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J E Bell

Publications and source records attributed to J E Bell.

At least 19 recordsLinked to original sources
PubMed2006

How a neuropsychiatric brain bank should be run: a consensus paper of Brainnet Europe II.

The development of new molecular and neurobiological methods, computer-assisted quantification techniques and neurobiological investigation methods which can be applied to the human brain, all have evoked an increased demand for post-mortem tissue in research. Psychiatric disorders are considered to be of neurobiological origin. Thus far, however, the etiology and pathophysiology of schizophrenia, depression and dementias are not well understood at the cellular and molecular level. The following will outline the consensus of the working group for neuropsychiatric brain banking organized in the Brainnet Europe II, on ethical guidelines for brain banking, clinical diagnostic criteria, the minimal clinical data set of retrospectively analyzed cases as well as neuropathological standard investigations to perform stageing for neurodegenerative disorders in brain tissue. We will list regions of interest for assessments in psychiatric disorder, propose a dissection scheme and describe preservation and storage conditions of tissue. These guidelines may be of value for future implementations of additional neuropsychiatric brain banks world-wide.

Brain↗
PubMed2006

Dura mater-associated Creutzfeldt-Jakob disease: experience from surveillance in the UK.

Between 1970 and 2003, seven cases of human dura mater-associated Creutzfeldt-Jakob disease (CJD) were identified in the UK. Furthermore, we identified a case of CJD in a porcine dura graft recipient. The mean incubation period of the human dura mater cases was 93 (range 45-177) months. The clinico-pathological features of the cases are described and compared with cases previously reported in the world literature.

Adult↗
PubMed2006

The Scottish Perinatal Neuropathology Study--clinicopathological correlation in stillbirths.

OBJECTIVE: To examine the neuropathology of fetuses dying before birth, to determine the timing of any brain damage seen and to ascertain clinical associations of pre-existing brain damage. DESIGN: Population-based observational study. SETTING: All 22 delivery units within Scotland, 1995-1998. SAMPLE: All stillborn fetuses > or =24 weeks of gestation excluding those with chromosomal abnormality or central nervous system/cardiothoracic malformation. METHODS: Clinical detail was collected on all stillborn fetuses. Requests for postmortem included separate request for detailed neuropathological examination. Stillborn fetuses were classified as full term antepartum (normal growth/growth restricted), preterm antepartum (normal growth/growth restricted), intrapartum (full term/preterm), multiple births and stillborn fetuses following abruptions. Clinicopathological correlation attempted to define the timing of brain insult. Placentas were examined for each case where available. MAIN OUTCOME MEASURES: Presence of established and/or recent brain damage. RESULTS Clinical details were available for 471 stillborn fetuses, and detailed neuropathology was possible in 191 cases. Of these 191, 13 were multiple births, 9 died following abruption, 12 were intrapartum deaths and 157 were antepartum stillborn fetuses (99 preterm and 58 full term). Recent or established brain damage was seen in 66% of the entire cohort. Thirty-five percent of all cases showed well-established hypoxic damage predating the last evidence of fetal life, and this was more common in preterm fetuses (P = 0.015), those fetuses with evidence of recent damage (P < 0.001), in pregnancies complicated by pregnancy-induced hypertension (P = 0.044) and those in whom the placenta was <10th centile (P = 0.002). CONCLUSIONS: Brain damage is commonly seen in stillborn infants, and in around one-third of cases, damage predates the period immediately before death. Factors suggesting suboptimal placental function are associated with such damage. Early identification of placental impairment may lead to improved pregnancy outcome.

Abruptio Placentae↗
PubMed2005

An immune control model for viral replication in the CNS during presymptomatic HIV infection.

