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Okazaki T, Kodama D, Yamadera M, Sugiyama Y, Tsuji H, Nishida F, Ooka Y, Nakamichi K, Hashikawa K, Yanagihara T. [Progressive multifocal leukoencephalopathy in a patient with rheumatoid arthritis under salazosulfapyridine treatment]. Rinsho Shinkeigaku 2021; 61:833-838. [PMID: 34789625 DOI: 10.5692/clinicalneurol.cn-001622] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection caused by JC virus (JCV) activation. We report an 85-years old man who had been diagnosed to have rheumatoid arthritis (RA) 1.5 years prior to diagnosis of PML, and had been treated with salazosulfapyridine (SASP). He developed weakness of the left upper limb, which progressed gradually for two months. A neurological examination on admission revealed severe palsy of the left upper limb without sensory disturbance, cognitive decline or gait disturbance. Brain MRI revealed white matter lesions in the right frontal lobe around the precentral gyrus. Cerebrospinal fluid (CSF) examination and peripheral lymphocyte counts were normal. HIV was ruled out serologically. There were no findings suggestive of malignancy. We suspected PML and stopped SASP. JCV-DNA was detected in CSF. There were enlarged nuclei positive with VP-1 immunostaining in the brain biopsy materials. Thus, the diagnosis of PML was definitive. Paralysis of the left upper limb began to improve one week after discontinuing SASP. Treatment with mefloquine and mirtazapine was initiated, but he developed severe interstitial pneumonia, which might be caused by mefloquine. Therefore, he underwent rehabilitation without medication. JCV-DNA became undetectable and white matter lesions decreased 6 months later. Paralysis improved and he had no problem with activities of daily living a year later. The risk factor for PML has changed over the last decade, and drugs such as biologics became significant risk factors for patients with autoimmune diseases. There are reports suggesting that systemic lupus erythematosus (SLE) and RA themselves might be independent risk factors for PML. Although there is no previous report of SASP inducing PML, SASP might be the culprit in our case. However, there is another possibility that SAPS and RA worked synergistically for the onset of PML.
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Affiliation(s)
| | | | | | | | | | | | - Yoko Ooka
- Department of Neurology, Osaka Police Hospital
| | - Kazuo Nakamichi
- Department of Virology 1, National Institute of Infectious Diseases
| | | | - Takehiko Yanagihara
- Department of Neurology, Osaka Police Hospital.,Osaka Neurological Research Institute
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Maillart E, Taoufik Y, Gasnault J, Stankoff B. Leucoencefalopatia multifocale progressiva. Neurologia 2018. [DOI: 10.1016/s1634-7072(18)89404-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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Progressive Multifocal Leukoencephalopathy: Recent Advances and a Neuro-Ophthalmological Review. J Neuroophthalmol 2016; 35:296-305. [PMID: 26132966 DOI: 10.1097/wno.0000000000000271] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Progressive multifocal leukoencephalopathy (PML) is a severe often fatal opportunistic infection of the central nervous system caused by reactivation of a ubiquitous polyoma virus, JC virus. Although typically characterized by multifocal asymmetric subcortical white matter lesions, it may be monofocal and affect the cortical gray matter. Among the broad spectrum of clinical manifestations that occurs with PML, visual complaints are common. EVIDENCE ACQUISITION Combination of representative personally observed cases of PML and comprehensive review of case series of PML from 1958 through 2014. RESULTS Neuro-ophthalmic signs and symptoms were reported in approximately 20%-50% of patients with PML and can be the presenting manifestation in half of these. A majority of these presentations occur from damage to cerebral visual pathways resulting in visual field defects, cortical blindness, and other disorders of visual association. Given the decreased frequency of infratentorial and cerebellar involvement, ocular motility disorders are less common. CONCLUSIONS Visual complaints occur in patients with PML and are often the presenting sign. Awareness of this condition is helpful in avoiding unnecessary delays in the diagnosis of PML and management of the underlying condition. Recent guidelines have established criteria for diagnosis of PML in the high-risk patient population and strategies to mitigate the risk in these populations.
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SantaCruz KS, Roy G, Spigel J, Bearer EL. Neuropathology of JC virus infection in progressive multifocal leukoencephalopathy in remission. World J Virol 2016; 5:31-37. [PMID: 26870672 PMCID: PMC4735552 DOI: 10.5501/wjv.v5.i1.31] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 10/10/2015] [Accepted: 12/15/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate the neuropathology of the brain in a rare case of remission following diagnosis of progressive multifocal leukoencephalopathy (PML).
METHODS: Consent from the family for an autopsy was obtained, clinical records and radiograms were retrieved. A complete autopsy was performed, with brain examination after fixation and coronal sectioning at 1 cm intervals. Fourteen regions were collected for paraffin embedding and staining for microscopic analysis. Histologic sections were stained with Luxol blue, hematoxylin/eosin, and immunostained for myelin basic protein, neurofilament, SV40 T antigen and p53. The biopsy material was also retrieved and sections were stained with hematoxylin/eosin and immunostained for SV40 and p53. Sections were examined by American Board of Pathology certified pathologists and images captured digitally.
RESULTS: Review of the clinical records was notable for a history of ulcerative colitis resulting in total colectomy in 1977 and a liver transplant in 1998 followed by immune-suppressive therapy. Neurological symptoms presented immediately, therefore a biopsy was obtained which was diagnosed as PML. Immunotherapy was adjusted and clinical improvement was noted. No subsequent progression was reported. Review of the biopsy demonstrated atypical astrocytes and enlarged hyperchromatic oligodendroglial cells consistent with JC virus infection. Strong SV40 and p53 staining was found in glial cells and regions of dense macrophage infiltration were present. On gross examination of the post-mortem brain, a lesion in the same site as the original biopsy in the cerebellum was identified but no other lesions in the brain were found. Microscopic analysis of this cerebellar lesion revealed a loss of myelin and axons, and evidence of axonal damage. This single burned-out lesion was equivocally positive for SV40 antigen with little p53 staining. Examination of thirteen other brain regions found no other occult sites.
CONCLUSION: Our study reveals residual damage, rare macrophages or other inflammation and minimal evidence of persistent virus. This case demonstrates the possibility of complete remission of PML.
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Hadjivassiliou M, Sanders DS, Aeschlimann D. The Neuroimmunology of Gluten Intolerance. NEURO-IMMUNO-GASTROENTEROLOGY 2016:263-285. [DOI: 10.1007/978-3-319-28609-9_15] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Hadjivassiliou M, Duker AP, Sanders DS. Gluten-related neurologic dysfunction. HANDBOOK OF CLINICAL NEUROLOGY 2014; 120:607-19. [PMID: 24365341 DOI: 10.1016/b978-0-7020-4087-0.00041-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The term gluten-related disorders (GRD) encompasses a spectrum of systemic autoimmune diseases with diverse manifestations. GRD are characterized by abnormal immunological responsiveness to ingested gluten in genetically susceptible individuals. Celiac disease (CD) or gluten-sensitive enteropathy is only one of a number of GRD. Extraintestinal manifestations include dermatitis herpetiformis (DH) and neurologic dysfunction. Furthermore it is only recently that the concept of extraintestinal manifestations without enteropathy has become accepted. In this chapter we review the spectrum of neurologic manifestations in GRD, discuss recent advances in their diagnosis, and look at their possible pathophysiologic mechanisms.
