Related Primary Central Nervous System Research Articles

Diagnostic value of EBV-DNA in CSF for PCNSL in AIDS patients with focal brain lesions: A meta-analysis of diagnostic test

Epstein-Barr virus (EBV) infection plays a crucial role in the progression of acquired immunodeficiency syndrome related primary central nervous system lymphoma (AR-PCNSL). This study aimed at evaluating the diagnostic value of cerebrospinal spinal fluid (CSF) EBV-deoxyribonucleic acid (DNA) for PCNSL in patients with infection of human immunodeficiency (HIV) virus through a meta-analysis of diagnostic test. A systematic search in PubMed, Embase, Web of Science, Wanfang, Chinese Biomedical Database and Chinese National Knowledge Infrastructure was conducted before May 10, 2022. Heterogeneity among the studies was assessed using Q test and I2 statistics. Publication bias was assessed using the Deek's funnel plot asymmetry test. Statistical analyses were performed using Stata 16.0 software. The pooled sensitivity, specificity, positive and negative likelihood ratios (PLR and NLR), diagnostic odds ratios (DOR) and 95% confidence intervals (CI) were caculated to evaluate the diagnostic value. A symmetric receiver operating characteristic (SROC) curve and the area under the SROC curve (AUC) were constructed to evaluate the test-performance. Twelve studies were included in the final analyses, with a total of 141 patients with AR-PCNSL and 590 controls. The pooled diagnostic values were sensitivity of 0.83 (95% CI: 0.73-0.90), specificity of 0.95 (95%CI: 0.89-0.98), PLR of 17.8 (95%CI: 6.8-46.1), NLR of 0.17 (95%CI: 0.10-0.30), DOR of 102 (95%CI: 28-379), and AUC of 0.94 (95%CI: 0.91-0.96). In summary the overall diagnostic value of CSF EBV-DNA is very high and it can be a reliable diagnostic biomarker for AR-PCNSL.

Case Report: Predominant brain superficial location of Epstein-Barr virus-related primary central nervous system diffuse large B cell lymphoma in a young woman with primary Sjögren’s syndrome

Epstein-Barr virus (EBV)- related primary central nervous system (CNS) diffuse large B cell lymphoma (DLBCL) is very rare in young patients without immunodeficiency. The predominant brain superficial location of EBV-related primary CNS DLBCL, and its’ concurrence with EBV-related lumbar-sacral radiculitis are special and have not been described previously. A young female patient presented with multiple cranial neuropathies, radiculopathy of lower limbs, and urinary retention. Her series brain magnetic resonance imaging (MRI) revealed dynamic changes, starting from lesions mainly in cranial nerves to mammillary body, pineal body, meninges, and finally in the bilateral cerebellum and cerebral lobes. Lumber spinal MRI showed enhancement in meninges and cauda equine roots. 18-fluorodeoxyglucose PET-CT revealed remarkably increased glucose metabolism in the lesions shown on the aforementioned brain MRI and lumbar spinal MRI, as well as right axillary lymph nodes. The biopsy of a whole axillary node on right side indicated EBV-related lymphoproliferation. Lumbar meninges and cauda nerves biopsy revealed chronic inflammation. By cerebral spinal fluid cytology and in situ hybridization, EBV-encoded small RNA (EBER) positive large B cell lymphoma was identified. The patient also had primary Sjögren’s syndrome (PSS). The patient died two weeks after treatment with rituximab, lenalidomide and methylprednisolone. She had survived for four and a half months since symptom onset. The patient presented with several stages of EBV-related complications in the nervous system, chronic EBV infection of lumbar-sacral radiculitis, and primary CNS DLBCL, indicating the process from chronic EBV infection to DLBCL in nervous system. Intracranial acute bacterium infection probably exacerbated the progression of CNS DLBCL. The concomitant sufferings of PSS reflected immune-dysfunction might have increased the risk of EBV-related CNS DLBCL in this young patient.

