High CSF Protein Level Research Articles

Clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma.

The clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma (ND-DLBCL) remains largely unexplored. One hundredND-DLBCL patients were consecutively enrolled as training cohort and another 26 ND-DLBCL patients were prospectively enrolled in validation cohort. CSF-ctDNA positivity (CSF(+)) was identified in 25 patients (25.0%) in the training cohort and 7 patients (26.9%) in the validation cohort, extremely higher than CNS involvement rate detected by conventional methods. Patients with mutations of CARD11, JAK2, ID3, and PLCG2 were more predominant with CSF(+) while FAT4 mutations were negatively correlated with CSF(+). The downregulation of PI3K-AKT signaling, focal adhesion, actin cytoskeleton, and tight junction pathways were enriched in CSF(+) ND-DLBCL. Furthermore, pretreatment CSF(+) was significantly associated with poor outcomes. Three risk factors, including high CSF protein level, high plasma ctDNA burden, and involvement of high-risk sites were used to predict the risk of CSF(+) in ND-DLBCL. The sensitivity and specificity of pretreatment CSF-ctDNA to predict CNS relapse were 100% and 77.3%. Taken together, we firstly present the prevalence and the genomic and transcriptomic landscape for CSF-ctDNA(+) DLBCL and highlight the importance of CSF-ctDNA as a noninvasive biomarker in detecting and monitoring of CSF infiltration and predicting CNS relapse in DLBCL.

CSF Findings in Relation to Clinical Characteristics, Subtype, and Disease Course in Patients With Guillain-Barré Syndrome.

To investigate CSF findings in relation to clinical and electrodiagnostic subtypes, severity, and outcome of Guillain-Barré syndrome (GBS) based on 1,500 patients in the International GBS Outcome Study. Albuminocytologic dissociation (ACD) was defined as an increased protein level (>0.45 g/L) in the absence of elevated white cell count (<50 cells/μL). We excluded 124 (8%) patients because of other diagnoses, protocol violation, or insufficient data. The CSF was examined in 1,231 patients (89%). In 846 (70%) patients, CSF examination showed ACD, which increased with time from weakness onset: ≤4 days 57%, >4 days 84%. High CSF protein levels were associated with a demyelinating subtype, proximal or global muscle weakness, and a reduced likelihood of being able to run at week 2 (odds ratio [OR] 0.42, 95% CI 0.25-0.70; p = 0.001) and week 4 (OR 0.44, 95% CI 0.27-0.72; p = 0.001). Patients with the Miller Fisher syndrome, distal predominant weakness, and normal or equivocal nerve conduction studies were more likely to have lower CSF protein levels. CSF cell count was <5 cells/μL in 1,005 patients (83%), 5-49 cells/μL in 200 patients (16%), and ≥50 cells/μL in 13 patients (1%). ACD is a common finding in GBS, but normal protein levels do not exclude this diagnosis. High CSF protein level is associated with an early severe disease course and a demyelinating subtype. Elevated CSF cell count, rarely ≥50 cells/μL, is compatible with GBS after a thorough exclusion of alternative diagnoses. This study provides Class IV evidence that CSF ACD (defined by the Brighton Collaboration) is common in patients with GBS.

1H NMR Using Metabolic Study in Body Fluids for Diagnosis of Cryptococcal Meningitis in Adults.

Cryptococcal meningitis is considered to affect HIV patients and those with impaired immune systems. Early identification and treatment are the keys to decreasing morbidity and mortality related to CM. Using 1H NMR spectroscopy, a prospective case-control study will assess the metabolic profile of adults' serum, urine, and CSF. The present multicentric study was conducted at Lucknow. The study included 150 participants, out of which there were 31 cryptococcal meningitis cases, 34 positive meningitis controls, and the rest, 85, were disease controls. The discriminant function analysis (DFA) of the three biofluids was used to find significant metabolites between the cases and the control group collectively. A group categorization between control group and the cases in serum, urine, and CSF samples was also made possible by the NMR spectral bin-based orthogonal signal correction and principal component analysis score plots of important metabolites produced from DFA. The cases group had a higher proportion of patients with higher CSF protein levels than the positive control group (BM and TM). Acetone was found among urine samples in both control samples, i.e., positive and negative. This is the first study to explore biomarkers in serum, urine, and CSF in addition to radiological features and clinical symptoms. Hence, a quick, non-invasive prognosis and diagnosis of cryptococcal meningitis in adults can be made using clinical and microbiological investigation, as well as metabolomic analysis of urine samples. This study shows that urine can be used as a biofluid to differentiate between Cryptococcus meningitis in adults. However, when compared to the negative control, our sample size was significantly smaller, necessitating further confirmation on a larger sample size.

