radiologic and clinical characteristics associated with each of these conditions—contrast-enhancing demyelination of white matter and relapsing and remitting steroid-responsive symptoms respectively—can be a significant diagnostic challenge.Case presentationWe describe a 57-year-old woman with an unusual clinical course who presented with multi-focal enhancing white matter lesions demonstrated to be inflammatory demyelination by brain biopsy. Despite a good initial response to steroids and rituximab for treatment of presumed tumefactive multiple sclerosis, the patient’s condition rapidly deteriorated, and a repeat brain biopsy six months later was consistent with a diagnosis of diffuse large B-cell lymphoma.ConclusionsEarly clinical suspicion for PCNSL and awareness that biopsied lesions may initially show sentinel demyelination suggestive of alternate diagnoses may be essential for early initiation of appropriate therapies and mitigation of disease progression. Clinical, pathophysiological, and diagnostic aspects of sentinel demyelination and PCNSL are discussed.

Acute Diseminated Encephalomyelitis: A Case Report and Review of Literature / Akut Disemine Ensefalomiyelit; Olgu Sunumu Ve Literatur Incelemesi

Acute disseminated encephalomyelitis (ADEM) is an autoimmune and monophasic central nervous system disease that principally affects brain and spinal cord by causing non-vasculitic inflammatory diffuse demyelination. ADEM is one of the rare causes of impaired consciousness in childhood. Incidence of the disease under the age of 20 is 1.5-3 / 100000 per year and it mostly occurs in children between the ages of 5-8 years. Underlying causes aren't defined clearly yet, however, infections and vaccinations are known as predisposing factors for the disease. Multifocal white matter lesions on magnetic resonance imaging (MRI) are characteristic signs of ADEM. In our case, hyperintense lesions in cerebrum were detected on cranial MRI subsequent to impaired consciousness and convulsion. No specific feature was found in cerebrospinal fluid analysis of the patient. In this paper, we present a three-year-old boy who developed ADEM subsequent to viral upper respiratory tract infection and had full recovery after high dose steroid therapy.

Battered child: Cranial imaging findings in a distinct case of non-accidental injury

Abstract A six months old male infant was referred to the emergency unit having sustained severe head trauma at home. The boy suffered from domestic violence, specifically from repeated “shaking” by the person responsible. The conducted trans-cranial ultrasound acquired in the emergency department exhibited huge bilateral hygromas and brain atrophy. Magnetic resonance imaging (MRI) was performed for further assessment of traumatic brain injury. MRI confirmed prior sonographic findings and additionally showed multifocal grey and white matter lesions consistent with subacute and chronic posttraumatic brain hemorrhage and hypoxic-ischemic encephalopathy. This case should raise awareness for the broad imaging spectrum of non-accidental injuries in infants and serve as a reminder for the usefulness of imaging not only for diagnostics and therapeutics but also for forensic purposes.

Progressive Multifocal Leukoencephalopathy (PML) – a Case Report.

Progressive Multifocal Leukoencephalopathy (PML) is a rare and usually fatal viral disease occurring almost exclusively in people with severe immune deficiency. This is a demyelinating disease of the central nervous system (CNS) that usually leads to death or severe disability. Patients usually present with focal CNS abnormalities like; hemiparesis, apathy, and confusion. Multifocal white matter lesions without mass effect lead to the diagnosis of PML. In this article we present a review of literature and report of a case of PML in which the patient’s clinical status and MR findings are typical. DOI: http://dx.doi.org/10.3329/pulse.v6i1-2.20355 Pulse Vol.6 January-December 2013 p.57-59

Encephalopathic Susac’s Syndrome associated with livedo racemosa in a young woman before the completion of family planning