A comparative study of multimodal magnetic resonance in the differential diagnosis of acquired immune deficiency syndrome related primary central nervous system lymphoma and infection

BackgroundPatients with acquired immune deficiency syndrome (AIDS) often suffer from opportunistic infections and related primary central nervous system lymphoma (AR-PCNSL). Both diseases showed multiple ring enhancement lesions in conventional magnetic resonance (MR). It is very difficult to make the differential diagnosis. We aimed to investigate whether multimodal MR (diffusion weighted imaging (DWI)/ apparent diffusion coefficient (ADC), 3D pseudo-continuous arterial spin labeling (3D-pCASL) and susceptibility-weighted imaging (SWI)) combined with conventional MR can differentiate AR-PCNSL from infections.MethodsThis was a prospective study. We recruited 19 AIDS patients who were divided into AR-PCNSL group (9 cases) and infection group (10 cases) by pathological results. We analyzed whether there was statistical (Fisher’s method) difference in multimodal MR between the two groups. We analyzed whether multimodal MR combined with conventional MR could improve the diagnosis of AR-PCNSL.ResultsThe lesions were more likely involved the paraventricular (0.020) and corpus callosum (0.033) in AR-PCNSL group in conventional MR. In multimodal MR, AR-PCNSL group showed low ADC value, with p values of 0.001. Infection group more inclined to high ADC value, with p was 0.003. In multimodal MR, AR-PCNSL group had more low signal intensity (grade 2–3) in the degree of intratumoral susceptibility signal intensity in SWI (SWI-ITSS), with p values of 0.001. The sensitivity, specificity of conventional MR in the diagnosis of AR-PCNSL was 88.9 and 70.0%. The conventional MR sequence combined with DWI/ADC sequence in the diagnosis of AR-PCNSL had a sensitivity of 100.0%, and a specificity of 60.0%. The sensitivity and specificity of the conventional MR sequence combined with the SWI-ITSS sequence in the diagnosis of AR-PCNSL were 100 and 70.0%. The conventional MR combined with ADC or SWI-ITSS improved the diagnosis of AR-PCNSL.ConclusionMultimodal MR could distinguish AR-PCNSL from infectious lesions. The multimodal MR (DWI/ADC or SWI-ITSS) combined with conventional MR could improve the diagnosis of AR-PCNSL. The ADC value should be attached importance in clinical work. When distinguishing AR-PCNSL from toxoplasmosis or tuberculoma, SWI should be used to obtain a correct diagnosis.

Primary CNS Posttransplant Lymphoproliferative Disease (PTLD): An International Report of 84 Cases in the Modern Era

We performed a multicenter, International analysis of solid organ transplant (SOT)-related primary central nervous system (PCNS) posttransplant lymphoproliferative disease (PTLD). Among 84 PCNS PTLD patients, median time of SOT-to-PTLD was 54 months, 79% had kidney SOT, histology was monomorphic in 83% and tumor was EBV+ in 94%. Further, 33% had deep brain involvement, 10% had CSF involvement, while none had ocular disease. Immunosuppression was reduced in 93%; additional first-line therapy included high-dose methotrexate (48%), high-dose cytarabine (33%), brain radiation (24%) and/or rituximab (44%). The overall response rate was 60%, while treatment-related mortality was 13%. With 42-month median follow-up, three-year progression-free survival (PFS) and overall survival (OS) were 32% and 43%, respectively. There was a trend on univariable analysis for improved PFS for patients who received rituximab and/or high-dose cytarabine. On multivariable Cox regression, poor performance status predicted inferior PFS (HR 2.61, 95% CI 1.32–5.17, p = 0.006), while increased LDH portended inferior OS (HR 4.16, 95% CI 1.29–13.46, p = 0.02). Moreover, lack of response to first-line therapy was the most dominant prognostic factor on multivariable analysis (HR 8.70, 95% CI 2.56–29.57, p = 0.0005). Altogether, PCNS PTLD appears to represent a distinct clinicopathologic entity within the PTLD spectrum that is associated with renal SOT, occurs late, is monomorphic and retains EBV positivity.