The brain is targeted by human immunodeficiency virus type 1 (HIV-1) during the course of untreated infection, leading to cognitive impairment, neurological damage and HIV encephalitis (HIVE). To study early dynamics of HIV entry into the brain, we examined a unique autopsy series of samples obtained from 15 untreated individuals who died in the presymptomatic stages of infection from non-HIV causes. HIV was detected and quantified by limiting dilution PCR and genetically characterized in the V3 region of env. Limiting dilution was shown to be essential for correct estimation of genetic partitioning between brain- and lymphoid-associated HIV populations. While no actively expressing HIV-infected cells were detected by immunohistochemistry, variable and generally extremely low levels of proviral DNA were detected in presymptomatic brain samples. V3 region sequences were frequently genetically distinct from lymphoid-associated HIV variants, with association index (AI) values similar to those observed in cases of HIVE. Infiltration of CD8 lymphocytes in the brain was strongly associated with expression of activation markers (MHCII; R = 0.619; P < 0.05), the presence of HIV-infected cells (proviral load; R = 0.608; P < 0.05) and genetic segregation of brain variants from populations in lymphoid tissue (AI value, R = -0.528; P approximately 0.05). CD8 lymphocytes may thus limit replication of HIV seeded into the brain in early stages of infection. Neurological complications in AIDS occur when this control breaks down, due to systemic immunosuppression from HIV that destroys CD8 lymphocyte function and/or through the evolution of more aggressive neuropathogenic variants.

Adult↗
PubMed2005

Distribution of apolipoprotein E alleles in a Scottish healthy newborn population.

The different alleles of the human apolipoprotein E polymorphism, ApoE epsilon2, epsilon3, epsilon4, have important implications for systemic lipid metabolism, immunological function and for the brain in maintenance and in response to injury. Few studies have focussed on their role in early life. The ApoE alleles and genotypes were ascertained in the cord blood of 371 full-term and normal Scottish newborn infants using PCR methodology. The results were compared to previously published data for Scottish adults in late middle age. There was a marginally significant over-representation of epsilon4 and under-representation of epsilon3 alleles in healthy infants as compared with adults. Inspection of the individual genotypes confirms the over-representation of ApoE 4/4 and 2/4 with a reduction in ApoE 2/3 and 3/3 when compared with Scottish adults. Although these results may have occurred by chance, the ApoE epsilon4 allele may confer an increased risk of premature death.

Alleles↗
PubMed2005

Brain damage and axonal injury in a Scottish cohort of neonatal deaths.

Despite the clinical and medicolegal significance attached to perinatal asphyxia, the neuropathological basis of this condition remains obscure. There are very few studies in the literature which correlate the pathological findings in neonatal brains with detailed epidemiological data, and none which are population based. In a Scotland-wide study of neonatal deaths, 70 brains have been examined. On the basis of glial and macrophage reactions, we previously identified infants with putative antepartum brain damage in this cohort and have related these reactions to signs of birth asphyxia. The present study explores the extent of neuronal/axonal injury in these infants since this is likely to be the basis for neurological deficits in surviving infants. We have also investigated these brains for beta-amyloid precursor protein (betaAPP) positivity to determine whether this is a useful marker of neuronal injury in neonates. Neuronal eosinophilia and karyorrhexes were detected in 43% and 27% of the cohort, respectively; maximally in the subiculum and ventral pons, but often present elsewhere. White matter damage was detected in 24% of cases but without classic cystic lesions of periventricular leucomalacia. betaAPP positivity was present in neuronal soma in 52% of cases and, in axons, in 27% of cases, and was seen from as early as 25-weeks gestation. Axonal bulbs were clearly delineated by betaAPP positivity and were usually located in the cerebral white matter and internal capsule, and infrequently in the brain stem. Although white matter damage and betaAPP axonal positivity were often detected in the same cases (P = 0.034), these features also occurred independently of each other. Both neuronal karyorrhexes and white matter betaAPP positivity were significantly correlated with the features of birth asphyxia, particularly a history of seizures. Immunocytochemistry for both betaAPP and glial fibrillary acidic protein proved useful in detecting neuropathological features which escaped detection on routine examination, particularly in preterm infants. The presence together of recent and older damage in individual brains suggests that there is an ongoing neuronal response to cerebral insults. We find that betaAPP is a useful marker of white matter damage in the neonatal brain. Immunopositivity for betaAPP in these circumstances is not attributable to inflicted or accidental trauma. While birth-related trauma cannot be ruled out, hypoxia/ischaemia is a likely cause in these infants. However, the exact pathogenesis of neuronal/axonal injury in the neonatal brain remains unclear.

Amyloid beta-Protein Precursor↗
PubMed2005

Evidence of a breakdown of corticostriatal connections in Parkinson's disease.