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Affiliation(s)
| | - Andrew P Duker
- Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK
| | - David S Sanders
- Department of Neurology, University of Cincinnati, Cincinnati, OH, USA
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JC polyomavirus (JCV) and monoclonal antibodies: friends or potential foes? Clin Dev Immunol 2013; 2013:967581. [PMID: 23878587 PMCID: PMC3708391 DOI: 10.1155/2013/967581] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Accepted: 06/13/2013] [Indexed: 12/13/2022]
Abstract
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS), observed in immunodeficient patients and caused by JC virus ((JCV), also called JC polyomavirus (JCPyV)). After the HIV pandemic and the introduction of immunomodulatory therapy, the PML incidence significantly increased. The correlation between the use of natalizumab, a drug used in multiple sclerosis (MS), and the PML development of particular relevance. The high incidence of PML in natalizumab-treated patients has highlighted the importance of two factors: the need of PML risk stratification among natalizumab-treated patients and the need of effective therapeutic options. In this review, we discuss these two needs under the light of the major viral models of PML etiopathogenesis.
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Berger JR, Aksamit AJ, Clifford DB, Davis L, Koralnik IJ, Sejvar JJ, Bartt R, Major EO, Nath A. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology 2013; 80:1430-8. [PMID: 23568998 DOI: 10.1212/wnl.0b013e31828c2fa1] [Citation(s) in RCA: 502] [Impact Index Per Article: 41.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE To establish criteria for the diagnosis of progressive multifocal leukoencephalopathy (PML). METHODS We reviewed available literature to identify various diagnostic criteria employed. Several search strategies employing the terms "progressive multifocal leukoencephalopathy" with or without "JC virus" were performed with PubMed, SCOPUS, and EMBASE search engines. The articles were reviewed by a committee of individuals with expertise in the disorder in order to determine the most useful applicable criteria. RESULTS A consensus statement was developed employing clinical, imaging, pathologic, and virologic evidence in support of the diagnosis of PML. Two separate pathways, histopathologic and clinical, for PML diagnosis are proposed. Diagnostic classification includes certain, probable, possible, and not PML. CONCLUSION Definitive diagnosis of PML requires neuropathologic demonstration of the typical histopathologic triad (demyelination, bizarre astrocytes, and enlarged oligodendroglial nuclei) coupled with the techniques to show the presence of JC virus. The presence of clinical and imaging manifestations consistent with the diagnosis and not better explained by other disorders coupled with the demonstration of JC virus by PCR in CSF is also considered diagnostic. Algorithms for establishing the diagnosis have been recommended.
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Affiliation(s)
- Joseph R Berger
- Department of Neurology, University of Kentucky, Lexington, USA.
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Abstract
Treatment of progressive multifocal leukoencephalopathy (PML) in a patient with exogenous immunosuppression starts with discontinuation of immunosuppressive medication. The restored host immunity will clear JC virus, the cause of PML, from the brain via cell-mediated immune mechanisms. Patients with solid-organ transplants will lose the transplanted organ, however, and patients who have autoimmune disorders may experience exacerbation of their underlying disease. These factors need to be weighed against the potentially fatal nature of PML. If the patient's immunosuppression is AIDS-related, highly active antiretroviral therapy (HAART) should be initiated if it has not previously been used. If the patient is already receiving HAART, the therapy should be changed to optimize treatment, with the goals of a nondetectable HIV viral load and normalization or near normalization of the CD4 count. For non-AIDS PML patients, daily intravenous cytosine arabinoside for 5 days can be offered if the patient is not pancytopenic and can tolerate a chemotherapeutic agent. For AIDS patients with PML or failing non-AIDS patients with neurologic deterioration, cidofovir can be considered. These therapies can be offered if neurologic stabilization satisfies the quality-of-life goals for the patient. For patients intolerant of other therapies or unsuited to them, oral mirtazapine or risperidone can be considered. The safety of these agents has been established in the treatment of psychiatric disease, but their efficacy has not yet been proven. Small interfering RNA (siRNA) therapy holds the promise of specific antiviral therapy, but delivery methods, safety, and efficacy are yet to be established.
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Affiliation(s)
- Allen J Aksamit
- Allen J. Aksamit, MD Mayo Clinic College of Medicine, Department of Neurology, 200 First Street SW, Rochester, MN 55905, USA.
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Abstract
Neurologic complications of celiac disease (CD) include ataxia and peripheral neuropathy, which can be the presenting symptoms and signs. Early diagnosis and intervention could prevent development of further neurologic and systemic complications. Questions remain regarding the prevalence of the neurologic complications, the pathophysiological mechanisms, and the effectiveness of therapy or response to a gluten-free diet.
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Stankoff B, Tourbah A, Taoufik Y, Gasnault J. Leucoencefalopatia multifocale progressiva. Neurologia 2010. [DOI: 10.1016/s1634-7072(10)70495-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Lionetti E, Francavilla R, Maiuri L, Ruggieri M, Spina M, Pavone P, Francavilla T, Magistà AM, Pavone L. Headache in pediatric patients with celiac disease and its prevalence as a diagnostic clue. J Pediatr Gastroenterol Nutr 2009; 49:202-207. [PMID: 19543115 DOI: 10.1097/mpg.0b013e31818f6389] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVES To establish the prevalence of headache in children with celiac disease (CD), the response to a gluten-free diet, and the prevalence of CD in children affected by headache. METHODS This hospital-based study included 2 steps. In the retrospective part, 354 children with CD answered a questionnaire investigating the presence of headache before and after the gluten-free diet. The same questionnaire was administered to 200 healthy children matched for sex and age. In the prospective part, 79 children affected by headache were screened for CD by antitransglutaminase IgA. Diagnosis of CD was confirmed by duodenal biopsy; before starting a gluten-free diet patients underwent a brain positron emission tomography study. After 6 months of follow-up children were reevaluated for the presence of headache. RESULTS Overall, 88 patients with CD complained of headaches before the diagnosis of CD as compared with 16 in the control group (24.8% vs 8%, P < 0.001). After the institution of a gluten-free diet, the headaches significantly improved in 68 children (77.3%), of whom 24 (27.3%) were headache-free during the study period. Four of 79 (5%) headache patients were found to have CD compared with 0.6% of the general population (P = 0.005). The brain positron emission tomography studies did not show any anomalies. During the follow-up, headaches improved in all 4 children with CD. CONCLUSIONS We recorded -- in our geographical area -- a high frequency of headaches in patients with CD and vice versa with a beneficial effect of a gluten-free diet. Screening for CD could be advised in the diagnostic work-up of patients with headache.