Bacterial meningitis presenting with a normal cerebrospinal fluid leukocyte count

ObjectivesWe describe clinical characteristics and outcome of adults with bacterial meningitis presenting with a normal CSF leukocyte count. MethodsWe studied community-acquired bacterial meningitis with a normal CSF leukocyte count (≤ 5 per mm3) in adults from a prospective nationwide cohort study. ResultsFrom 2006 through 2020, 39 of 2,357 (2%) episodes presented with a normal CSF leukocyte count. Immunocompromising conditions were present in 19 of 39 patients (49%), compared to 690 of 2303 (30%) in patients with elevated leukocytes (P = 0.02). The triad of fever, neck stiffness, and altered consciousness was present in 6 of 34 patients (18%). CSF protein was abnormal in 25 of 37 patients (68%). We identified 3 clinical subgroups: those with severe pneumococcal meningitis (20 patients [51%]), with mainly sepsis (8 [21%]), and a miscellaneous group (11 [28%]). All patients with severe pneumococcal meningitis presented with high CSF protein levels and 18 of 19 (95%) had bacteria in the CSF Gram stain. Outcome was unfavorable in 23 of 39 (59%) patients and 12 (31%) died. ConclusionPatients with bacterial meningitis may present with normal CSF leukocyte counts. In these patients, CSF protein levels and Gram staining are important diagnostic parameters.

Frequency and clinical correlates of anti-nerve antibodies in a large population of CIDP patients included in the Italian database.

To investigate the frequency and clinical correlates of anti-nerve autoantibodies in an unselected series of Italian patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) METHODS: Sera from 276 CIDP patients fulfilling the EFNS/PNS criteria and included in the Italian CIDP database were examined for the presence of anti-nerve autoantibodies. Results were correlated with the clinical data collected in the database. Anti-neurofascin155 (NF155) antibodies were found in 9/258 (3.5%) patients, anti-contactin1 (CNTN1) antibodies in 4/258 (1.6%) patients, and anti-contactin-associated protein1 (Caspr1) in 1/197 (0.5%) patients, while none had reactivity to gliomedin or neurofascin 186. Predominance of IgG4 isotype was present in 7of the 9 examined patients. Anti-NF155 patients more frequently had ataxia, tremor, and higher CSF protein levels than antibody-negative patients. Anti-CNTN1 patients more frequently had a GBS-like onset, pain, and ataxia and had more severe motor impairment at enrollment than antibody-negative patients. They more frequently received plasmapheresis, possibly reflecting a less satisfactory response to IVIg or steroids. IgM antibodies against one or more gangliosides were found in 6.5% of the patients (17/260) and were more frequently directed against GM1 (3.9%). They were frequently associated with a progressive course, with a multifocal sensorimotor phenotype and less frequent cranial nerve involvement and ataxia. Anti-paranodal and anti-ganglioside antibodies are infrequent in patients with CIDP but are associated with some typical clinical association supporting the hypothesis that CIDP might be a pathogenically heterogeneous syndrome possibly explaining the different clinical presentations.

Neurofunctional outcomes in patients with anti-leucine-rich glioma inactivated 1 encephalitis.

To evaluate the cognitive and neurofunctional outcomes in patients with anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis. A cohort follow-up study was performed after a median of 33months (range 6-78) from disease onset to the last follow-up in patients diagnosed with anti-LGI1 encephalitis, to assess the neurofunctional outcomes using modified Rankin Scale (mRS), activities of daily living (ADL), neuropsychiatric inventory (NPI) and modified telephone interview for cognitive status (TICS-M). Remote symptomatic seizure and clinical relapses were also recorded. The clinical, laboratory features, and treatment responses that characterize the disability were analyzed. The results showed that 81 of 86 (94.2%) patients with anti-LGI1 encephalitis were successfully followed up, while eight (9.9%) died after discharge. Among the 73survivors, clinical relapses occurred in 18 (24.7%) patients, and those with relapses were at a higher risk of developing remote symptomatic seizure (p=.019). Although 85.2% of the patients became functionally independent (mRS ≤2), the sequelae of symptomatic seizure, neuropsychiatric symptoms, and cognitive deficits were found in 11.0%, 21.9%, and 39.7% of the patients, respectively. Residual cognitive deficits primarily occurred in the elderly subjects as well as those with symptoms of memory deficit, psychiatric disorders, sleep disturbance, disturbance of consciousness at diagnosis, and higher CSF protein levels. Although most patients survived and became functionally independent, a subset of patients could not return to all premorbid activities. They may have clinical relapses or suffer from remote symptomatic seizure, neuropsychiatric symptoms, and cognitive impairment.

Determining the clinical characteristics and prognostic factors for the outcomes of Japanese encephalitis in adults: A multicenter study from southern Taiwan.

In Southeast Asia, Japanese encephalitis (JE) is an important cause of viral encephalitis which may cause severe neurological sequelae. JE affects mostly children; therefore, clinical presentations and prognosis of adult JE patients are seldom addressed. This study aimed to describe the clinical characteristics and prognostic factors for the outcome of adult JE patients. Medical records of adult JE patients with acute encephalitis syndrome during 2001-2018 from five medical centers in southern Taiwan were reviewed. Clinical characteristics, brain images, and prognostic factors for outcomes were analyzed. Patients were divided into the good outcome (GO) group and poor outcome (PO) group according to their Glasgow Coma Scale (GCS) scores (GCS >8 vs.≤8) at discharge. Sixty-eight patients (men, 61.8%; median age, 50 years) were included. Summer is the epidemic season, and the number of cases peaked in June. The most common symptoms at initial presentation were altered consciousness and fever (both 94.1%), followed by headache (51.4%). The most commonly involved brain regions were thalamus (55.7%) and basal ganglion (37.7%). The median GCS score at nadir was 8, and the median time from onset to nadir was five days. Fifty-two patients were included in the GO group, while 16 were included in the PO group. On multivariate analysis, flaccidity, rigidity, and elevated CSF protein level were identified as independent prognostic factors for PO. Initial clinical presentations of abnormal muscle tone including flaccidity, rigidity and high CSF protein levels are independent prognostic factors for PO in adult JE patients.