BackgroundSusac’s Syndrome (SS) consists of the triad of encephalopathy, branch retinal artery occlusions (BRAO) and hearing loss (HL). Histopathologically, SS is characterised by a microangiopathy, and some observations suggest that an immune-mediated damage of endothelial cells might play a role. These findings also implicate a similarity between SS and other autoimmune diseases, most notably juvenile dermatomyositis (JDM). However, SS and JDM are commonly thought to affect distinct and non-overlapping sets of organs, and it is currently not clear how these specificities arise. Moreover, in the absence of clinical trials, some authors suggest that therapeutic approaches in SS should rely on the model of other autoimmune diseases such as JDM.Case presentationHere, we report a case of SS in a 32-year-old pregnant woman. She initially was admitted to the hospital with subacute severe encephalopathy and multifocal neurologic signs. As cranial magnetic resonance imaging (MRI) revealed multifocal white matter lesions including the corpus callosum, erroneously a diagnosis of multiple sclerosis (MS) was made, and intravenous methylprednisolone (IVMP) therapy was initiated. A few days later, an exanthema appeared on the trunk and extremities, which was diagnosed as livedo racemosa (LR). Several weeks later, the patient was readmitted to the clinic with an obscuration of her left visual hemifield and a bilateral HL. Ophthalmologic examination revealed extensive ischemic damage to both retinae. Now the correct diagnosis of SS was established, based on the above triad of clinical symptoms in conjunction with typical MRI and fundoscopic findings. When SS was diagnosed, the standard therapy with intravenous cyclophosphamide (IVCTX) was not instituted because of a significant risk of permanent infertility. Instead, sustained control of disease activity could be achieved with a therapeutic regime combining prednisolone, intravenous immunoglobulins (IVIG), mycophenylate mofetil (MM), and methotrexate (MTX).ConclusionsAn association with LR has only been described in very few cases of SS before and further underlines the pathogenetic relationship between SS and other autoimmune diseases such as JDM. In young women with SS and the desire for a child the combination of MM and MTX may represent a reasonable alternative to IVCTX.

Autosomal dominant mutations in POLG and C10orf2: association with late onset chronic progressive external ophthalmoplegia and Parkinsonism in two patients

Mutations in nuclear genes which encode proteins involved in mitochondrial DNA (mtDNA) replication or maintenance can cause mtDNA depletion or multiple mtDNA deletions in post-mitotic tissue, causing a range of mitochondrial diseases. Mutations in two such genes, POLG, which encodes the catalytic subunit of the mitochondrial polymerase gamma and C10orf2, which encodes Twinkle, a DNA helicase, are typically associated in adults with autosomal dominant or recessive CPEO, and very rarely, CPEO and Parkinsonism [1, 2]. Here, we describe our findings in two patients with late-onset CPEO, white matter changes and Parkinsonism. Patient-1 presented at age 63 years with CPEO, ptosis, congenital cataracts, vision loss with macular degeneration, hearing loss, dysarthria, dysphagia, sensorimotor polyneuropathy, fatigue, migraine, cardiomyopathy and depression. At age 67, he developed asymmetric resting tremor and impaired balance. Examination at age 71 revealed CPEO, facial diplegia, mild symmetric rigidity, intermittent, predominantly right-sided resting tremor and multidirectional head tremor, bradykinesia, and ataxic gait (broad based stance with inability to tandem). Total baseline UPDRS Part III was 26. Treatment with carbidopa/levodopa (25/ 100 mg three times daily) improved the symptoms (reduction of total UPDRS III to 14) but was not sufficiently tolerated, and the tremor was subsequently stabilized with low dose clonazepam. Motor symptoms have remained stable over the last three years. Brain MRI showed mild atrophy and very subtle multifocal subcortical white matter lesions (Fig. 1a–c). Family history was positive for congenital cataracts, thyroid disease, and premature menopause (age 27) in his daughter, who declined genetic testing. Muscle biopsy (quadriceps) showed chronic myopathic changes, subsarcolemmal accumulation of mitochondria, some containing paracrystalline inclusions, and multiple mtDNA deletions following southern blotting. Sequencing of POLG revealed a heterozygous c.2828G [A; p.Arg943His mutation in exon 18, previously described in two families with autosomal dominant CPEO, in one together with primary ovarian failure [1, 3]. Patient-2, a 74 year old man with a 10 year history of bilateral ptosis, slowly progressive bilateral CPEO, progressive left-sided ‘‘weakness,’’ mild, proximal myopathy and fatigue on exertion, presented at age 66 with reduced dexterity and nocturnal muscle cramps. Four years later, he developed mild, asymmetric, predominantly left-sided Parkinsonism including hypomimia, mild resting tremor, and moderate bradykinesia, with UPDRS scores as follows: Part I (2), Part II (8), Part III (10). Cerebral DAT scan revealed reduced striatal dopamine uptake. He declined dopaminergic treatment. The motor symptoms have remained stable over the last four years. Brain MRI demonstrated mild, non-specific white matter lesions (Fig. 1d–f). Family history was negative for CPEO and Parkinsonism. Muscle biopsy (quadriceps) revealed a predominance of type II fibres, some fibres with numerous central nuclei, some cytochrome oxidase negative fibres, and multiple B. R. Brandon M. Soni Rush University Medical Center, Chicago, IL, USA