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Affiliation(s)
- Elena Lionetti
- Department of Paediatrics, University of Catania, Catania, Italy.
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Stoner GL. Implications of progressive multifocal leukoencephalopathy and JC virus for the etiology of MS. Acta Neurol Scand 2009. [DOI: 10.1111/j.1600-0404.1991.tb03954.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Haines ML, Anderson RP, Gibson PR. Systematic review: The evidence base for long-term management of coeliac disease. Aliment Pharmacol Ther 2008; 28:1042-66. [PMID: 18671779 DOI: 10.1111/j.1365-2036.2008.03820.x] [Citation(s) in RCA: 138] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND While gluten-free diet is an effective treatment for coeliac disease, the need for and goals of long-term management of patients are poorly defined. AIM To review systematically the complications and associations of coeliac disease, to identify potential risk factors, to define ways of assessing risk factors and to provide a strategy for management. METHODS Review of medical literature from 1975. RESULTS There is an increasing list of potential complications and/or conditions associated with coeliac disease, in particular, autoimmune disease, malignancy and bone disease. Risk factors that may predict or influence long-term outcomes include genetic susceptibility, environmental factors predominantly gluten ingestion, persistent small intestinal inflammation/injury and nutritional deficiencies. Genotyping of patients is yet to have an established clinical role in long-term management. Assessment of adherence to the gluten-free diet largely relies upon skilled dietary history, but the ultimate test is duodenal histopathology, which is the only currently established means of assessing healing. Symptoms, serology or other non-invasive means are poor predictors of healing and the likelihood of complications. CONCLUSION Evidence (albeit limited) that adherence to a gluten-free diet and mucosal healing prevent and/or ameliorate complications indicates that a planned long-term strategy for follow-up is essential.
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Affiliation(s)
- M L Haines
- Department of Gastroenterology, Monash University Department of Medicine, Box Hill Hospital, Box Hill, and Walter and Eliza Hall Institute, Parkville, Vic., Australia
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Lee MH, Chen YZ, Wang LS, Yen PS, Hsu YH. Progressive multifocal leukoencephalopathy in an AIDS patient. J Formos Med Assoc 2007; 106:S24-8. [PMID: 17493905 DOI: 10.1016/s0929-6646(09)60362-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Progressive multifocal leukoencephalopathy (PML) is a demyelinating brain disease caused by Jamestown Canyon virus (JCV). This disease is an important cause of morbidity and mortality in acquired immunodeficiency syndrome (AIDS) patients. We report a 34-year-old man infected with HIV-1 who presented with frequent general tonic clonic seizure and left side weakness for 2 months. Clinical features and magnetic resonance imaging (MRI) findings with hyperintensity on T2-weighted imaging and low density on T2 fluid attenuated inversion recovery involving multiple white matter were compatible with PML. He died of sepsis 2 months after diagnosis. Autopsy demonstrated progressive multifocal leukoencephalopathy according to characteristic histopathologic picture with multifocal demyelination, bizarre astrocytes formation and basophilic intranuclear inclusion bodies in the oligodendrocytes. JCV genome was demonstrated in the nucleus of oligodendrocytes using in situ hybridization. In conclusion, in AIDS patients with neurologic signs and typical MRI findings who present with multifocal demyelination lesions, PML should be diagnosed clinically.
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Affiliation(s)
- Ming-Hsing Lee
- Department of Pathology, Tzu-Chi University and Buddhist Tzu-Chi General Hospital, Hualien, Taiwan
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Bermejo Velasco PE, Burgos García A. [Neurological complications of celiac disease]. Med Clin (Barc) 2006; 127:500-507. [PMID: 17043005 DOI: 10.1157/13093268] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Abstract
Infection by Polyomavirus JC is a model of chronic active viral infection, closely controlled by the immune system. Progressive multifocal leucoencephalopathy (PML) is a deadly demyelinating disease of the central nervous system, consecutive to the lytic infection of oligodendrocytes by JC virus. Reactivation of JC virus occurs only in the setting of severe cellular immune deficiency. During the last 25 years, the incidence of PML has significantly increased related to the AIDS pandemic and, more recently, to the growing use of immunosuppressive drugs. There is no specific antiviral treatment for PML. Nevertheless, the availability of highly active antiretroviral therapy has changed the clinical course of PML in HIV-infected individuals. One-year mortality has decreased from 90 percent to approximately 50 percent as a result of reconstitution of the immune system. Recent advances in JC virus biology give new perspectives to the pathogenesis of PML. New trends in the understanding of the cellular immune response against the JC virus have direct implications for patient management and may lead to develop future strategy of immunotherapies for PML.
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Affiliation(s)
- J Gasnault
- UF de Suite et Réadaptation, Service de Médecine Interne et des Maladies Infectieuses, Hôpital Universitaire de Bicêtre, APHP, Paris.
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Vaknin A, Eliakim R, Ackerman Z, Steiner I. Neurological abnormalities associated with celiac disease. J Neurol 2005; 251:1393-7. [PMID: 15592736 DOI: 10.1007/s00415-004-0550-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2003] [Revised: 04/20/2004] [Accepted: 05/10/2004] [Indexed: 10/26/2022]
Abstract
BACKGROUND Celiac disease (CD) is a gluten-sensitive enteropathy in genetically susceptible individuals. Anecdotal reports suggest that the nervous system might be affected in the disorder, but the severity and prevalence of such an involvement have not been systematically evaluated. MATERIALS AND METHODS Analysis of files of CD patients diagnosed between 1980 and 1999 for neurological abnormalities. Diagnosis of CD was based on the modified criteria of the European Society for Pediatric Gastroenterology and Nutrition. RESULTS Of 148 CD patients, 18 (12%) had 21 neurological disorders that could not be attributed to any other condition including muscle abnormality (3), epilepsy (3), psychiatric disease (4), peripheral neuropathy (3), cerebrovascular disease (1), myelopathy (1) and Down syndrome (2). Other disorders probably unrelated to CD were present in 8 patients. CONCLUSION If this association is not coincidental, both the central and the peripheral nervous systems may be affected in CD by a spectrum of neurological disorders that are either the outcome of CD or share the same pathogenesis with the enteropathy.
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Affiliation(s)
- Adi Vaknin
- Department of Neurology, Hadassah University Hospital, Jerusalem, Israel
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Demir E, Liebert UG, Söylemezoglu F, Yalaz K, Köse G, Anlar B. Childhood case of progressive multifocal leukoencephalopathy with improved clinical outcome. J Child Neurol 2005; 20:241-4. [PMID: 15832618 DOI: 10.1177/08830738050200031301] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
A 6-year-old boy who had been in remission from acute lymphoblastic leukemia for 2.5 years presented with seizures, hemiparesis, visual loss, and white- and gray-matter lesions on cranial magnetic resonance imaging. The diagnosis of progressive multifocal leukoencephalopathy was established on the detection of JC virus DNA by polymerase chain reaction in brain tissue. The patient was administered several anticonvulsants, amantadine, acyclovir, and ganciclovir. He showed partial recovery. This case illustrates the possibility of long-term survival in progressive multifocal leukoencephalopathy with normal immunologic parameters.