WED 243 Enhancing our knowledge of leptomeningeal disease – a case of DL-GNT

A 57-year-old woman presented with several weeks of headache associated with neck stiffness, drowsiness and nausea. She developed diplopia with right-sided 6th nerve palsy and subsequently developed a complex ophthalmoplegia and right-sided ptosis.Repeated lumbar punctures showed high opening pressures of up to 60 cm H2O and high protein levels up to 2.48 g/L. She developed episodes of marked loss of responsiveness but EEGs showed only generalised slowing. Brain imaging was essentially normal. An MRI Spine showed an enhancing intramedullary hyperintensity T8-T10 with overlying meningeal enhancement. A CT-PET scan revealed uptake along the cord consistent with diffuse infiltration or a meningitis – biopsy was inconclusive but macroscopically the dura was thickened with calcification observed on the spinal cord surface. A brain biopsy did not aid diagnosis and unfortunately the patient deteriorated with increasing severity of headaches and drowsiness. She died after a number of cardiorespiratory arrests.At post-mortem, thickened meninges showed a glioneuronal cell infiltrate and a diagnosis of diffuse leptomeningeal glioneuronal tumour (DL-GNT). WHO recently described DL-GNT in the 2016 update of CNS tumour classification. Previous case reports of this rare disease have concerned adults and children. DL-GNT should be considered in cases of radiological leptomeningeal enhancement and high CSF protein levels.

Autoimmune neuropathy

Such neuropathies as Guillain-Barre syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are caused by autoimmune mechanisms targeting peripheral nervous system and called as autoimmune neuropathies. Anti-glycolipid antibodies are frequently detected in the acute-phase sera from patients with GBS. Each antibody is closely associated with a certain clinical feature (anti-GM1 IgG and pure motor GBS, anti-GQ1b IgG and Fisher syndrome, etc). Mixtures of two different glycolipids (glycolipid complexes, GLCs) are sometimes specifically recognized by IgG antibodies in GBS. Those antibodies may recognize novel epitopes formed by carbohydrate portions of two glycolipids, such as GD1a/GD1b, GM1/GalNAc-GD1a, GM1/GQ1b, etc. Glycoarray is an efficient method for detecting antibodies against numerous GLCs. In contrast, anti-glycolipid antibodies are rarely detected in CIDP. Recently, IgG4 antibodies against neurofascin (NF) 155, a paranodal protein, are reported to be present in about 10% of patients with CIDP. Patients with anti-NF 155 antibody-positive CIDP frequently have ataxia, tremor, distal-dominant weakness, and remarkably high CSF protein level. Abnormal paranodal lesions such as loss of the transvers bands were observed by electron microscope in those patients. Plasmapheresis (PP) and intravenous immunoglobulin (IVIg) are effective for GBS, and steroids as well as PP and IVIg are effective for CIDP. However, the responses to IVIg were reported to be poor in anti-NF 155 antibody-positive CIDP. The auto-antibodies can be used as biomarkers and some of them are involved in the pathogenetic mechanisms. Development of novel therapy is required for severe and intractable cases of GBS and CIDP.

Combination of Rituximab with Chemotherapy Improved Outcome of Newly Diagnosed Primary CNS Lymphoma: A Retrospective Study of 209 Unselected Patients Referred to a Single Institution