Dendritic spines are important structures which receive synaptic inputs in many regions of the CNS. The goal of this study was to test the hypothesis that numbers of dendritic spines are significantly reduced on spiny neurones in basal ganglia regions in Parkinson's disease as we had shown them to be in a rat model of the disease [Exp Brain Res 93 (1993) 17]. Postmortem tissue from the caudate and putamen of patients suffering from Parkinson's disease was compared with that from people of a similar age who had no neurological damage. The morphology of Golgi-impregnated projection neurones (medium-sized spiny neurones) was examined quantitatively. The numerical density of dendritic spines on dendrites was reduced by about 27% in both nuclei. The size of the dendritic trees of these neurones was also significantly reduced in the caudate nucleus from the brains of PD cases and their complexity was changed in both the caudate nucleus and the putamen. Dendritic spines receive crucial excitatory input from the cerebral cortex. Reduction in both the density of spines and the total length of the remaining dendrites is likely to have a grave impact on the ability of these neurones to function normally and may partly explain the symptoms of the disorder.

Aged↗
PubMed2005

Influence of HAART on HIV-related CNS disease and neuroinflammation.

Neuroinflammation has an established link with AIDS-related dementia but has not been investigated in the post-highly active anti-retroviral therapy (HAART) era. In this autopsy study we examined post-HAART cases in Edinburgh for the presence of HIV-related pathology and in well-treated cases for evidence of neuroinflammation. We focused on basal ganglia and the hippocampus, 2 key areas of the brain for cognitive functioning and compared pre- and post-HAART cases for neuroinflammatory status. We find evidence, post-HAART, that there is a high level of microglial/macrophage activation that is comparable with the levels seen, pre-HAART, in HIV encephalitis (HIVE) and AIDS cases. This result was maximal in the hippocampus where microglial/macrophage upregulation in the HAART-treated group exceeded that seen in HIVE. In the basal ganglia, HAART-treated cases showed significantly higher levels of CD68-positive microglia/macrophages than in control brains (p = 0.004), and in the hippocampus levels were significantly higher than those seen in control cases, pre-HAART AIDS, and presymptomatic brains (p = 0.01). However, lymphocyte levels in the areas examined were low in HAART-treated cases. We conclude that there is a surprising degree of ongoing neuroinflammation in HAART-treated patients, particularly in the hippocampus. This may pose a threat for the future health of individuals maintained long-term on HAART therapy.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Third ventricular chordoid glioma: clinicopathological study of two cases with evidence for a poor clinical outcome despite low grade histological features.

Chordoid glioma of the third ventricle is a rare glial tumour whose precise histogenesis remains uncertain. We describe two cases that presented recently to our department and review the background literature. The neoplasm tends to occur in women and its clinical presentation is variable, resulting from acute hydrocephalus or impingement upon local structures. However, the radiological appearance is distinct, with an ovoid shape, hyperdensity and uniform contrast enhancement on computerized tomography and magnetic resonance imaging. Intraoperative smear diagnosis is difficult because of the lack of specific features, although the presence of metachromatic extracellular mucin may be useful. The characteristic histological appearance is that of cords and clusters of cohesive, oval-to-polygonal epithelioid cells with abundant eosinophilic cytoplasm and a mucinous background. There is often a mixed chronic inflammatory infiltrate with lymphocytes and plasma cells with Russell bodies. The main differentials for histological diagnosis include chordoid meningiomas, pilocytic astrocytomas and ependymomas. An immunohistochemical panel including antibodies to glial fibrillary acidic protein, CD 34, epithelial membrane antigen, pan cytokeratin, S100 and vimentin can be used to distinguish between these possibilities. Ultrastructurally the tumour cells have basal lamina and microvilli, reminiscent of ependymomas. The clinical outcome in our cases was poor because of the location of the lesion and its close relation to the hypothalamus. Limited follow-up after surgery with or without radiotherapy suggests that as-full-as-possible resection favours a better outcome, although surgery in this area carries significant operative risks.

Adult↗
PubMed2005

Does drug abuse alter microglial phenotype and cell turnover in the context of advancing HIV infection?