Progressive multifocal leucoencephalopathy (PML): A novel complication of brentuximab vedotin from the Southern Network on Adverse Reactions (SONAR) project.

e22181 Background: BV is FDA approved for angio-immunoblastic large cell lymphoma and refractory Hodgkin’s lymphoma (HL). BV-linked PML cases reviewed. Methods: Case 1—Age:47/HIV negative male relapsed stage IIIB mixed cellularity undergoing treatment with BV. Prior therapies: 8 cycles of ABVD, ESHAP, BEAM, autologous stem cell transplant, involved field radiotherapy to the neck and mediastinum in 2008 and GVD ending in 2009. A 2011 relapse treated with BV q 3 weeks. Patient complained of impaired coordination and left greater than right dysdiadokinesis after 2 BV doses. Third BV cycle administered. Patient formed dysarthria, left-sided hemianopsia, hemiparesis. CSF analysis for JC virus DNA by PCR positive. Patient died shortly after. Case 2—Age:38/female revealed cutaneous anaplastic T-cell lymphoma refractory started on BV in mid-2011 led to loss of cutaneous tumors. A day after 2ndBV dose, difficulty finding words and unsteady gait. MRI revealed multifocal white matter lesions in bilateral cerebral hemispheres. Brain biopsy revealed PML. Prednisone initiated. Patient continued mixed non-fluent aphasia, quadriparesis, gait ataxia. MRI showed white matter lesions and contrast enhancement consistent with IRIS. High dose oral corticosteroids continued. Repeat MRI shows decreased lesion load, resolution of enhancement. Patient improving. Case 3—Age:72/female stage IB mycosis fungoides (MF) controlled with topical steroids and nitrogen mustard, phototherapy and interferon alpha, developed painful ulcerated plaques and tumors 4 years after diagnosis. BV administered, clinical response of skin tumors, decreased pain. Two weeks after 3rdBV dose: disoriented, poor short term memory. MRI revealed right frontal white matter. CSF sent for JC virus DNA was negative. Patient died 2 months after last BV dose. Autopsy: demyelination associated JC virus positive cells. Results: Shown. Conclusions: Unexpected PML occurrences after 2 or more BV doses, with IRIS and survival in 1 patient.

Jacobsen syndrome: a rare differential diagnosis of multifocal white matter lesions

Introduction: White matter lesions can have many causes. Two half-sisters (same mother) were presented to us for further examination. In both patients Jacobsen syndrome has been diagnosed.

Brain morphological abnormalities in 49,XXXXY syndrome: A pediatric magnetic resonance imaging study

As a group, people with the sex chromosome aneuploidy 49,XXXXY have characteristic physical and cognitive/behavioral tendencies, although there is high individual variation. In this study we use magnetic resonance imaging (MRI) to examine brain morphometry in 14 youth with 49,XXXXY compared to 42 age-matched healthy controls. Total brain size was significantly smaller (t = 9.0, p < .001), and rates of brain abnormalities such as colpocephaly, plagiocephaly, periventricular cysts, and minor craniofacial abnormalities were significantly increased. White matter lesions were identified in 50% of subjects, supporting the inclusion of 49,XXXXY in the differential diagnosis of small multifocal white matter lesions. Further evidence of abnormal development of white matter was provided by the smaller cross sectional area of the corpus callosum. These results suggest that increased dosage of genes on the X chromosome has adverse effects on white matter development.