Introduction: Treatment of first-line therapy of primary CNS lymphoma (PCNSL) is based on high-dose methotrexate and cytarabine combination chemotherapy. Consolidation radiotherapy is mainly withdrawal for patients older than 60 years old regarding the excessive rate of neurological toxicity. Rituximab improved outcome of systemic diffuse large B-cell lymphoma but no data from randomized phase III trial is available to prove such outcome improvement for PCNSL. We introduced in daily practice intravenous rituximab in combination with chemotherapy for B-cell PCNSL in first-line therapy in 2004. The goal of this study is to determine whether such therapeutic modification improves PCNSL patient's outcome.Methods: Patients were from consecutive PCNSL cases (N=209) included in Leon Berard Cancer Centre registry (Lyon, France), from 1987 to 2011 (date of diagnosis). Median age of patients was 63 years (range, 26-87), 56% were male, 51% had a performance status (PS) >1, 63% had an involvement of deep structures of brain, 66% a high CSF protein level, 12% a meningeal involvement and 42% a high LDH level. Of the 171 available patients, 16% had 0-1, 60% had 2-3, and 24% had 4-5 adverse IELSG prognostic scores, respectively. Patients were all treated by chemotherapy, 92% and 63% of them by high-dose methotrexate and cytarabine containing chemotherapy, respectively followed by brain radiotherapy for 108 patients (58%). Intravenous rituximab was used in combination with chemotherapy in 61 patients (29%) between 2004 and 2011.Results: No difference in term of clinical characteristics (median age, PS, tumor site, CSF protein level, meningeal involvement, LDH level) was observed between patients treated with or without rituximab in combination with chemotherapy. With the median of 86.3 months (18.2-259), the median progression free survival (PFS) and overall survival (OS) for whole series were 17.3 months (95%CI, 10.7-25.9) and 35.6 months (95%CI, 22.7-50.0), respectively. The 3-year PFS were 55.5% (95%CI, 43-67) and 31.1% (95%CI, 24-39) for patients treated or not with rituximab, respectively (P=0.001). The 3-year OS were 73.6% (95%CI, 61-83) and 39.9% (95%CI, 32-48) for patients treated or not with rituximab, respectively (P<0.0001). A multivariate analysis was performed to test the impact of the addition of rituximab over clinical prognostic factors (age, PS, tumor site, CSF protein level, meningeal involvement, LDH level, IELSG score). Age>60 years (HR=1.74; 95%CI, 1.22-2.46; P=0.002), meningeal involvement (HR=2.33; 95%CI 1.42-3.85; P=0.0009) and used of rituximab (HR=0.50; 95%CI, 0.32-0.78; P=0.002) were identified as independent predictors of PFS. OS was significantly influenced by age>60 years (HR=1.94; 95%CI, 1.36-2.77; P=0.0002), PS (HR=1.76; 95%CI, 1.26-2.46; P=0.001), meningeal involvement (HR=2.17; 95%CI, 1.30-3.61; P=0.003) and used of rituximab (HR=0.39; 95%CI, 0.24-0.62; P=0.0001) in multivariate analysis. In a prognostic model integrating the IELSG score (0-1 vs. 2-3 vs. 4-5) (P=0.0002 for PFS and P<0.0001 for OS), used of rituximab was independently associated with the improvement of PFS (HR=0.60; 95%CI, 0.39-0.91; P=0.02) and OS (HR=0.44; 95%CI, 0.26-0.72; P=0.001). Disease free survival including patients who reached a complete response at the end of the first-line treatment was also improved by the used of rituximab (not reached versus 3.2 years, P=0.04). We also observed in this daily practice study, a reduction of the used of radiotherapy as first-line consolidation treatment (69% vs. 34%, P<0.001) before (1987-2003) and after (2004-2011) rituximab period.Conclusion: In this retrospective analysis, we showed that PCNSL patients treated with intravenous rituximab in combination with first-line chemotherapy had a better outcome. The frequency of consolidation radiotherapy was reduced for these patients treated at rituximab era. In multivariate analysis, CSF involvement was an independent adverse prognostic factor that inclines to improve meningeal explorations and propose new therapeutic options for CSF positive PCNSL patients. DisclosuresNo relevant conflicts of interest to declare.

English

OBJECTIVES: To study the clinical profile of ABM and analyse the differences in clinical presentation among young infant, toddler, compared to school going children. And to find out the bacteriological profile and sensitivity pattern of ABM. MATERIALS AND METHODS: The present study is a prospective non-randomized single arm study. Children with the diagnosis of ABM admitted to the department of Pediatrics Govt. General Hospital, Kurnool from January 2013 to October 2013 are included in the study. Clinical details of all patients were recorded CSF was analysed by routine biochemical methods, and microbiological studies on special media. The children were managed as per the standard protocols. RESULTS: In a study period of 1 year During the study period 74 children (1.5% of all admissions) satisfied the criteria of ABM in early childhood;. The incidence of Acute Bacterial Meningitis was 1.45% of total Pediatric admissions. Of the 74 cases 25 died. Mortality rate was 33.79%.mortality observed was more in less than one year of age. Chief presentation was high fever, refusal of feeds, altered sensorium and seizures. The final etiological diagnosis (as per LAT and/or cultures) were 32 cases are positive for culture and sensitivity of ABM and Biochemically and Cell count wise 74 cases are positive for ABM. CSF has grown pneumococci in 8 (25%) cases, Coagulase positive Staph. Aureus in 3 (9.38%) cases, Coagulase negative Staph. Aureus in 3(15.63%) cases, Nesseria Meningitides in 3 (9.38%), Klebsiella in 4 (12.50%) cases, E coli, Enterococci and Pseudomonous in 9 (28.13%) The outcome in the present study with respect to death is 33.78% and 45.95% of patients Survived with complications, 20.27% of patients survived without complications. CONCLUSION: The incidence and Mortality were significantly high in low socio economic group. The incidence and mortality was high in lesser age group. Mortality is very high with high CSF protein and low sugar levels. Pneumococci and coagulase negative staphylococci are predominant causes of morbidity and mortality associated with ABM.