The aim of this study was to test the effects of drug abuse, in particular opiate abuse, on the phenotype and turnover of microglial cells within the brain in the context of advancing HIV infection. Basal ganglia and hippocampus sections were studied in 51 cases divided into six groups: HIV-negative normal controls, HIV-negative drug abusers, AIDS nondrug abusers, AIDS drug abusers, HIV encephalitis (HIVE) nondrug abusers and HIVE drug abusers. None of the cases studied had received highly active anti-retroviral therapy (HAART). Microglial phenotypes were defined using CD14, CD16, CD68 and major histocompatibility class II (MHC II). Microglial turnover was assessed using terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL) (DNA damage), BAX (proapoptotic marker), Fas (CD95) (proapoptotic), proliferating cell nuclear antigen (PCNA) (proliferation and DNA repair), Ki-67 (cell proliferation) and BCL-2 (antiapoptosis). We find increased expression of MHC II and CD16 in response to drug abuse. We also noted increased levels of TUNEL positivity in drug abusers compared to nondrug abusers, although conversely we found lower levels of BAX in those who had abused drugs. We find no evidence of microglial proliferation in any of our study groups, including HIVE, although HIV infection leads to increased expression of CD16, CD68 and MHC II. CD14 expression was restricted to perivascular microglia in all groups (including normal controls) apart from the two HIVE groups where some but not all cases also showed parenchymal expression of CD14. In contrast, CD16 was found in parenchymal microglia in all groups. Using high-pressure antigen retrieval and tyramide signal amplification, we find moderately high levels of CD16 expression in the parenchyma of normal brains which is not normally observed using standard avidin/biotin complex (ABC) techniques. This suggests that a low basal expression of CD16 occurs in many resident microglial cells which may potentially be upregulated in HIV-infected individuals. From these data, we suggest that not all the CD16+ parenchymal cells detected in AIDS brains (using ABC) represent influx of monocyte lineage cells from the blood. Finally the increased expression of MHC II and CD68 detected in drug abusers with HIVE compared to nondrug abusers with HIVE suggests that the combination of drug abuse and HIV infection has a greater deleterious effect on the brain than either individual insult on its own.

Adolescent↗
PubMed2005

Hyperphosphorylated tau and amyloid precursor protein deposition is increased in the brains of young drug abusers.

Drug abuse is a major problem worldwide. The incidence of drug-related deaths attributed to opiate abuse is increasing annually. Apart from routine examination, little is known of the neuropathology of drug abuse. We, and others, have shown previously that drug abuse is associated with microglial activation. We hypothesised that neuroinflammation might lead to premature neurodegeneration in drug abusers. We investigated the brains of young opiate abusers (n=34, all<40 years) for the presence of proteins associated with neurodegenerative diseases and compared them with the brains of age-matched, non-drug users (n=16) all of whom died suddenly. Detailed immunohistochemical analysis of the hippocampus, brainstem and basal ganglia for hyperphosphorylated tau, beta-amyloid, beta-amyloid precursor protein (betaAPP) and ubiquitin demonstrated an excess of AT 8-positive neurofibrillary tangles (NFT) in the drug abusers. These were not only more prevalent in the drug abusers than in controls (44%vs. 19%) but also involved more brain areas. In controls NFT were confined to the entorhinal cortex whereas in drug users they were also found in the subiculum, temporal neocortex, nucleus basalis of Meynert and the locus coeruleus. Virtually no amyloid plaques were present but betaAPP positivity was again much more common in drug abusers than controls (73%vs. 20% in the brainstem and 59%vs. 23% in the temporal lobe). There is no suggestion that these drug abusers had displayed major cognitive impairment although detailed neuropsychological assessment is difficult in this subject group. Likely causes of hyperphosphorylated tau deposition in drug abuse include hypoxic-ischaemic injury, microglial-associated cytokine release and possibly drug-associated neurotoxicity or hepatitis. Head injury, which is another major risk factor, does not appear to have contributed to our findings. Genetic factors also merit consideration. It is unclear at present how much of the hyperphosphorylated tau detected in these young drug abusers represents a transitory phenomenon.

Adolescent↗
PubMed2004

An update on the neuropathology of HIV in the HAART era.