PML-IRIS in a patient treated with brentuximab

A 38-year-old woman was diagnosed with cutaneous anaplastic T-cell lymphoma that proved refractory to methotrexate, bexarotene, denileukin diftitox, interferon γ-1b, interferon α-2b, vorinostat, and pralatrexate. She was therefore started on the newly approved monoclonal anti-CD30 antibody brentuximab vedotin. Treatment with brentuximab 1.8 mg/kg IV every 3 weeks quickly led to disappearance of her cutaneous tumors. The day after her second brentuximab infusion she developed word-finding difficulties and unsteady gait. Due to further neurologic deterioration, she was admitted to an outside hospital. Brain MRI revealed multifocal enhancing white matter lesions throughout bilateral cerebral hemispheres and posterior fossa (figure, A-C). Brain biopsy was performed 15 days after her last brentuximab dose to rule out metastases and she was diagnosed with progressive multifocal leukoencephalopathy (PML) (figure, J). The patient was discharged home with hospice care. Upon discharge, she was started on prednisone 50 mg daily to help treat her eczema. Her family brought her to our clinic for a second opinion.

Structure and activity of the only human RNase T2

Mutations in the gene of human RNase T2 are associated with white matter disease of the human brain. Although brain abnormalities (bilateral temporal lobe cysts and multifocal white matter lesions) and clinical symptoms (psychomotor impairments, spasticity and epilepsy) are well characterized, the pathomechanism of RNase T2 deficiency remains unclear. RNase T2 is the only member of the Rh/T2/S family of acidic hydrolases in humans. In recent years, new functions such as tumor suppressing properties of RNase T2 have been reported that are independent of its catalytic activity. We determined the X-ray structure of human RNase T2 at 1.6 Å resolution. The α+β core fold shows high similarity to those of known T2 RNase structures from plants, while, in contrast, the external loop regions show distinct structural differences. The catalytic features of RNase T2 in presence of bivalent cations were analyzed and the structural consequences of known clinical mutations were investigated. Our data provide further insight into the function of human RNase T2 and may prove useful in understanding its mode of action independent of its enzymatic activity.

Incidental Multifocal White Matter Lesions in Pediatric Magnetic Resonance Imaging

This study sought to describe the occurrence and potential significance of white matter abnormalities of unknown cause on pediatric cranial magnetic resonance scans, and to review the literature. We included 16 children in whom white matter abnormalities were incidentally revealed on magnetic resonance scans performed during a 7-year period at a tertiary pediatric medical center. Background data were retrospectively collected from medical files. White matter lesions were classified by size, location, and extent. Indications for imaging included convulsive disorder (n = 5), headache (n = 5), endocrine disorder (n = 4), and others. Patients' abnormalities did not correlate with the locations and patterns of white matter lesions. No changes in lesions were evident over time. Given the absence of evident benefits from repeated imaging studies, we suggest they are not warranted in every patient, and should be tailored according to clinical course. Further investigations of incidental intracranial findings are required in this age group.

092 A case of necrotising sarcoid granulomatosis involving the central nervous system

We report a 62-year-old Caucasian lady who presented with a progressive history of unsteadiness, vertigo, falls and cognitive decline. MRI brain and spinal cord showed multifocal white matter lesions and...

Rnaset2 mutant zebrafish model familial cystic leukoencephalopathy and reveal a role for RNase T2 in degrading ribosomal RNA

T2-family acidic endoribonucleases are represented in all genomes. A physiological role for RNase T2 has yet to be defined for metazoa. RNASET2 mutation in humans is linked with a leukoencephalopathy that arises in infancy characterized by cortical cysts and multifocal white matter lesions. We now show localization of RNASET2 within lysosomes. Further, we demonstrate that loss of rnaset2 in mutant zebrafish results in accumulation of undigested rRNA within lysosomes within neurons of the brain. Further, by using high field intensity magnetic resonance microimaging, we reveal white matter lesions in these animals comparable to those observed in RNASET2-deficient infants. This correlates with accumulation of Amyloid precursor protein and astrocytes at sites of neurodegeneration. Thus we conclude that familial cystic leukoencephalopathy is a lysosomal storage disorder in which rRNA is the best candidate for the noxious storage material.

RNASET2-deficient cystic leukoencephalopathy: a new lysosomal disorder

Background: We recently described that human RNASET2-deficiency results in cystic leukoencephalopathy (Nat Genet 2009; 41:773–775). The clinical phenotype as well as the brain MRI pattern of these patients cannot be differentiated from neonatally asymptomatic congenital CMV brain infection. Patients manifest with psychomotor impairment, micro- or normocephaly, spasticity and in some cases also epilepsy. Brain abnormalities include multifocal white matter lesions, bilateral cysts in the anterior part of the temporal lobe, enlarged inferior horns and – as an inconsistent finding – calcifications.

