Paraneoplastic neurological syndromes are unusual in prostatic cancer, and paraneoplastic cerebellar degeneration associated with adenocarcinoma of the prostate is rare. Here we report a 68year old man who developed progressive ataxia in the setting of stage D2 adenocarcinoma of the prostate and whose MRI showed cerebellar atrophy. The patient's serum produced a previously undescribed pattern of immunoreactivity, binding to nuclei and cytoplasm of Purkinje cells, deep cerebellar neurons, scattered cells in the molecular and granule cell layers, and neuronal populations in thalamus, cerebral cortex, and hippocampus but not with liver or kidney. The patient's IgG also labeled a 65kDa protein, discrete from Yo antigen, in Western blots of Purkinje cell lysates and did not react with blotted recombinant HuD, Ri, Yo, or amphiphysin proteins. Sera from neurologically normal patients with adenocarcinoma of the prostate did not contain this antibody, and the patient's serum did not react with normal prostate or with prostatic adenocarcinomas from other individuals. Prostatic adenocarcinoma may occasionally be accompanied by development of anticerebellar antibodies. Adenocarcinoma of the prostate should be considered as a possible underlying malignancy in older males with unexplained progressive cerebellar degeneration.

Progressive multifocal leucoencephalopathy (PML) is an opportunistic demyelinating infection of immunocompromised patients, caused by the human polyomavirus, JC virus. Prior to 2005, PML had not been described in patients with MS. In early 2005, however, two cases of PML were reported in patients with MS treated with the alpha-antegrin inhibitor, natalizumab. A third case was subsequently described in a patient with Crohn's disease who had also received the agent. These three cases resulted in withdrawal of natalizumab from the market and have had major implications for its reintroduction into clinical use. In this review, we discuss current knowledge concerning PML and its causative agent, the possible role of natalizumab in initiating PML in patients with MS, and the challenges posed by the risk of this infection as the drug returns to clinical use.

Primary cultures of lungs, kidneys, and glial cells derived from mid-gestation Syrian hamsters were inoculated with 105 hemagglutinating units of murine K-papovavirus and were serially subcultivated to allow appearance of lines of persistently infected or transformed cells. K virus did not replicate in renal cell cultures and produced only transient productive infection of lung cells. Evidence of K virus-induced cell transformation was not detected in either of these cultures. Inoculation of glial cultures with K virus, however, resulted initially in a protracted infection in which 80–100 percent of cells expressed K virus V antigen for 18 subcultivations and in which cloning experiments suggested that all cells in the culture contained the viral genome. After 18 subcultivations numbers of positive cells rapidly dimished, and cells appeared which exhibited altered morphology and density dependence. These altered cells (KVHG3 cells) grew well in serum-free media, could be cloned in soft agar, and were negative for infectious virus or K virus V antigen. Although KVHG3 cells did not exhibit staining when reacted with antisera to K virus T antigen, Southern blot analysis of these cultures demonstrated the presence of K virus DNA integrated into the host chromosomal DNA and indicated that some rearrangement of the viral genome had occurred. Attempts to produce tumors in hamsters with these cells were unsuccessful, as were attempts to induce tumors in newborn hamsters by intracranial inoculation of K virus. The present study demonstrates that K virus is capable of causing productive infection and cell transformation in primary cultures of fetal hamster glial cells but that other hamster cell types are relatively resistant to the virus and that both K virus and K virus-transformed hamster cells are poorly oncogenic for hamstersin vivo.

A Neurology Clerkship Core Curriculum was recently approved by the American Academy of Neurology, the American Neurological Association, and the Association of University Professors of Neurology.1 This curriculum has been considered a landmark effort because it represents a broad consensus of “virtually every leading neurologist teaching medical students” in the United States.2 The objective of this curriculum is to address the educational needs of future physicians, regardless of whether they pursue neurology as a specialty. The proposed curriculum is assumed to include a required, 4-week clerkship placed in the 3rd year of the medical school experience. Although the curriculum has been defined, “almost nothing about evaluation of achieving the goals of the clerkship” is available.2 We decided to elicit feedback from students to determine whether the goals of our clerkship were being achieved. We also reasoned that our predominantly 4th year clerkship would provide a more experienced perspective on the question of 3rd year vs 4th year placement of the clerkship. Our 4-week clerkship is offered at multiple sites. The numbers of students in each placement during the 4 years of this study (1999 to 2003) were University Hospital (111), Veterans Administration …