This review compares the neuropathology of highly active antiretroviral therapy (HAART)-treated HIV+ individuals with the reported central nervous system (CNS) findings from the pre-HAART era. HAART has had considerable success in combating HIV-related immune collapse and has prevented many of the former end-stage complications of AIDS. However, with increased survival times the prevalence of minor HIV-associated cognitive impairment appears to be rising among treated patients and this may be a particular risk for older individuals. HIV encephalitis (HIVE) is still prevalent in treated patients although attenuated forms of HIVE and CNS opportunistic disorders are also observed. Some subjects show very significant CNS lymphocytic infiltrates in the context of HAART-induced immune reconstitution. HIV-associated cognitive impairment correlates best with the increased presence of activated, though not necessarily infected, microglia and CNS macrophages. This suggests that indirect mechanisms of neuronal injury and loss occur in HIV/AIDS as a basis for dementia since neurones are not themselves productively infected. Research to elucidate the mechanisms of neuronal injury in HIV/AIDS may contribute to the understanding of CNS function not only in HAART-treated subjects but also in other neurodegenerative disorders.

Acquired Immunodeficiency Syndrome↗
PubMed2004

The Scottish perinatal neuropathology study: clinicopathological correlation in early neonatal deaths.

BACKGROUND: A proportion of neonatal deaths from asphyxia have been shown to be associated with pre-existing brain injury. OBJECTIVES: (a) To compare the epidemiology of infants displaying signs of birth asphyxia with those not showing signs; (b) to examine the neuropathology and determine if possible the timing of brain insult comparing asphyxiated with non-asphyxiated infants; (c) to compare the clinical features of those born with birth asphyxia with and without pre-labour damage. METHODS: Over a two year period, all 22 Scottish delivery units collected clinical details on early neonatal deaths. Requests for post mortem included separate requests for detailed neuropathological examination of the brain. Infants were classified into two groups: birth asphyxia and non-birth asphyxia. Clinicopathological correlation was used to attempt to define the time of brain insult. RESULTS: Detailed clinical data were available on 137 of 174 early neonatal deaths that met the inclusion criteria. Seventy of 88 parents who had agreed to post mortem examination consented to a detailed examination of additional samples from the brain; in 53 of these cases the infant was born in an asphyxiated condition. All asphyxiated and encephalopathic infants, 38% of mature and 52% of preterm infants with features of birth asphyxia but without encephalopathy, and only one of 12 infants without any signs of birth asphyxia showed damage consistent with onset before the start of labour. CONCLUSIONS: In a large proportion of neonatal deaths, brain injury predates the onset of labour. This is more common in infants born in an asphyxiated condition.

Apgar Score↗
PubMed2003

Phenotypic analysis of peripheral blood gammadelta T lymphocytes and their targeting by human immunodeficiency virus type 1 in vivo.

There is increasing evidence that a wider range of lymphoid cell types other than CD4(+) T helper lymphocytes are infected with HIV-1 in vivo, including CD8 lymphocytes, natural killer cells, and reticulodendritic cells. Each potentially contributes to the reservoir of infected cells that resist antiviral treatment and to the impairment of immune responses in AIDS. By quantitative PCR for HIV proviral sequences we have now obtained evidence for substantial infection of gammadelta lymphocytes, contributing 3-45% of the proviral load in peripheral blood. A large proportion of gammadelta lymphocytes constitutively expressed the chemokine receptors CCR5 and CXCR4, with evidence for marked up-regulation of CD8 in samples from HIV-infected individuals, corresponding to an activated phenotype. That gammadelta lymphocytes might be susceptible to HIV infection was investigated using in vitro infectivity assays of recombinant HIV-expressing green fluorescent protein, followed by flow cytometry. gammadelta, CD4, and CD8 lymphocytes were each productively infected, with gammadelta lymphocytes showing the greatest susceptibility. For each cell type, blocking assays with an anti-CD4 monoclonal antibody indicated that entry was CD4-dependent.

Adult↗
PubMed2003

Neuronal injury in hippocampus with human immunodeficiency virus transactivating protein, Tat.

Patients with human immunodeficiency virus infection may develop a dementing illness. Using both in vitro and in vivo models, we investigated the susceptibility of the hippocampal formation to the Tat protein of human immunodeficiency virus. We also determined the pattern of hippocampal injury in patients with human immunodeficiency virus encephalitis. Following exposure of hippocampal slices to Tat, marked susceptibility of CA3 region with relative insensitivity of the CA1/2 region was observed. Injection of Tat into different regions of the rat hippocampus produced similar neuronal loss in both CA3 region and the dentate gyrus. In animals administered Tat, lesions were dose-dependent and immunohistochemical staining showed marked gliosis and loss of microtubule associated protein-2 in the affected areas at 3 days post-injection. Interestingly, synaptophysin staining was relatively preserved. In hippocampal tissue from patients with human immunodeficiency virus encephalitis, loss of microtubule-associated protein-2 staining was reduced in the molecular layer of the dentate gyrus. The results of our experiments demonstrate a unique pattern of hippocampal injury in organotypic culture and rats exposed to Tat. Our observations that patients with human immunodeficiency virus reveal a similar pattern of damage suggests that Tat protein may be pathophysiological relevant in human immunodeficiency virus encephalitis.