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Affiliation(s)
- Ercan Demir
- Department of Pediatric Neurology, Hacettepe University, Ankara, Turkey
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Abstract
OBJECTIVE During the past 2 decades, celiac disease (CD) has been recognized as a multisystem autoimmune disorder. A growing body of distinct neurologic conditions such as cerebellar ataxia, epilepsy, myoclonic ataxia, chronic neuropathies, and dementia have been reported, mainly in middle-aged adults. There still are insufficient data on the association of CD with various neurologic disorders in children, adolescents, and young adults, including more common and "soft" neurologic conditions, such as headache, learning disorders, attention-deficit/hyperactivity disorder (ADHD), and tic disorders. The aim of the present study is to look for a broader spectrum of neurologic disorders in CD patients, most of them children or young adults. METHODS Patients with CD were asked to fill in a questionnaire regarding the presence of neurologic disorders or symptoms. Their medical charts were reviewed, and those who were reported as having neurologic manifestations underwent neurologic examination and brain imaging or electroencephalogram if required. Their neurologic data were compared with that of a control group matched for age and gender. RESULTS Patients with CD were more prone to develop neurologic disorders (51.4%) in comparison with control subjects (19.9%). These disorders include hypotonia, developmental delay, learning disorders and ADHD, headache, and cerebellar ataxia. Epileptic disorders were only marginally more common in CD. In contrast, no difference was found in the prevalence of tic disorders in both groups. Therapeutic benefit, with gluten-free diet, was demonstrated only in patients with transient infantile hypotonia and migraine headache. CONCLUSION This study suggests that the variability of neurologic disorders that occur in CD is broader than previously reported and includes "softer" and more common neurologic disorders, such as chronic headache, developmental delay, hypotonia, and learning disorders or ADHD. Future longitudinal prospective studies might better define the full range of these neurologic disorders and their clinical response to a gluten-free diet.
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Affiliation(s)
- Nathanel Zelnik
- Department of Pediatrics, Carmel Medical Center, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
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von Einsiedel RW, Samorei IW, Pawlita M, Zwissler B, Deubel M, Vinters HV. New JC virus infection patterns by in situ polymerase chain reaction in brains of acquired immunodeficiency syndrome patients with progressive multifocal leukoencephalopathy. J Neurovirol 2004; 10:1-11. [PMID: 14982723 DOI: 10.1080/13550280490269691] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Progressive multifocal leukoencephalopathy (PML), caused by the human polyomavirus JC (JCV), is an opportunistic infection of the central nervous system (CNS), the histopathological diagnosis of which can be made by routine staining. Very low copy numbers of JCV nucleic acid can be detected in paraffin sections by the specific and highly sensitive in situ polymerase chain reaction (in situ PCR). The authors evaluated JCV infection in 12 acquired immunodeficiency syndrome (AIDS) patients with PML by comparison of hematoxylin and eosin (H&E) staining, in situ hybridization (ISH), and in situ PCR. Phenotype of infected cells was determined by immunohistochemistry with antibodies against glial fibrillary acidic protein (GFAP) or cluster of differentiation 68 (CD68), focusing on cells containing low JC viral copy numbers, and on cell types that are normally not associated with papovavirus infection. The number of detectable JCV-positive oligodendrocytes increased markedly upon PCR amplification and hitherto unknown oligodendrocytic staining patterns were discernible: JCV DNA was detectable in both nucleus and cytoplasm, in cytoplasm only, and as ghost-cell silhouettes appearing as a membranous "rim" of staining product in some cells. The authors suggest that the staining patterns correspond to different stages of the viral replication cycle. Some human immunodeficiency virus (HIV)-type giant cells (HIV-GCs) were shown to contain JCV DNA, thus probably revealing a double infection. Macrophages and HIV-GCs showed staining in the cytoplasm and the nuclei, indicating that they not only may phagocytize JCV particles but may also be actively infected. CD68-positive GCs were occasionally noted to contain a complete JCV DNA-positive nucleus in their center, and were accordingly called JCV-type giant cells (JCV-GCs). Rarely, JCV DNA signals were noted in vascular endothelium. No JCV infection was detectable in lymphocytes, neurons, or in brain tissue of JCV-negative age-matched controls. The authors report new findings concerning inter- and intracellular JCV infection patterns in PML, possibly shedding new light on JCV susceptibility of different cell types in the brain of AIDS patients with PML.
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Affiliation(s)
- Regina W von Einsiedel
- Department of Psychiatry, Laboratory of Molecular Biology, University of Heidelberg, Heidelberg, Germany.
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Sabath BF, Major EO. Traffic of JC virus from sites of initial infection to the brain: the path to progressive multifocal leukoencephalopathy. J Infect Dis 2002; 186 Suppl 2:S180-6. [PMID: 12424695 DOI: 10.1086/344280] [Citation(s) in RCA: 100] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder of the human brain caused by infection with the human polyomavirus, JC. Up to 80% of humans express serum antibodies to JC virus (JCV), yet considerably fewer people develop PML-predominantly those under immunosuppressive conditions. Recent research showed JCV infection in multiple tissues throughout the body, suggesting sites for viral latency. These observations allow the proposal of pathways that JCV may use from sites of initial infection to the brain. Results from investigations into cell-surface receptors, intracellular DNA-binding proteins, and variant viral regulatory regions also suggest mechanisms that may regulate cellular susceptibility to JCV infection. Together, these data elucidate how JCV may establish infection in various cell types, persist latently or become reactivated, and ultimately reach the brain to cause PML.
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Affiliation(s)
- Bruce F Sabath
- Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke/NIH, 36 Convent Drive, Bldg. 36, Rm. 5W21, Bethesda, MD 20892, USA
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Abstract
Coeliac disease is the prototypical gluten-sensitive disease. Clinico-pathological features heal on a gluten-free diet and relapse when gluten is reintroduced. An immunopathology is suspected. A number of neurological syndromes may be associated with coeliac disease but it is unclear whether these are directly or indirectly caused by gluten ingestion. It has been proposed that idiopathic ataxias and central nervous system white matter disease are gluten-sensitive syndromes. This is an exciting hypothesis because it offers new therapeutic possibilities including simple exclusion diets. However, interpretation is difficult because occult sub-clinical coeliac disease occurs commonly and background prevalence needs to be accounted for in population-based studies. This review will attempt to summarize the pertinent literature on this fascinating topic.
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Affiliation(s)
- Adrian J Wills
- Department of Neurology, Queen's Medical Centre, Nottingham, UK.