Archetype SV40, obtained directly from its natural host, is characterized by a single 72-bp enhancer element. In contrast, SV40 grown in cell culture almost invariably exhibits partial or complete duplication of the enhancer region. This distinction has been considered important in studies of human tumor material, since SV40-associated tumor isolates have been described having a single enhancer region, suggesting natural infection as opposed to possible contamination by laboratory strains of virus. However, the behavior of archetypal SV40 in cultured cells has never been methodically studied. In this study we reengineered nonarchetypal 776-SV40 to contain a single 72-bp enhancer region and used this reengineered archetypal DNA to transfect a number of simian and human cell lines. SV40 DNA recovered from these cells was analyzed by restriction endonuclease analysis, PCR, and DNA sequencing. Reengineered archetype SV40 propagated in green monkey TC-7 or BSC-1 kidney cells remained without enhancer region duplication even after extensive serial virus passage. Archetype SV40 grown in all but one of the rhesus or human cell lines initially appeared exclusively archetypal. However, when virus from these cell types was transferred to green monkey cells, variants with partial enhancer duplication appeared after as little as a single passage. These findings suggest (1) that virus with a single 72-bp enhancer may persist in cultured cells of simian and human origin; (2) that variants with partially duplicated enhancer regions may arise within cell lines in quantities below limits of detection; (3) that these variants may enjoy a selective advantage in cell types other than those from which they arose (e.g., green monkey kidney cells); and (4) that certain cell lines may support a selective growth advantage for the variants without supporting their formation. Our data indicate that enhancer duplication may also occur in human as well as rhesus kidney cells. Thus, detection of enhancer region duplication may not, a priori, indicate laboratory contamination, nor does detection of a single 72-bp enhancer exclude the possibility that contamination may have occurred. These findings may be of relevance to studies attempting to detect SV40 DNA in human tumors or other clinical specimens.

Prior to the discovery of antibiotics, bacterial meningitis was almost invariably fatal: over 95% of individuals developing bacterial meningitis died, and the few individuals surviving infection were neurologically devastated. With the advent of antibiotics, bacterial meningitis became a treatable condition, and the primary objective in the patient with bacterial meningitis became, appropriately, prompt diagnosis and initiation of antibiotic therapy. Until the latter part of the twentieth century, bacterial meningitis was predominantly a condition of infancy and early childhood, caused in large part by Haemophilus influenzae type B. Streptococcus pneumoniae , although the most common cause of meningitis in adults, received relatively little attention in terms of its pathogenesis, mechanisms of injury, and optimal therapy. Immunization against Haemophilus influenzae type B brought about a profound decrease in cases of early childhood meningitis in developed countries. Streptococcus pneumoniae is now the most common agent of bacterial meningitis for children as well as adults (Schuchat et al ., 1997). The article by Kastenbauer et al ., in this issue of Brain , reminds us that there is much about the pathogenesis of pneumococcal meningitis which we still do not understand and that, despite antibiotics, current therapy of S. pneumoniae meningitis leaves …

Anti-Hu antibody is an antineuronal autoantibody found in a subset of patients with paraneoplastic neurological disease. The antibody was first associated with small cell carcinoma of the lung and is most often used as a marker for this neoplasm in patients presenting with suspected paraneoplastic syndromes. Here we report a patient with a multifaceted neurological disorder in the setting of Merkel cell carcinoma. The patient's serum contained antibodies against the Hu antigen, and the expression of the Hu antigen was demonstrated in the patient's tumor.