Distinguishing primary central nervous system lymphoma from other central nervous system diseases: a neurosurgical perspective on diagnostic dilemmas and approaches

White matter diseases, including demyelinating or inflammatory disorders, may be indistinguishable clinically and radiologically from some central nervous system (CNS) tumors. In such situations, determination of the final diagnosis is difficult. An example is the differential diagnosis of non-acquired immunodeficiency syndrome-related primary central nervous system lymphoma (PCNSL) and multiple sclerosis (MS), a demyelinating disease. Unfortunately, delayed diagnosis and treatment of PCNSL can negatively affect prognosis. The authors reviewed the cases of eight patients with PCNSL or MS. In each case, the initial diagnosis (PCNSL or MS) was equivocal. In these cases, conventional diagnostic approaches were not definitive, thus further delaying diagnosis. The initial symptoms, the selected diagnostic tests, and the presumptive as well as final diagnosis for each case are discussed. The final diagnosis was PCNSL in six cases and MS in two. The uncertainty about the clinical or initial pathological presentation required further diagnostic evaluation in all cases. Two important neurosurgical guidelines are the avoidance of corticosteroid agents and performance of biopsy sampling rather than volumetric tumor resection. Highvolume lumbar puncture, slit-lamp examination/vitrectomy, new CNS imaging techniques, and repeated biopsy procedures also proved helpful. In PCNSL, early definitive diagnosis and treatment are the keys to successful outcomes. Knowledge of strategies essential to early diagnosis lessens the need for brain biopsy sampling, but this procedure is still usually necessary. In such selected cases, biopsy sampling is appropriate even when pathological investigation shows MS rather than PCNSL. Complete resection is not indicated in PCNSL and can lead to additional sequelae.

Antiviral and Immunomodulatory Treatment for AIDS-Related Primary Central Nervous System Lymphoma: AIDS Malignancies Consortium Pilot Study 019

PurposeA consistent association with Epstein-Barr Virus (EBV) distinguishes acquired immunodeficiency syndrome (AIDS)–related primary central nervous system lymphoma (PCNSL) from that which occurs in the general population. Recent descriptions of long-term remissions in patients with posttransplantation EBV-associated PCNSL who received EBV-specific therapy suggest some antitumor effect is anti-EBV mediated. Patients and MethodsWe enrolled 4 patients with AIDS-related PCNSL into a novel antiviral and immunomodulatory protocol. An additional patient was treated in a similar fashion off protocol. Treatment consisted of intravenously administered zidovudine (1.5 g twice daily), ganciclovir (5 mg/kg twice daily), and interleukin-2 (2,000,000 U twice daily). After 2 weeks of therapy, patients were switched to oral ganciclovir (1 g 3 times daily), patient-specific, highly active, antiretroviral therapy, and subcutaneous interleukin-2 (2,000,000 U 3 times weekly). A final patient was treated with intravenous zidovudine and hydroxyurea. All 6 patients had advanced-stage AIDS as reflected by a CD4+ T-lymphocyte cell count of < 50/μL and a detectable human immunodeficiency virus (HIV).1 viral RNA load (median copies, 135,000/mL; range, 2170-360,000/mL). One of 4 protocol-enrolled patients remains in complete remission with > 4 years' follow-up. ResultsThree patients died from complications of progressive PCNSL. Two patients treated off protocol exhibited favorable responses and remain in complete remission at 28 months and 52 months, respectively. Grade 3/4 myelosuppression was uniformly noted, but there were no clinically significant hemorrhagic or infectious complications. ConclusionWe conclude that for patients with AIDS and PCNSL, treatments with dual efficacy against HIV and EBV merit further investigation. Our experience provides a platform for future studies.

Ganciclovir Is Associated with Low or Undetectable Epstein-Barr Virus DNA Load in Cerebrospinal Fluid of Patients with HIV-Related Primary Central Nervous System Lymphoma

Epstein-Barr virus (EBV) is pathogenically linked to human immunodeficiency virus (HIV)-related primary central nervous system lymphoma (PCNSL) and is found in virtually all HIV-related PCNSL cases. The objective of this study was to assess the effect of ganciclovir on EBV DNA replication in patients with HIV-related PCNSL. EBV DNA was measured by real-time polymerase chain reaction in cerebrospinal fluid and plasma samples from 25 patients with HIV-related PCNSL. Eight of these patients were receiving ganciclovir for concurrent cytomegalovirus infections. EBV DNA was detected in cerebrospinal fluid samples obtained from 15 (88%) of 17 ganciclovir-untreated patients and 4 (50%) of 8 ganciclovir-treated patients (P = .028). EBV DNA load was significantly lower for treated patients, compared with untreated patients (median value, 2.15 vs. 4.16 log copies/mL; P = .001). Analysis of sequential cerebrospinal fluid samples from 7 patients showed that EBV DNA decreased in samples obtained from 2 patients following the start of ganciclovir administration but did not decrease in samples obtained from the 5 untreated patients. In addition, patients who received ganciclovir survived longer than the untreated patients (median duration of survival, 181 vs. 72 days; P = .006). The effect of ganciclovir on EBV DNA load in cerebrospinal fluid supports the hypothesis that EBV is replicating in patients with PCNSL. This observation, together with the effect of ganciclovir therapy on patient survival, suggests that this drug might be useful for the management of PCNSL.