Systemic T Cell Large Granular Lymphocyte Lymphoma with Multifocal White Matter Degeneration in the Brain of a Japanese Domestic Cat

A 10-year-old spayed female Japanese domestic cat exhibited clinical symptoms suggesting pancreatitis. One month later the cat exhibited Horner's syndrome and was euthanized. At necropsy, multiple neoplastic masses were found in the intestines, spleen, kidneys, urinary bladder, and lungs. On cytology, many neoplastic lymphocytic cells had fine to large cytoplasmic granules, suggesting large granular lymphocyte (LGL) lymphoma. Histopathological examinations revealed infiltrative proliferation of the neoplastic cells in almost organs. Immunohistochemically, the neoplastic cells were intensely positive for CD3 and granzyme B. In the brain, there were multifocal white matter lesions characterized by diffuse myelin loss with mild infiltration of the neoplastic cells. Based on these findings, the cat was diagnosed as LGL lymphoma presumptively of intestinal origin with systemic involvement.

Susac syndrome in a young child

Susac syndrome is a microangiopathy of unknown origin affecting the brain, retina and inner ear. This rare entity is often misdiagnosed as a demyelinating condition such as multiple sclerosis or acute disseminated encephalomyelitis. A high index of suspicion must be present as the majority of patients do not have the complete clinical triad at the time of onset of symptoms. The radiologist plays an important role when the disease is suspected and helps orient the investigations. The syndrome has characteristic imaging features on MRI that include multifocal white matter and occasional grey matter lesions, the corpus callosum being always involved. The predominant central callosal lesions, especially with rapid cystic transformation (central callosal holes) can be considered pathognomonic of this condition in the appropriate clinical setting. This disease is extremely rare in children. We report a case of Susac syndrome in a 9-year-old girl to increase the awareness among paediatric radiologists of this entity, which is usually not considered as a differential diagnosis of multifocal white matter involvement in this age group.

A novel cerebral microangiopathy with endothelial cell atypia and multifocal white matter lesions: a direct mycoplasma infection?

A novel cerebral microangiopathy with endothelial cell atypia and multifocal white matter lesions: a direct mycoplasma infection?

Acute disseminated encephalomyelitis mimicking late CNS relapse of acute lymphoblastic leukaemia: case report

BackgroundAcute encephalomyelopathy occurring after an allogeneic bone marrow transplant for leukaemia is a diagnostic emergency. The diagnosis can be challenging since there is a wide set of alternative diagnoses, including opportunistic infections and relapse of the leukaemia.Case presentationA 13-year old girl presented with a severe acute myelopathy and encephalopathy. She was in prolonged remission from a central nervous system and bone marrow relapse of an acute lymphoblastic leukaemia, treated with allogeneic bone marrow transplantation. Neuroimaging showed multifocal grey and white matter lesions of demyelinating appearance in the brain and entire spine. Immunophenotyping and cytogenetic investigations of the girl's cerebrospinal fluid lymphocytosis excluded a late central nervous system relapse of her leukaemia. The diagnosis was acute disseminated encephalomyelitis. With standard immunosuppressive therapy, the girl had early cerebral recovery but a prolonged period of recovery from her myelopathy.ConclusionAcute disseminated encephalomyelitis should be considered in the differential diagnosis of acute encephalomyelopathy after bone marrow transplantation for leukaemia. Demyelinating syndromes such as acute disseminated encephalomyelitis may be late sequelae of bone marrow transplantation.

Acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) presents as an acute-onset neurological dysfunction following a triggering event such as an infection or vaccination. Patients present with polysymptomatic neurological dysfunction, and imaging shows multifocal white matter lesions in the brain and spinal cord. Clinical evaluation, magnetic resonance imaging, and cerebrospinal fluid study are most useful in establishing the diagnosis and ruling out important differential diagnoses. Corticosteroids are the mainstay of treatment and the role of other modalities of treatment, such as plasma exchange and intravenous immunoglobulin, require further study. Prognosis is generally good. The recently proposed consensus definitions are likely to facilitate delineation of ADEM from other acquired demyelinating disorders.