Adolescent↗
PubMed2003

Relationship of Nef-positive and GFAP-reactive astrocytes to drug use in early and late HIV infection.

Reactive astrocytosis is a well-documented feature of HIV encephalitis (HIVE), but it is unclear whether restricted infection of astrocytes contributes to this phenomenon. In addition, the part played by reactive and/or infected astrocytes in AIDS-related dementia is not fully understood. In this study of patients at different stages of the human immunodeficiency virus (HIV) infection, who had been treated at most with one antiretroviral drug, reactive astrocytes were identified by immunopositivity for glial fibrillary acidic protein (GFAP) and infected astrocytes by positivity for HIV Nef protein. Results were compared for drug-using AIDS patients with (n=9) and without (n=7) HIVE, for presymptomatic HIV-positive drug users (n=12) and for control HIV-negative subjects (n=20), including a group who used drugs (n=10). GFAP-reactive astrocytes in both grey and white matter were significantly more numerous in HIVE subjects than in each of the other groups but did not correlate with viral load. Nef-positive astrocytes were confined to HIVE cases and to white matter, but were numerous in only one subject who was treatment-naive. Nef-positive microglia were identified in all HIVE cases and in occasional AIDS and presymptomatic subjects who did not have HIVE. The results suggest that astrocytes may form an additional viral reservoir in late HIV infection and may contribute to HIVE. However, the number of GFAP-positive astrocytes was neither increased in pre-AIDS nor in drug abuse, in contrast with microglia which we have shown previously to be up-regulated in both states.

AIDS Dementia Complex↗
PubMed2003

B lymphocytes in the normal brain: contrasts with HIV-associated lymphoid infiltrates and lymphomas.

In recent years evidence has accumulated which suggests that the brain may not be the immunologically privileged site it was once considered to be. It is now widely accepted that T lymphocytes perform surveillance functions in normal brain parenchyma. However, as yet there are no reports of B lymphocytes entering brain parenchyma in the healthy state. This study aimed to determine first the prevalence of B lymphocytes in normal brain, and subsequently whether advancing HIV infection led to changes in the brain B lymphocyte population, which might contribute to the increased risk of lymphoma seen in AIDS. Our results show that B lymphocytes do enter all parts of the normal human brain in very low numbers and that the B lymphocytes within the brain parenchyma display an activated (CD23 positive) phenotype. In contrast, intravascular B lymphocytes have a much lower expression of activation markers. B lymphocytes were found in increased numbers in both the brain parenchyma and perivascular spaces of pre-AIDS brains. However, brains from the majority of AIDS subjects, including those with primary CNS lymphoma (PCNSL) (outside the area of neoplastic involvement) contained fewer B lymphocytes than normal or pre-symptomatic HIV-infected brains. A subset of AIDS brains, previously shown to have pleomorphic lymphoid infiltrates in the perivascular spaces, had significantly increased numbers of B lymphocytes in both the brain parenchyma and perivascular spaces. Virtually all AIDS-related PCNSL are known to be Epstein-Barr Virus (EBV) positive, in contrast to non-HIV PCNSL and non-CNS AIDS-related lymphomas. We examined the EBV status of brain parenchymal B lymphocytes to investigate whether EBV-positive B lymphocytes are more frequent in HIV-infected brains than normal, thus explaining the propensity for CNS lymphomas in AIDS. In situ hybridization studies showed EBV positivity only in AIDS-related PCNSL cases within the lymphoma deposits. PCR-based studies detected high EBV copy numbers in PCNSL tumour tissue, and low copy numbers in AIDS cases with pleomorphic lymphoid infiltrates. As none of the B lymphocytes in this latter group were EBV positive on in situ hybridization, bearing in mind that this appears to be a prerequisite for PCNSL development, we find no evidence that pleomorphic infiltrates represent a pre-malignant PCNSL state.

Adolescent↗