Changing pattern of primary cerebral lymphoma in the highly active antiretroviral therapy era

Before the introduction of highly active antiretroviral therapy (HAART), human immunodeficiency virus (HIV)-related primary central nervous system lymphoma (PCNSL) represented one of the most prevalent causes of focal brain lesions in HIV-infected people. The prognosis of PCNSL was very poor, with median survival time not exceeding 2 months. Brain biopsy was the method of choice for the definitive diagnosis, but it was and remains an invasive procedure with morbidity and mortality as well as considerable costs in terms of patients' management and quality of life. The strict association between AIDS-PCNSL and Epstein-Barr virus led to the suggestion that EBV DNA in cerebrospinal spinal fluid (CSF) might serve as a diagnostic marker, reducing the time required for diagnosis and allowing a minimally invasive approach. The clinical usefulness of this methodology has been largely demonstrated through clinical practice. After the introduction of HAART in clinical practice, a survival benefit has been observed for most persons with acquired immunodeficiency syndrome (AIDS)-associated opportunistic infections and cancers. In particular, for patients with non-Hodgkin lymphoma, a higher likelihood of response to chemotherapy as well as a longer survival has been found as a consequence of the use of combined antiretroviral therapy. Although larger studies did not show significant changes in survival of HIV-infected patients with PCNSL in the era of HAART, small case series and anecdotal reports showed the benefit of HAART in the treatment of PCNSL. Nevertheless, these patients' survival still remains very poor and it could be hypothesized that, other than specific cancer prognostic determinants and severe immunodeficiency, viral pathogenesis as well as EBV-specific immunologic dysfunction may be responsible.

Human immunodeficiency virus-related primary central nervous system lymphoma: factors influencing survival in 111 patients.

The current study evaluated factors influencing survival in patients diagnosed with human immunodeficiency virus (HIV)-related primary central nervous system lymphoma (PCNSL), with a focus on the effects of therapeutic radiotherapy (RT) and highly active antiretroviral therapy (HAART). A retrospective chart review of patients with a diagnosis of HIV-related PCNSL at one of five university hospitals between 1987 and 1998 was performed. Clinical details including antiretroviral agent use, brain imaging scan results, RT use, and survival outcomes were recorded. One hundred eleven patients with HIV-related PCNSL were identified. The annual incidence decreased significantly between 1992 and 1995 and between 1996 and 1998 (P = 0.04). The median survival period was 50 days (mean, 109 days; range, 4-991 days), with improved survival for patients diagnosed after 1993. Patients treated with two or more antiretroviral agents had improved survival (P = 0.01), as did patients who received RT (P < 0.0001). For patients who received RT, completion of the prescribed course and treatment to > or = 30 Gray (Gy) independently predicted a more favorable outcome. RT used in conjunction with antiretroviral therapy involving two or more agents had an additive positive effect on survival. For patients who did not receive RT, poor performance status and encephalopathy predicted a shorter survival duration. The results of the current study suggest that HAART and treatment with RT to > or = 30 Gy improve survival for patients with HIV-related PCNSL. This combination of therapies may provide a standard of care as the basis for further trials of chemotherapy, novel adjunctive treatment, and quality of life assessment.