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Aksamit AJ. Treatment of non-AIDS progressive multifocal leukoencephalopathy with cytosine arabinoside. J Neurovirol 2001; 7:386-90. [PMID: 11517422 DOI: 10.1080/13550280152537292] [Citation(s) in RCA: 86] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Abstract
This open label study determined the outcome of non-AIDS progressive multifocal leukoencephalopathy patients treated with a standard dose of intravenous cytosine arabinoside. Nineteen patients with PML proven by brain biopsy or spinal fluid polymerase chain reaction were treated with intravenous cytosine arabinoside 2 mg/kg per day for 5 days and followed for neurologic outcome by neurologic examination and MRI scanning. Seven of 19 PML patients treated with cytosine arabinoside intravenously improved neurologically. The range of follow-up for these patients was 2.0 to 4.5 years. All were left with neurologic deficits but were functionally improved, and 6 of 7 were able to independently carry out the activities of daily living. Twelve PML patients showed no evidence of response and died rapidly of their disease after treatment (range, 8 days to 6 months). All who survived their neurologic disease recovered from treatment-induced pancytopenia. Cytosine arabinoside given intravenously to non-AIDS PML patients in this small study was associated with a 36% chance of developing stabilization at 1 year. Treatment was associated with significant bone marrow toxicity. The improvement in MRI scan changes in those patients who responded took 6 weeks or longer.
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Affiliation(s)
- A J Aksamit
- Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, USA.
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Abstract
A number of neurological syndromes have been described in association with coeliac disease. These include disorders of the central nervous system encompassing epilepsy, myoclonus, ataxia, internuclear opthalmoplegia, multifocal leukoencephalopathy and dementia. Most of these associated conditions show a poor response to gluten restriction. Peripheral neuropathies, of axonal and demyelinating types, have also been reported and may respond to elimination of gluten from the diet. The mechanism underlying these processes remains obscure but may be immunological or related to trace vitamin deficiencies. Controversially, it has also been claimed that occult coeliac disease accounts for a substantial proportion of patients with neurological dysfunction of unknown cause. Some authorities recommend that cryptogenic ataxias and neuropathies should be routinely screened for the presence of gluten-sensitivity but this remains contentious and has not been universally accepted. This review will attempt to review the clinical and pathological findings in this condition and speculate on pathogenesis and directions for future research.
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Affiliation(s)
- A J Wills
- Department of Neurology, University Hospital Nottingham, UK.
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Pellecchia MT, Scala R, Filla A, De Michele G, Ciacci C, Barone P. Idiopathic cerebellar ataxia associated with celiac disease: lack of distinctive neurological features. J Neurol Neurosurg Psychiatry 1999; 66:32-5. [PMID: 9886447 PMCID: PMC1736152 DOI: 10.1136/jnnp.66.1.32] [Citation(s) in RCA: 75] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
OBJECTIVES To determine the occurrence of celiac disease in a population of ataxic patients without definite diagnosis and to characterise distinctive features which may help to differentiate cerebellar ataxia with and without celiac disease. METHODS Twenty four ataxic patients without definite diagnosis (group A) and 23 ataxic patients with definite diagnosis (group B) were screened for antigliadin (AGAs) and antiendomysium antibodies (EMAs). Patients with a positive AGA or EMA test underwent endoscopic biopsy of the duodenal mucosa. RESULTS There was an increased prevalence of celiac disease in group A (3/24) compared with group B (0/23). None of the celiac patients presented gastrointestinal symptoms or malabsorption signs. None of the ataxic patients with celiac disease had early onset ataxia. CONCLUSIONS Celiac disease is associated with ataxic syndromes without definite diagnosis, suggesting that it plays a part in the pathogenesis of some ataxic syndromes. The absence of distinctive neurological features in ataxic patients with celiac disease suggests that a search should be made for celiac disease markers in all ataxic patients without definite diagnosis.
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Affiliation(s)
- M T Pellecchia
- Dipartimento di Scienze Neurologiche, Sistematica-Università di Napoli Federico II, Italy
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29
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Berger JR, Levy RM, Flomenhoft D, Dobbs M. Predictive factors for prolonged survival in acquired immunodeficiency syndrome-associated progressive multifocal leukoencephalopathy. Ann Neurol 1998; 44:341-9. [PMID: 9749600 DOI: 10.1002/ana.410440309] [Citation(s) in RCA: 132] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Progressive multifocal leukoencephalopathy (PML) complicating the acquired immunodeficiency syndrome (AIDS) is typically inexorably progressive with death usually occurring within 6 months of symptom onset. Occasional patients have been observed to survive longer than 1 year, often with remission of clinical features. In this study, we identify predictive factors for prolonged survival in patients with biopsy proven, AIDS-associated PML, by comparing 7 patients with survival exceeding 12 months from symptom onset with 45 patients with shorter survivals. PML was the presenting manifestation of AIDS in 5 (71.4%) of 7 long-term survivors compared with 8 (17.8%) of 45 short-term survivors. CD4 T-lymphocyte counts were substantially higher in the long-term survivors, with 3 (42.9%) of 7 having counts exceeding 300 cells/mm3 in comparison with only 1 (4.3%) of 23 short-term survivors. Contrast enhancement on radiographic imaging was observed in 3 (50%) of 6 long-term survivors in comparison with 4 (8.9%) of 45 short-term survivors. Neurological recovery and radiographic improvement were not observed in any short-term survivors but were seen in 5 (71.4%) long-term survivors. There was no association between treatment modalities and survival. Predictors of long-term survival in AIDS patients with PML include PML as the heralding manifestation of AIDS, high CD4 T-lymphocyte count at disease onset, lesion enhancement on computed tomographic scan or magnetic resonance imaging, and evidence of recovery of neurological function.
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Affiliation(s)
- J R Berger
- Department of Neurology, University of Kentucky College of Medicine, Lexington 40536-0284, USA
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Albrecht H, Hoffmann C, Degen O, Stoehr A, Plettenberg A, Mertenskötter T, Eggers C, Stellbrink HJ. Highly active antiretroviral therapy significantly improves the prognosis of patients with HIV-associated progressive multifocal leukoencephalopathy. AIDS 1998; 12:1149-54. [PMID: 9677163 DOI: 10.1097/00002030-199810000-00006] [Citation(s) in RCA: 102] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE To evaluate the impact of different antiretroviral therapies on the prognosis of AIDS patients affected by progressive multifocal leukoencephalopathy (PML). METHODS A retrospective analysis of all HIV-infected patients admitted to hospital between 1988 and 1996 found 29 patients (25 men) with histologically or PCR-confirmed PML. Their mean age was 39.3 years. The median CD4 cell count was 40 x 10(6)/l (mean, 106 x 10(6)/l). Six patients had CD4 cell counts > 200 x 10(6)/l. Fourteen patients never received or stopped antiretroviral therapy following diagnosis (group A), 10 patients were treated with nucleoside analogues alone (group B), and five patients started highly active antiretroviral therapy (HAART) including protease inhibitors (group C). RESULTS The median survival following the onset of symptoms was 131 days, but differed significantly between the three groups: group A, 127 days; group B, 123 days; group C, > 500 days (P < 0.0002 for the difference between group C versus group A and B, stratified log-rank test). As of July 1997, four out of five patients on HAART were still alive 391, 500, 543, and 589 days after diagnosis of PML and have either experienced a resolution of the symptoms (three patients) or had progressed very slowly (one patient). A multivariate analysis using Cox regression found younger age at diagnosis to be the only other variable associated with improved survival (P < 0.02). CD4 cell count, gender, prior AIDS diagnosis, mode of HIV transmission, and therapy with foscarnet, cytarabine, or interferon-alpha did not affect survival in this cohort (P > 0.1). CONCLUSION This study of a large cohort of patients with confirmed PML indicates that AIDS patients with PML may benefit significantly from HAART. All patients with PML should be offered optimal antiretroviral combination therapy.