Updated Results Confirm Favorable Outcome of Immunocompetent Patients with Primary CNS Lymphoma Treated By C5R Protocol in Combination with Intravenous Rituximab and Intrathecal Liposomal Cytarabine: A Multicentric Prospective Phase 2 Study of the Lymphoma Study Association (LYSA)

Background: The LNHCP93 trial is an intensive high-dose methotrexate and cytarabine containing chemotherapy (CT) derived from CT regimens used for Burkitt lymphomas (C5R protocol) followed by brain radiotherapy (RT) showing favorable long-term survival in Primary CNS Lymphoma (PCNSL) patients younger than 60 years. In order to improve antitumor activity of C5R protocol, we prospectively evaluated the addition of intravenous rituximab and intrathecal (IT) liposomal cytarabine to CT before RT for 18 to 60 years old immunocompetent patients with PCNSL in the R-C5R protocol. We previously presented the results of the primary objective of the R-C5R protocol, showing an improvement of the complete and unconfirmed complete response rate (CR/CRu) after immuno-CT from 33% in the LNHCP93 to 66% in the R-C5R protocol. We also showed no additional severe toxicities as compare to C5R with the addition of intravenous rituximab and IT liposomal cytarabine. We present here the updated results of the 53 patients included in this multicentric prospective phase 2 study from the lymphoma study association (LYSA) with a median follow-up 28 months (range, 1.08-75.04).Methods: This prospective study was designed for 18 to 60 years old immunocompetent patients with confirmed CD20 positive diffuse large B-cell lymphoma PCNSL. Fifty-three patients included between August 2007 and September 2011 received two courses of methotrexate, cyclophosphamide, doxorubicin, vincristine, prednisone (COPADEM) followed by two courses of methotrexate, cytarabine (CYM) administred at 21-day intervals from day 1 to day 21. At each day 1, intravenous rituximab 375mg/m2 and at each day 3 IT liposomal cytarabine 50mg were infused. After immuno-CT, a brain RT was planned for all patients and then patients were followed every 4 months during the first 2 years and then every 6 months for the next 3 years. Neurotoxicity was evaluated by a Mini-Mental State Examination (MMSE) test.Results: The median age of the 53 PCNSL patients was 55 years (range, 36-60), 57% were male, 42% had a performance status (PS)>1, 55% had an involvement of deep structures of brain, 45% a high CSF protein level and 36% a high LDH level. Clinical characteristics according to the MSKCC score was as follows: 16 patients (32%) ≤50 years (class 1); 23 patients (46%) >50 years and KPS≥70 (class 2); 11 patients (22%) >50 years and KPS<70 (class 3). Of the 39 available patients, 38% had 0-1, 38% had 2, 21% had 3 and 3% had 4 adverse IELSG prognostic scores, respectively. Median MMSE score assessed for 42 patients at baseline was 26 (range, 3-30). Forty-five patients (85%) completed the fourth cycles of immune-CT and three patients (5.7%) died of acute toxicity. Forty-two patients (79%) underwent RT, 23 of them with a reduced whole brain RT (median 26 Gy) and a boost to the tumor bed. With a median follow-up of 28 months, 20 patients progressed or relapsed (37.7%). The 3-year progression free survival (PFS) rate of whole cohort was 58% (95%CI, 42.5% to 71%). The 3-year PFS rates were 64.2%, 63.5% and 53% for patients with MSKCC class 1, 2 and 3, respectively (P=0.53); the 3-year PFS rates were 86% and 39% for patients with 0-1 and 2-4 adverse IELSG prognostic scores, respectively (P=0.02). The 3-year PFS rates were 66% and 80% for patients who received a reduced whole brain RT with a boost and patients treated with whole brain RT (P=0.25), respectively. At relapse or progression, 18 patients received a salvage treatment that allowed five CR/CRu. Five patients received a high-dose CT with autologous stem cell transplantation at relapse. The 3-year overall survival (OS) rate for whole cohort was 67% (95%CI, 48.3% to 80.1%). The median MMSE score was 29 (range, 23-30) for the 11 patients evaluated between 18 and 24 months after the beginning of treatment.Conclusions: With the addition of intravenous rituximab and IT liposomal cytarabine, R-C5R protocol provided promising outcome results with a 3-year PFS and OS of 58% and 67%, respectively. These results compared favorably with historical controls included in the LNHCP93 who presented a 3-year PFS and OS of 44% and 58%, respectively. IELSG score remained a strong prognostic factor for the patients treated with this schedule and could be helpful to stratify consolidation treatment after response to primary immunochemotherapy in particular patients with 2-4 IELSG score. DisclosuresGhesquieres:Mundipharma: Honoraria. Off Label Use: Liposomal cytarabine formulation had demonstrated better efficacy compared to standard cytarabine for the treatment of lymphomatous meningitis and is off label use in first line therapy of primary CNS lymphoma. Morschhauser:Mundipharma: Honoraria.