53 Oral First results of the phase II EORTC trial 20962 evaluating high-dose MTX-based chemotherapy followed by consolidating radiotherapy in non-AIDS related primary central nervous system lymphoma (NAPCL)

53 Oral First results of the phase II EORTC trial 20962 evaluating high-dose MTX-based chemotherapy followed by consolidating radiotherapy in non-AIDS related primary central nervous system lymphoma (NAPCL)

Epstein-Barr virus-targeted therapy for AIDS-related primary lymphoma of the central nervous system

Epstein-Barr virus (EBV) targeted therapeutic strategies for viral associated malignant diseases have received only perfunctory consideration, first, because latent herpesviruses have been intractable to antiviral chemotherapy and, second, because the role EBV has in maintenance of the malignant cell phenotype has been uncertain. Two patients with EBV related primary central nervous system lymphoma (PCNSL) in the setting of advanced AIDS, were treated with low dose hydroxyurea based on in vitro anti-EBV activity. The responses obtained here suggest the promise of antiviral approaches in select cancers.

Epstein‐Barr virus in monitoring the response to therapy of acquired immunodeficiency syndrome–related primary central nervous system lymphoma

To evaluate the value of Epstein-Barr virus DNA (EBV-DNA) assay in cerebrospinal fluid (CSF) for monitoring the response to treatment in acquired immunodeficiency syndrome–related primary central nervous system lymphoma (AIDS-PCNSL), 9 human immunodeficiency virus–infected patients with biopsy-proven AIDS-PCNSL who underwent multimodal therapy were investigated for EBV-DNA detection in CSF by semiquantitative nested polymerase chain reaction (PCR). Tumoral tissue expression of bcl-6 oncogene protein and of EBV-encoded latent membrane protein (LMP-1) was also investigated. The 2 patients who had a response to chemotherapy showed a reduction of mean EBV-DNA concentration values after chemotherapy and displayed a large noncleaved morphology and a BCL-6+/LMP-1− phenotype. Conversely, the 4 patients with progressive disease after chemotherapy showed increasing mean values of EBV-DNA and displayed an immunoblastic morphology and a BCL-6−/LMP-1+ phenotype. No significant changes were observed for patients with stable disease. EBV-DNA burden reduction was significantly associated with prolonged survival. These results suggest that EBV-DNA monitoring might be helpful in predicting response to chemotherapy and in segregating distinct biological and prognostic categories of AIDS-PCNSL. Ann Neurol 1999;45:259–261

Evaluation of cerebrospinal fluid EBV-DNA and IL-10 as markers for in vivo diagnosis of AIDS-related primary central nervous system lymphoma.

Acquired immunodeficiency syndrome (AIDS)-related primary central nervous system lymphoma (PCNSL) is almost always associated with the Epstein-Barr virus (EBV), and EBV-DNA in cerebrospinal fluid (CSF) has been indicated as a useful tumour marker for this HIV-related neoplasm. AIDS lymphomas also show an enhanced production of IL-10 which is generally associated with the presence of EBV in lymphoma cells. We performed a prospective study in 19 HIV seropositive patients with brain mass lesions, and in 21 other AIDS patients with or without other neurological disorders, to assess the in vivo diagnostic value of EBV-DNA and of IL-10 levels in the CSF for primary lymphoma of the central nervous system (CNS). EBV-DNA was detected by a nested polymerase chain reaction (PCR) in the CSF from seven of eight patients with PCNSL, diagnosed by brain biopsy (87.5% sensitivity) and in none of the 11 controls with brain mass lesions (100% specificity) and of the other 21 AIDS patients with or without neurological disorders. The only patient with PCNSL without detectable EBV-DNA in the CSF was also negative for EBV-DNA in the lymphoma tissue, whereas the samples of the other seven brain lymphomas were all positive for EBV-DNA by nested PCR. Therefore 100% of patients with an EBV-positive primary CNS lymphoma had detectable EBV-DNA in the CSF. No patient from the control group without PCNSL with EBV-negative CSF developed a lymphoma after a mean follow-up of 157 +/- 173 d. IL-10 levels in the CSF from the patients with PCNSL were not significantly different from those in the other groups of patients with AIDS. Due to uniformly high levels in the CSF from AIDS patients, IL-10 is not a useful diagnostic marker for AIDS-related brain lymphoma. The detection of EBV-DNA from the CSF by nested PCR is an extremely sensitive and specific diagnostic tool for AIDS-related PCNSL and should be further evaluated as a possible alternative in patients from whom brain biopsy is not advisable.