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Affiliation(s)
- H Albrecht
- Emory University, Atlanta, Georgia 30303, USA
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31
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Dörries K, Arendt G, Eggers C, Roggendorf W, Dörries R. Nucleic acid detection as a diagnostic tool in polyomavirus JC induced progressive multifocal leukoencephalopathy. J Med Virol 1998. [DOI: 10.1002/(sici)1096-9071(199803)54:3<196::aid-jmv10>3.0.co;2-g] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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32
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Hadjivassiliou M, Chattopadhyay AK, Davies-Jones GA, Gibson A, Grünewald RA, Lobo AJ. Neuromuscular disorder as a presenting feature of coeliac disease. J Neurol Neurosurg Psychiatry 1997; 63:770-5. [PMID: 9416814 PMCID: PMC2169858 DOI: 10.1136/jnnp.63.6.770] [Citation(s) in RCA: 72] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVES To describe the range of neuromuscular disorders which may be associated with cryptic coeliac disease. METHODS Nine patients were described with neuromuscular disorders associated with circulating antigliadin antibodies, whose duodenal biopsies later confirmed the diagnosis of coeliac disease. Neurological symptoms antedated the diagnosis of coeliac disease in all, and most had minimal or no gastrointestinal symptoms at the onset of the neuromuscular disorder. RESULTS Three patients had sensorimotor axonal peripheral neuropathy, one had axonal motor peripheral neuropathy, one had probable inclusion body myositis and axonal motor peripheral neuropathy, one had polymyositis and sensorimotor peripheral neuropathy, one had mononeuropathy multiplex, one had neuromyotonia, and one had polyneuropathy. CONCLUSION A wide range of neuromuscular disease may be the presenting feature of coeliac disease. This represents the first report of inclusion body myositis and neuromyotonia associated with coeliac disease. Estimation of circulating antigliadin antibodies should be considered in all patients with neuromuscular disease of otherwise obscure aetiology.
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Affiliation(s)
- M Hadjivassiliou
- Department of Neurology, Royal Hallamshire Hospital, Sheffield, UK
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33
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O'Brien MD, Honavar M. Progressive multifocal leucoencephalopathy treated with cytosine arabinoside: 12 year follow up and postmortem findings. J Neurol Neurosurg Psychiatry 1997; 62:427-8. [PMID: 9120477 PMCID: PMC1074120 DOI: 10.1136/jnnp.62.4.427-a] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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von Giesen HJ, Neuen-Jacob E, Dörries K, Jablonowski H, Roick H, Arendt G. Diagnostic criteria and clinical procedures in HIV-1 associated progressive multifocal leukoencephalopathy. J Neurol Sci 1997; 147:63-72. [PMID: 9094062 DOI: 10.1016/s0022-510x(96)05311-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The diagnosis of definite progressive multifocal leukoencephalopathy (PML) has been a neuropathological domain. We reviewed all Human Immunodeficiency Virus Type 1 (HIV-1) seropositive patients in our institution between 01.01.1989 and 31.12.1994 and identified 20/823 cases with PML by clinical and imaging criteria. Diagnosis was neuropathologically confirmed in 5 cases. Diagnostic criteria included rapid onset (< 2 weeks) of multifocal neurological signs and symptoms, advanced immunosuppression and asymmetric uni- or multifocal white matter lesions without mass effect, contrast enhancement or cortical atrophy in magnetic resonance imaging (MRI). The overall incidence of PML was stable over the observation period (approximately equal to 2.5%). The mean age at onset (41.7 years) was significantly lower compared to HIV-1 seronegative PML patients (peak in the sixth decade of life), male patients prevailed (100%). Mean survival (3.9 months) was extremely short. Human polyoma virus JC (JCV) polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF) demonstrated a considerable rate of possible cerebral co-infection with HIV-1 and JCV as well as subclinical infection with JCV. Therefore demonstration of JCV deoxyribonucleic acid by PCR in the CSF alone is not sufficient for clinical PML diagnosis. We present diagnostic criteria on the basis of epidemiological, neuroradiological and CSF parameters that allow us to make the clinical diagnosis of PML. Although quick and safe, routine stereotactic brain biopsy is not necessary to confirm the diagnosis.
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Affiliation(s)
- H J von Giesen
- Department of Neurology, Heinrich-Heine-Universität, Federal Republic of Germany.
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35
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Affiliation(s)
- K Dörries
- Institut für Virologie und Immunbiologie, Universität Würzburg, Germany
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36
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Bhatia KP, Morris JH, Frackowiak RS. Primary progressive multifocal leukoencephalopathy presenting as an extrapyramidal syndrome. J Neurol 1996; 243:91-5. [PMID: 8869394 DOI: 10.1007/bf00878538] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
We report a 63-year-old woman with a progressive illness which began as a parkinsonian syndrome with bilateral rest tremor, limb rigidity and a gait disorder followed by cognitive decline, visuomotor apraxia and visual agnosia. She died 10 years after the onset of the illness and at autopsy the brain showed characteristic changes of progressive multifocal leukoencephalopathy (PML) with the presence of the JC virus confirmed by in situ hybridisation. Neuropathology also showed some unusual features in the form of atypical linear lesions at the cortico-white matter junction. Some of these lesions were active while others were inactive and similar to the rarely described "burnt out" lesions of PML. PML can in rare cases occur without an underlying immune disorder or malignancy (primary PML) and a parkinsonian syndrome can be produced by a predominantly white matter disorder.