Aβ-related angiitis

To analyze the clinical findings, response to therapy, and outcomes of patients with cerebral vascular amyloid-β (Aβ) deposition with and without inflammatory vascular infiltration. We report 78 consecutive patients with cerebral vascular Aβ deposition examined at Mayo Clinic Rochester over 25 years (1987 through 2011). Specimens reviewed by a neuropathologist showed 40 with vascular Aβ peptide without inflammation (cerebral amyloid angiopathy [CAA]), 28 with granulomatous vasculitis (Aβ-related angiitis or ABRA), and 10 with perivascular CAA-related inflammation. We also matched findings in 118 consecutive patients with primary CNS vasculitis (PCNSV) without Aβ seen over 25 years (1983 through 2007). Compared to the 40 with CAA, the 28 with ABRA were younger at diagnosis (p = 0.05), had less altered cognition (p = 0.02), fewer neurologic deficits (p = 0.02), and fewer intracranial hemorrhages (<0.001), but increased gadolinium leptomeningeal enhancement (p = 0.01) at presentation, and less mortality and disability at last follow-up (p < 0.001). Compared with PCNSV, the 28 patients with ABRA were older at diagnosis (p < 0.001), had a higher frequency of altered cognition (p = 0.05), seizures/spells (p = 0.006), gadolinium leptomeningeal enhancement (p < 0.001), and intracerebral hemorrhage (p = 0.02), lower frequency of hemiparesis (p = 0.01), visual symptoms (p = 0.04), and MRI evidence of cerebral infarction (p = 0.003), but higher CSF protein levels (p = 0.03). Results of treatment and outcomes in ABRA and PCNSV were similar. ABRA appears to represent a distinct subset of PCNSV.

A Multicentric Prospective Phase 2 Study of Intravenous Rituximab and Intrathecal Liposomal Cytarabine in Combination with C5R Protocol Followed by Brain Radiotherapy for Immunocompetent Patients with Primary CNS Lymphoma: A Lymphoma Study Association (LYSA) Trial

AbstractAbstract ▪796▪This icon denotes a clinically relevant abstract Background:The LNHCP93 trial is an intensive high-dose methotrexate and cytarabine containing chemotherapy (CT) derived from CT regimens used for Burkitt lymphomas (C5R protocol) followed by brain radiotherapy (RT) showing favourable long-term survival in Primary CNS Lymphoma (PCNSL) patients younger than 60 years: the complete response (CR) rate was 33%, the 5-year progression-free survival (PFS) and overall survival (OS) rates were 31% and 42%, respectively with however 9% of toxic death. Rituximab improves outcome of systemic Diffuse Large B-Cell Lymphoma (DLBCL) but it is unclear if its addition is useful in PCNSL with DLBCL histology. Intrathecal (IT) liposomal cytarabine (Depocyt) which shows a long-CSF half-life and better efficacy compared to IT methotrexate and free cytarabine in lymphomatous meningitis is also an attractive treatment for PCNSL. Methods:In order to improve antitumor activity of C5R protocol, we prospectively evaluated the addition of intravenous rituximab and IT liposomal cytarabine to CT before RT for 18 to 60 years old immunocompetent patients with PCNSL. The primary objective of this study is the complete and unconfirmed complete response rate (CR/CRu) after immuno-CT, according to International Primary CNS Lymphoma Collaborative Group response criteria. The number of patients was calculated in order to improve the 30% CR/CRu rate of LNHCP93 study up to 50%. The secondary objectives were side effect profile including acute and late neurological toxicities, PFS and OS. Patients received two courses of methotrexate, cyclophosphamide, doxorubicin, vincristine, prednisone (COPADEM) followed by two courses of methotrexate, cytarabine (CYM) administred at 21-day intervals from day 1 to day 21. At each day 1, intravenous rituximab 375mg/m2and at each day 3 IT liposomal cytarabine 50mg were infused. After immuno-CT, a brain RT was planned for all patients. A new response assessment was performed after RT. Patients were followed every 4 months for the first two years and then every 6 months. Neurotoxicity was evaluated by a Mini-Mental State Examination (MMSE) test. Results:Fifty-three PCNSL patients with a confirmed diagnosis of CD20 positive DLBCL were included between August 2007 and September 2011: median age was 55 years (range, 36–60), 57% were male, 42% had a performance status >1, 55% had an involvement of deep structures of brain, 45% a high CSF protein level and 36% a high LDH level. Median MMSE score assessed for 42 patients at baseline was 26 (range 3–30). After immuno-CT, 22 patients achieved a CR and 13 a CRu (CR + CRu, 66%), 7 a partial response (13%), 6 had a stable or progressive disease (11%) and 5 (10%) were not evaluated due to early death (n=2) or toxicities (n=3). For 45 patients who completed the fourth cycles, CR/CRu rate was 75.6%. Thirty-one patients (58%) presented at least one serious adverse event, mainly infections (25 patients, 47%). At least one red blood cell and platelet transfusions were given in 94% and 68% of patients, respectively and 57% of patients experienced a febrile neutropenia. Forty-two patients (79%) underwent RT, 23 of them with a reduced whole brain RT (median 26 Gy) and a boost to the tumor bed. With a median follow-up of 22 months, 15 patients progressed or relapsed (28.3%) and 13 patients died (24.5%), 3 (5.7%) of them from acute toxicity. The 2-year PFS and OS rates are 67% (95%CI, 50.0% to 79.4%) and 82% (95%CI, 67.0% to 90.7%), respectively. Median MMSE score was 27 (range, 26–30) for the 7 patients evaluated between 12 and 18 months after the beginning of treatment. Conclusions:With the addition of intravenous rituximab and intrathecal liposomal cytarabine, C5R protocol provided higher CR/CRu rate and promising outcome results with a 2-year PFS of 67% as compared to historical controls. No additional severe toxicities were observed compared to C5R protocol and with short follow-up no neurocognitive decline was observed. Disclosures:Off Label Use: Depocyt (intrathecal liposomal cytarabine) is off-label used in first line therapy of Primary CNS Lymphoma but approval for treatment of lymphomatous meningitis. Morschhauser:Roche: Honoraria. Blay:Roche: Honoraria, Research Funding.