Annals of NeurologyVolume 47, Issue 1 p. 4-5 Editorial Cytotoxic T cells in paraneoplastic cerebellar degeneration John E. Greenlee MD, John E. Greenlee MD Neurology Service, Veterans Affairs Medical Center and Department of Neurology, University of Utah School of Medicine, Salt Lake City, UTSearch for more papers by this author John E. Greenlee MD, John E. Greenlee MD Neurology Service, Veterans Affairs Medical Center and Department of Neurology, University of Utah School of Medicine, Salt Lake City, UTSearch for more papers by this author First published: 19 April 2001 https://doi.org/10.1002/1531-8249(200001)47:1<4::AID-ANA3>3.0.CO;2-2Citations: 10AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Dropcho EJ, Chen YT, Posner JB, Old LJ. Cloning of a brain protein identified by autoantibodies from a patient with paraneoplastic cerebellar degeneration. Proc Natl Acad Sci USA 1987; 84: 4552–4556 2 Sakai K, Mitchell DJ, Tsukamoto T, Steinman L. Isolation of a complementary DNA clone encoding an autoantigen recognized by an anti–neuronal cell antibody from a patient with paraneoplastic cerebellar degeneration. Ann Neurol 1990; 28: 692–698 3 Fathallah-Shaykh H, Wolf S, Wong E, et al. Cloning of a leucine-zipper protein recognized by the sera of patients with antibody-associated paraneoplastic cerebellar degeneration. Proc Natl Acad Sci USA 1991; 88: 3451–3454 4 Borges LF, Elliott PJ, Gill R, et al. Selective extraction of small and large molecules from the cerebrospinal fluid by Purkinje neurons. Science 1985; 228: 346–348 5 Borges LF, Busis NA. Intraneuronal accumulation of myeloma proteins. Arch Neurol 1985; 42: 690–695 6 Jaeckle KA, Stroop WG, Greenlee JE, et al. Intraventricular injection of paraneoplastic anti–Purkinje cell antibody in a rat model. Neurology 1986; 36: 332 (Abstract) 7 Graus F, Illa I, Agusta M, et al. Effect of intraventricular injection of anti-Purkinje cell antibody (anti-Yo) in a guinea pig model. J Neurol Sci 1991; 106: 82–87 8 Greenlee JE, Burns JB, Rose JW, Jaeckle KA. Uptake of systemically administered human anticerebellar antibody by rat Purkinje cells following blood-brain barrier disruption. Acta Neuropathol Berl 1995; 89: 341–345 9 Sakai K, Gofuku M, Kitagawa Y, et al. Induction of anti–Purkinje cell antibodies in vivo by immunizing with a re- combinant 52-kDa paraneoplastic cerebellar degeneration–associated protein. J Neuroimmunol 1995; 60: 135–141 10 Tanaka M, Tanaka K, Onodera O, Tsuji S. Trial to establish an animal model of paraneoplastic cerebellar degeneration with anti-Yo antibody: 1. Mouse strains bearing different MHC molecules produce antibodies on immunization with recombinant Yo protein but do not cause Purkinje cell loss. Clin Neurol Neurosurg 1995; 97: 95–100 11 Tanaka K, Tanaka M, Igarashi S, et al. Trial to establish an animal model of paraneoplastic cerebellar degeneration with anti-Yo antibody: 2. Passive transfer of murine mononuclear cells activated with recombinant Yo protein to paraneoplastic cerebellar degeneration lymphocytes in severe combined immunodeficiency mice. Clin Neurol Neurosurg 1995; 97: 101–105 12 Greenlee JE, Parks TN, Jaeckle KA. Type IIa (“anti-Hu”) antineuronal antibodies produce destruction of rat cerebellar granule neurons in vitro. Neurology 1993; 43: 2049–2054 13 Furneaux HM, Wong E. Incubation of tumor cells with anti-Hu monoclonal results in apoptosis. Neurology 1994; 44(Suppl 2): A377 (Abstract) 14 Albert ML, Darnell JC, Bender A, et al. Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nat Med 1998; 4: 1321–1324 15 Tanaka M, Tanaka K, Shinozawa K, et al. Cytotoxic T cells react with recombinant Yo protein from a patient with paraneoplastic cerebellar degeneration and anti-Yo antibody. J Neurol Sci 1998; 161: 88–90 16 Tanaka M, Tanaka K, Idezuka J, Tsuji S. Failure to detect cytotoxic T cell activity against recombinant Yo protein using autologous dendritic cells as the target in a patient with paraneoplastic cerebellar degeneration and anti-Yo antibody. Exp Neurol 1998; 150: 337–338 17 Albert ML, Austin LM, Darnell RB. Detection and treatment of activated T cells in the cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration. Ann Neurol 2000; 47: 9–17 Citing Literature Volume47, Issue1January 2000Pages 4-5 ReferencesRelatedInformation

The past several years have seen major advances in our understanding of neurological infectious diseases, their diagnosis, and their treatment. Along with these advances, however, new information about infectious agents and new therapeutic options have also introduced both uncertainty and controversy in the approach and management of patients with diseases of the central nervous system. Here, we discuss six such areas: the long-term efficacy of HAART therapy in treatment of HIV infection; the role of viral infection in chronic fatigue syndrome; Rasmussen's encephalitis as an infectious or autoimmune disease; the spectrum of neurological diseases caused by rickettsial infection; the role of Mycoplasma pneumoniae in human central nervous system disease; and the possible association of Chlamydia pneumoniae and human herpesvirus 6 with multiple sclerosis.

Nonpolio enteroviral encephalitis usually presents as a diffuse, generalized encephalitis. Focal cerebral involvement by nonpolioviruses is uncommon, and neuroradiologic studies in these cases are usually normal. The authors present a case of a 5-year-old male with an acute encephalitic illness and bilateral lesions of the hippocampi on magnetic resonance imaging. Enteroviral nucleic acids were detected in the cerebrospinal fluid by the reverse transcription polymerase chain reaction. The findings suggest that enteroviral infection should be considered in the differential diagnosis of acute bilateral hippocampal encephalitis in patients in whom polymerase chain reaction fails to demonstrate the presence of herpes simplex virus.

Anti-Yo (type I) autoantibodies reactive with Purkinje cell cytoplasmic antigens of 34 and 62 kd are found in the serum and cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration associated with cancer of the ovary, uterus, adnexa, or breast. Anti-Yo antibody response is rarely associated with other tumors. Here, we present a patient who developed paraneoplastic cerebellar degeneration and anti-Yo antibody response in association with transitional cell carcinoma of the bladder. The presence of anti-Yo antibodies was confirmed by immunofluorescence assay and by Western blot analysis against both Purkinje cell lysates and the CDR62 fusion protein. Yo antigen was demonstrated in sections of the patient's tumor. Antibody titers fell after tumor removal. Transitional cell carcinoma should be considered in patients presenting with subacute cerebellar degeneration and anti-Yo antibody response in whom ovarian, adnexal, uterine, or breast cancer cannot be detected.