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Affiliation(s)
- K P Bhatia
- University Department of Clinical Neurology, Institute of Neurology, London, UK
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37
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Shimada H, Noda K, Mori M, Aoki N, Tajima M, Kato K. Papovavirus detection by electron microscopy in the brain of an elderly patient without overt progressive multifocal leukoencephalopathy. Virchows Arch 1994; 424:569-72. [PMID: 8032537 PMCID: PMC7087722 DOI: 10.1007/bf00191445] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Virions resembling papovavirus were demonstrated in glial cells in the brain of an aged patient without overt progressive multifocal leukoencephalopathy. The patient was not in a severely immunocompromised state. On histological examination, only a few tiny incomplete necrotic foci were found in the subcortical area. These foci were widely dispersed. Rare, swollen oligodendroglial cells and astrocytes in which papovavirus capsid protein (VP-1) was demonstrated immunohistochemically were present around the foci. The two typical types of virus particles i.e. 35 to 40 nm round particles and elongated particles, were observed in the nuclei of the swollen glial cells. The latter were in the minority. Distinct crystals were also found in the nuclei. The centre-to-centre distance of the particles in the crystals, about 40 nm, and the electron-opaque spots of the round-shaped virions and of the elongated particles, were indicative of structural subunits of papovavirus capsids. This case provides further evidence that papovavirus, possibly JC virus, may be reactivated in the brains of aged patients who are not in an immunocompromised state.
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Affiliation(s)
- H Shimada
- Department of Pathology, Tokyo Medical College, Japan
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Abstract
Biotinylated DNA:DNA in situ hybridization was used for determining the presence of JC virus in brain tissues of 67 patients thought to have progressive multifocal leukoencephalopathy. Sixty patients had acquired immunodeficiency syndrome (AIDS) or other illnesses that decreased the cell-mediated immunity. Two patients had no underlying disease, and five others had chronic illnesses not typically associated with reduced cell-mediated immunity. In situ hybridization with biotinylated probe provides specificity and ease of interpretation. The presence of virus can be correlated at the single-cell level with attendant pathologic changes in oligodendrocytes and astrocytes. Not only archival tissue but also tiny fragments of brain biopsy material can be evaluated successfully. Quantifying the technique suggests that the nucleus of a cell labeling for JC virus DNA averages 1,000 copies of replicating genome. Identification of an infected cell is pathologically significant even when only a few such cells are present in a biopsy specimen. Biotinylated DNA or RNA probes are equally effective in identifying infected cells. In situ hybridization will likely continue to be a useful adjunctive procedure for the evaluation of brain tissue from patients suspected of having progressive multifocal leukoencephalopathy.
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Affiliation(s)
- A J Aksamit
- Department of Neurology, Mayo Clinic, Rochester, MN 55905
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39
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von Einsiedel RW, Fife TD, Aksamit AJ, Cornford ME, Secor DL, Tomiyasu U, Itabashi HH, Vinters HV. Progressive multifocal leukoencephalopathy in AIDS: a clinicopathologic study and review of the literature. J Neurol 1993; 240:391-406. [PMID: 8410079 DOI: 10.1007/bf00867351] [Citation(s) in RCA: 87] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
We reviewed the clinical, radiographic, and pathologic features of 15 patients with the acquired immune deficiency syndrome (AIDS) and progressive multifocal leukoencephalopathy (PML). Brain tissue from 10 autopsy and 6 biopsy specimens was studied using: in situ hybridization (ISH) for JC virus (JCV), immunohistochemistry for human immunodeficiency virus (HIV) p24 antigen, and electron microscopy. Thirteen patients presented with focal neurologic deficits, while 2 presented with a rapid decline in mental status. PML was commonly the initial opportunistic infection of AIDS and produced hemiparesis, dementia, dysarthria, cerebellar abnormalities, and seizures. Magnetic resonance imaging was more sensitive than computed tomography in detecting lesions, and often showed multifocal areas of PML. CD4+ T-cell counts were uniformly low (mean 84/mm3), except in 1 patient who improved on 3'-azido-3'-deoxythymidine (AZT). PML involved the cerebral hemispheres, brain stem, cerebellum, and cervical spinal cord. The distribution of brain involvement was consistent with hematogenous dissemination of the virus. In 2 brain specimens, multiple HIV-type giant cells were present within the regions involved by PML. When co-infection by HIV and papovavirus was present, PML dominated the pathological picture. ISH for JCV showed virus in the nuclei of oligodendrocytes and astrocytes. Occasionally there was staining for JCV in the cytoplasm of glial cells and in the neuropil, the latter possibly a correlate of papovavirus spread between myelin sheaths, as seen by electron microscopy. ISH demonstrated more extensive foci of PML than did routine light microscopy.
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40
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Piattella L, Zamponi N, Cardinali C, Porfiri L, Tavoni MA. Endocranial calcifications, infantile celiac disease, and epilepsy. Childs Nerv Syst 1993; 9:172-5. [PMID: 8374923 DOI: 10.1007/bf00272271] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
The authors report on five patients (three female, two male) with multiple brain calcifications, infantile celiac disease, and epilepsy. The clinical, neuroradiological, neurophysiological, EEG and evolutional aspects are assessed. The authors propose that all patients with brain calcifications which cannot be traced to other known pathologies should undergo diagnostic tests for a malabsorption syndrome; analogously, patients affected with infantile celiac disease should undergo EEG, followed by a neuroradiological examination if the EEG pattern is found to be altered.
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Affiliation(s)
- L Piattella
- Children's Neuropsychiatric Ward, Regional Pediatric Hospital G. Salesi, Ancona, Italy
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41
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Ambrosetto G, Antonini L, Tassinari CA. Occipital lobe seizures related to clinically asymptomatic celiac disease in adulthood. Epilepsia 1992; 33:476-81. [PMID: 1592023 DOI: 10.1111/j.1528-1157.1992.tb01695.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
We report the electroclinical ictal findings of four epileptic patients with clinically asymptomatic celiac disease (CD). Celiac disease diagnosis was suspected by past history and/or computed tomography (CT) findings in all patients and confirmed by laboratory tests and jejunal biopsy. All patients had paroxysmal visual manifestations and ictal EEG discharges arising from the occipital lobe. Epilepsy evolution was favorable in two patients and severe in 2, regardless of CT evidence of occipital corticosubcortical calcifications in 2 patients. Occipital lobe seizures may be characteristic of the epilepsy related to CD, and epileptic patients with these seizures of unknown etiology should be carefully investigated for malabsorption. If past history and/or laboratory tests suggest gastrointestinal (GI) dysfunction they should also undergo small intestinal biopsy even if they do not have GI tract symptoms.