Communicating hydrocephalus following surgery and adjuvant radiochemotherapy for glioblastoma

Communicating hydrocephalus is an uncommon complication in patients treated for glioblastoma multiforme (GBM). Its pathogenesis remains unclear. The authors evaluated the clinical and radiological factors associated with the onset of communicating hydrocephalus and the impact of ventriculoperitoneal (VP) shunt surgery on the outcome of these patients. One hundred twenty-four patients harboring GBM, who had undergone craniotomy for tumor resection and adjuvant radiochemotherapy, were retrospectively assessed. Seven of them developed communicating hydrocephalus and were treated with VP shunt surgery. Clinical and radiological estimates included Karnofsky Performance Scale (KPS) score, previous surgery, overall survival (OS), CSF pressure and components, tumor location, and leptomeningeal dissemination. All 7 patients who developed communicating hydrocephalus had undergone at least 2 craniotomies for tumor resection before the onset of hydrocephalus (p = 0.0006; Fisher exact test). Six cases showed high levels of CSF proteins. There was a highly significant relationship between ventricular opening at surgery for tumor recurrence and onset of hydrocephalus (p = 0.0002; Fisher exact test). In these patients, VP shunt surgery was followed by a significant improvement of KPS score (p = 0.0180; Wilcoxon signed-rank test). The median OS after VP shunt insertion was 5 ± 2.9 months. Ventricular opening after radiochemotherapy and high CSF protein levels are significant predictors of communicating hydrocephalus in patients with GBM. The VP shunt surgery improves quality of life in these patients.

Prediction of ventriculoperitoneal shunt dependency in patients with aneurysmal subarachnoid hemorrhage

Patients with subarachnoid hemorrhage treated using external ventricular drainage due to obstructive hydrocephalus commonly remain shunt-dependent. Based on identified risk factors for external ventricular drain (EVD) challenge failure, the authors sought to determine the likelihood that a patient will require a permanent shunt. The authors reviewed 89 consecutive cases of aneurysmal subarachnoid hemorrhage with obstructive hydrocephalus for parameters associated with EVD challenge failure and permanent shunt requirement. Significant parameters were combined in a discriminant function analysis to create a failure risk index (FRI). Linear regression analysis was performed correlating the FRI with the actual rate of shunt dependency. Patients requiring a permanent shunt had: a larger third ventricular diameter (7.0 vs 5.4 mm; p = 0.02) and a higher Hunt and Hess grade (3 vs 2; p = 0.02) at the time of admission; and a larger third ventricular diameter (6.6 vs 5.2 mm; p = 0.04), a larger bicaudate diameter (31.9 vs 30.2 mm; p = 0.03), and higher CSF protein levels (76.5 vs 40.3 mg/dl; p < 0.0001) at the onset of EVD challenge. These patients were also more likely to be female (p = 0.01) and have a posterior circulation location of their aneurysm (p = 0.01). The FRI score was calculated based on a weighted combination of the above parameters. Linear regression analysis between FRI values and the percentage of patients who required a permanent shunt had a correlation coefficient of 91%; the risk of a permanent shunt requirement increased linearly with a rising FRI score. An FRI score created by discriminant function analysis can predict whether or not a permanent shunt is required, even if separate factors are not in agreement with each other or show a weak correlation when considered separately. An increased FRI score was strongly and linearly correlated with the risk of EVD challenge failure. A prospective study is necessary to validate the FRI.

Caractéristiques cliniques, biologiques et évolutives des méningites à streptocoque du groupe B de l'enfant