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Affiliation(s)
- G Ambrosetto
- Institute of Neurology, University of Bologna, Italy
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42
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Major EO, Amemiya K, Tornatore CS, Houff SA, Berger JR. Pathogenesis and molecular biology of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin Microbiol Rev 1992; 5:49-73. [PMID: 1310438 PMCID: PMC358223 DOI: 10.1128/cmr.5.1.49] [Citation(s) in RCA: 378] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Studies of the pathogenesis and molecular biology of JC virus infection over the last two decades have significantly changed our understanding of progressive multifocal leukoencephalopathy, which can be described as a subacute viral infection of neuroglial cells that probably follows reactivation of latent infection rather than being the consequence of prolonged JC virus replication in the brain. There is now sufficient evidence to suggest that JC virus latency occurs in kidney and B cells. However, JC virus isolates from brain or kidney differ in the regulatory regions of their viral genomes which are controlled by host cell factors for viral gene expression and replication. DNA sequences of noncoding regions of the viral genome display a certain heterogeneity among isolates from brain and kidney. These data suggest that an archetypal strain of JC virus exists whose sequence is altered during replication in different cell types. The JC virus regulatory region likely plays a significant role in establishing viral latency and must be acted upon for reactivation of the virus. A developing hypothesis is that reactivation takes place from latently infected B lymphocytes that are activated as a result of immune suppression. JC virus enters the brain in the activated B cell. Evidence for this mechanism is the detection of JC virus DNA in peripheral blood lymphocytes and infected B cells in the brains of patients with progressive multifocal leukoencephalopathy. Once virus enters the brain, astrocytes as well as oligodendrocytes support JC virus multiplication. Therefore, JC virus infection of neuroglial cells may impair other neuroglial functions besides the production and maintenance of myelin. Consequently our increased understanding of the pathogenesis of progressive multifocal leukoencephalopathy suggests new ways to intervene in JC virus infection with immunomodulation therapies. Perhaps along with trials of nucleoside analogs or interferon administration, this fatal disease, for which no consensus of antiviral therapy exists, may yield to innovative treatment protocols.
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Affiliation(s)
- E O Major
- Section on Molecular Virology and Genetics, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland 20892
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44
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Knight RS, Hyman NM, Gardner SD, Gibson PE, Esiri MM, Warlow CP. Progressive multifocal leucoencephalopathy and viral antibody titres. J Neurol 1988; 235:458-61. [PMID: 3210049 DOI: 10.1007/bf00314247] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Progressive multifocal leucoencephalopathy (PML) is caused by a papovavirus but serum antibody titres are generally considered unhelpful in clinical diagnosis because antibodies to the commonest causal agent (JC virus) are frequently found in normal adults. There is little published information about CSF titres but usually they have not been useful. Two cases of PML, confirmed by autopsy, are described where CSF antibody to JC virus was measured. In one case the JC antibody titre was significantly higher in the CSF than the serum and we suggest that this finding is diagnostically useful. In this case there was a transient stabilization of the disease following treatment with cytarabine with a change in antibody titres suggestive of reduced viral replication in the central nervous system and a host response to the infection. In the other case, which was untreated, rising serum antibody levels indicated active infection with a host response.
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Affiliation(s)
- R S Knight
- Department of Neurology, Radcliffe Infirmary, Oxford, UK
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45
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Stoner GL, Soffer D, Ryschkewitsch CF, Walker DL, Webster HD. A double-label method detects both early (T-antigen) and late (capsid) proteins of JC virus in progressive multifocal leukoencephalopathy brain tissue from AIDS and non-AIDS patients. J Neuroimmunol 1988; 19:223-36. [PMID: 2842376 DOI: 10.1016/0165-5728(88)90004-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
A new double-label immunocytochemical method detects JC virus (JCV) early (T-antigen) and late (capsid) proteins simultaneously in cryostat sections of progressive multifocal leukoencephalopathy (PML) brain tissue from both acquired immunodeficiency syndrome (AIDS) and non-AIDS patients. T-antigen is detected with a monoclonal antibody (PAb 416) followed by goat anti-mouse IgG and mouse Clono-PAP, while capsid proteins are detected by a rabbit polyclonal antiserum to capsid proteins followed by biotinylated goat anti-rabbit IgG and streptavidin-alkaline phosphatase conjugate. The substrates are 3,3'-diaminobenzidine and Vector Red I, respectively. With this method some infected glial cells stain for late (capsid) antigens in the nucleus, while others show early protein (large T-antigen) immunoreactivity. The latter are likely to be astrocytes infected abortively or oligodendrocytes in the early stages of a productive JCV infection.
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Affiliation(s)
- G L Stoner
- Laboratory of Experimental Neuropathology, NINCDS, National Institutes of Health, Bethesda, MD 20892
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Brücke T, Kollegger H, Schmidbauer M, Müller C, Podreka I, Deecke L. Adult coeliac disease and brainstem encephalitis. J Neurol Neurosurg Psychiatry 1988; 51:456-7. [PMID: 3361346 PMCID: PMC1032889 DOI: 10.1136/jnnp.51.3.456] [Citation(s) in RCA: 26] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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47
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Abstract
A case of slowly progressing cerebellar syndrome and pathologically confirmed adult coeliac disease is presented. Neurological symptoms progressed although the patient had no enteric complaints. This case seems to be identical with 18 previously reported cases of encephalopathy and adult coeliac disease. However, the aetiology and pathogenesis of the encephalopathy are still not known.
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Krupp LB, Lipton RB, Swerdlow ML, Leeds NE, Llena J. Progressive multifocal leukoencephalopathy: clinical and radiographic features. Ann Neurol 1985; 17:344-9. [PMID: 4004155 DOI: 10.1002/ana.410170407] [Citation(s) in RCA: 145] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Between April 1982 and March 1984 7 pathologically confirmed cases of progressive multifocal leukoencephalopathy (PML) were diagnosed at our institution. Only 1 case had been seen in the preceding twenty years. Four patients had acquired immunodeficiency syndrome (AIDS). The others had chronic lymphocytic leukemia, Hodgkin's lymphoma, and systemic lupus erythematosus. All patients presented with progressive neurological deficits. In most, the initial computed tomographic (CT) scan was disproportionately less abnormal than the clinical findings. In 5 patients the first CT scan revealed hypodensities of the cerebral white matter which lacked mass effect and did not enhance with contrast agent. The lesions were observed to enlarge progressively on CT scans but often lagged behind the rate of clinical evolution. Although 3 patients were treated with cytosine arabinoside, none improved. PML had similar clinical, radiographic, and pathological features in the AIDS and non-AIDs patients. Of 79 AIDS patients cared for at our institution between December 1979 and December 1983, 3.8% had PML. PML should be suspected in AIDS patients in the presence of the characteristic CT features, especially when CT-clinical dissociation occurs.
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Speelman JD, ter Schegget J, Bots GT, Stam J, Verbeeten B. Progressive multifocal leukoencephalopathy in a case of acquired immune deficiency syndrome. Clin Neurol Neurosurg 1985; 87:27-33. [PMID: 3987138 DOI: 10.1016/0303-8467(85)90062-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The case of a 40-year-old homosexual male with A.I.D.S. (Acquired Immune Deficiency Syndrome) and P.M.L. (Progressive Multifocal Leukoencephalopathy) is described. The importance of a brain biopsy for diagnostic procedures, especially in the case of a patient with A.I.D.S. is stressed. The diagnosis P.M.L. has been made by means of light- and electronic microscopical examination, and the presence of JCV-DNA in the brain tissue has been confirmed by dot hybridization. Various antiviral treatments did not show any effect on the course of the P.M.L.
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Hayashi T, Sumiyoshi A, Tanaka M, Araki S, Minamishima Y. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY. Pathol Int 1985. [DOI: 10.1111/j.1440-1827.1985.tb02216.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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