The group B streptococcal meningitis (GBS) remains an important cause of child's morbidity and mortality. The purposes of this work were to appreciate the GBS place among the bacterial meningitis, to define clinical and biological factors associated with death and to study the immediate complications. This study concerned 276 GBS meningitis listed by the observatory of GPIP/ACTIV on the child's bacterial meningitis in France from January, 2001 to December, 2005. This report is one of the biggest series of child's GBS meningitis published to this day. The GBS was the third germ in frequency responsible for bacterial meningitis at every age (13 %) : 65 % of the GBS meningitis affected infants less than one month of age, 29 % infants between 1 month and 3 months of age and only 6 % infants more than 3 months of age. The male/female ratio in GBS meningitis was nearly equal (51 % vs 49 %). There was no variation of the GBS meningitis number according to the season. The serotype III was mostly involved in this cohort (81 %) followed by the serotype I (13 %). Statistically we observed a significant decline in the number of early onset meningitis from 2001 to 2004 whereas the number of late meningitis and the total meningitis cases were stable. The biological results mostly present in child's GBS meningitis were a high CSF protein level (95 %), a CSF neutrophil count more than fifteen percent (90 %), a low CSF glucose level (83.5 %), leukopenia (49 %) or a normal blood level leukocyte (38 %). Eighty three percent of the children affected by GBS meningitis were term infants. However, the prematurity seemed to be a risk factor to develop late meningitis (age between 7 days and 3 months) and very late meningitis (after 3 months) but no early onset meningitis. Prematurity, convulsions, shock, coma, assisted ventilation, high CSF protein level, weak CSF cell level and leukopenia seemed to be factors associated with death in the GBS meningitis. The mortality of the GBS meningitis was still 14 % and the immediate complications were observed in 62 % of cases, the most frequent being convulsions (45 %). The GBS meningitis in children remains a frequent problem in pediatrics despite intra partum antibioprophylaxy and thus must encourage to strengthen the prevention of these meningitis.

Long-Term Follow-Up of 132 Immunocompetent Primary Central Nervous System Lymphomas Treated at Leon Berard Cancer Centre: Proposition of a New Prognostic Model.

This study was aimed at analyzing long-term data on survival, relapse, and treatment-related neurotoxicity in all patients with newly diagnosed primary CNS lymphoma (PCNSL) and patients specifically treated with the C5R protocol (Blay et al, Blood 86:2922, 1995). We also identified prognostic factors of survival in order to propose a predictive model.132 patients with PCNSL seen at Leon Berard cancer centre between 1984 and 2006 were analyzed. Median age was 59 years (range: 26–81); 49% of the patients had a performance status (PS) of 2 to 4; 8% had leptomeningeal and ocular involvement. Initial treatment was chemotherapy and radiotherapy in 122 patients and chemotherapy alone in 10. Fifteen patients did not receive high-dose methotrexate as part of initial chemotherapy. The median overall (OS) and progression-free survival (PFS) for the whole series were 21.6 and 13.3 months for a median follow-up of 84.2 months. Twenty-five (19%) patients experienced toxic death, 24 (18%) progressed during treatment and 39 (30%) relapsed. Neurotoxicity was observed in 16% of the patients. Of the 49 patients receiving the intensive C5R protocol, 6 (12%) experienced toxic death, 3 (6%) progressed during treatment, 17 (35%) relapsed and 14% developed leukoencephalopathy. Median OS and PFS for patients treated with the C5R protocol were 73.8 and 44.4 months, respectively. Univariate analysis of the whole series showed that age over 60 years, elevated serum LDH, PS greater than 1 and the International Extranodal Lymphoma Study Group score were prognostic factors for OS and PFS, but not the presence of deep or multiple lesions or a high CSF protein level. The backward regression model integrating age, serum LDH, number and location of lesions, and CSF protein level showed that age, serum LDH and a tumor location within deep regions were predictive of OS and PFS. Four prognostic groups presenting 0, 1, 2 or 3 factors could be significantly distinguished regarding OS and PFS. [Display omitted] This study allowed to identify a new prognostic model using 3 factors. This model has the interest to withdraw the PS which could be a subjective data and CSF protein level for which the accurate cutoff is not well known. This study also showed that, with a long follow-up, patients treated with the C5R protocol have excellent OS and PFS.

Aseptic meningitis: a 2-year review of diagnoses reached in a tertiary neurological and infectious disease centre

Aseptic meningitis is a frequent diagnostic problem, with little data available regarding its prevalence and the commonly identified causes. To identify the common diagnostic tests requested, and their subsequent yields in obtaining a diagnosis in adult cases of aseptic meningitis in a tertiary neurological and infectious disease centre. Cases of aseptic meningitis were retrospectively reviewed for a 2-year period. Of the 43 cases reviewed, a diagnosis based on subsequent microbiological, histological and immunological testing was obtained in 17 (40%). Altered levels of consciousness, and higher CSF protein levels were significantly more common in those patients attaining a definite diagnosis. The median duration of admission to hospital in the undiagnosed group was 12 days, which may be improved with increased accuracy and availability of diagnostic techniques such as polymerase chain reaction.

A Case of Chronic Inflammatory Demyelinating Polyneuropathy in a Girl with Type 1 DM

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated disorder characterized by the symmetrical weakness in both proximal and distal muscles for at least 2 months, hyporeflexia or areflexia, nerve conduction abnormalities, and high CSF protein level. Diabetes mellitus, monoclonal gammopathy, hepatitis C infection, HIV infection, SLE, Sjogren syndrome and lymphoma have been associated with CIDP. The incidence of CIDP in diabetes is not known exactly, but occur more common among diabetic than nondiabetic patients. There is sometimes a difficulty in distinguishing between diabetic polyneuropathy and CIDP, but differential diagnosis is important because CIDP is treatable with immune-modulating therapy. We report a case of CIDP in 22-year-old girl with type 1 DM who presented with generalized motor weakness and walking disturbance which were treated with iv immunoglobulin