Comparison of Common Monogenic Defects in a Large Predominantly Antibody Deficiency Cohort.

BACKGROUND: Predominantly antibody deficiencies (PADs) are the most common primary immunodeficiencies, characterized by hypogammaglobulinemia and inability to generate effective antibody responses. OBJECTIVE: We intended to report most common monogenic PADs and to investigate how patients with PAD who were primarily diagnosed as suffering from agammaglobulinemia, hyper-IgM (HIgM) syndrome, and common variable immunodeficiency (CVID) have different clinical and immunological findings. METHODS: Stepwise next-generation sequencing and Sanger sequencing were performed for confirmation of the mutations in the patients clinically diagnosed as suffering from agammaglobulinemia, HIgM syndrome, and CVID. RESULTS: Among 550 registered patients, the predominant genetic defects associated with agammaglobulinemia (48 Bruton's tyrosine kinase [BTK] and 6 µ heavy chain deficiencies), HIgM syndrome (21 CD40 ligand and 7 activation-induced cytidine deaminase deficiencies), and CVID (17 lipopolysaccharides-responsive beige-like anchor deficiency and 12 atypical Immunodeficiency, Centromeric instability, and Facial dysmorphism syndromes) were identified. Clinical disease severity was significantly higher in patients with µ heavy chain and CD40 ligand mutations compared with patients with BTK (P = .003) and activation-induced cytidine deaminase (P = .009) mutations. Paralysis following live polio vaccination was considerably higher in patients with µ heavy chain deficiency compared with BTK deficiency (P < .001). We found a genotype-phenotype correlation among patients with BTK mutations regarding clinical manifestation of meningitis and chronic diarrhea. Surprisingly, we noticed that first presentations in most patients with Immunodeficiency, Centromeric instability, and Facial dysmorphism were respiratory complications (P = .008), whereas first presentations in patients with lipopolysaccharides-responsive beige-like anchor deficiency were nonrespiratory complications (P = .008). CONCLUSIONS: This study highlights similarities and differences in the clinical and genetic spectrum of the most common PAD-associated gene defects. This comprehensive comparison will facilitate clinical decision making, and improve prognosis and targeted treatment.

Management of neoplastic meningitis.

Leptomeningeal dissemination of tumor cells, also referred to as neoplastic meningitis, is most frequently seen in patients with late-stage cancer and mostly associated with a poor prognosis. Basically, neoplastic meningitis may affect all patients with a malignant tumor but is most common in patients affected by lung cancer, breast carcinoma, melanoma or hematologic neoplasms such as lymphoma and leukemia. Controlled clinical trials are largely lacking which results in various non-standardized treatment regimens. The presence of solid tumor manifestations in the CNS as well as the extracranial tumor load defines the most appropriate treatment approach. Radiation therapy, systemic chemotherapy and intrathecal treatment must be considered. For each patient, the individual situation needs to be carefully evaluated to determine the potential benefit as well as putative side effects associated with any therapy. A moderate survival benefit and particularly relief from pain and neurological deficits are the main treatment goals. Here, we summarize the management of patients with neoplastic meningitis and review the available treatment options.

Impacto da vacina pneumocócica conjugada 10-valente na meningite pneumocócica na região metropolitana de Salvador, Bahia / Impact of pneumococcal conjugate vaccine 10-valent pneumococcal meningitis in the metropolitan region of Salvador, Bahia

INTRODUÇÃO: Em 2010, a vacina conjugada 10-valente (PCV10) foi incorporada ao programa nacional de imunizações (PNI) brasileiro. Este imunobiológico confere imunização contra os dez principais tipos capsulares de Streptococcus pneumoniae, patógeno responsável por diversas manifestações clínicas e com elevada contribuição nas taxas de incidência e mortalidade por meningite, que é a condição clínica mais grave. OBJETIVO: O presente estudo teve como objetivo avaliar o impacto da PCV10 na epidemiologia da meningite pneumocócica na região metropolitana de Salvador (RMS) Bahia, comparando o período anterior (2008-2010) e posterior (2011-2013) a sua utilização, bem como realizar uma caracterização molecular minuciosa a partir de uma série histórica (1996-2012) entre os isolados resistentes a enicilina (PNSSP com CIM≥ 0,125 μg/mL) e para os sorotipos não-vacinais (2008-2012). MATERIAL E MÉTODOS: Foram incluídos todos casos de meningite pneumocócica confirmados laboratorialmente no período entre 1996 a 2013. Taxas de incidência para a Salvador e RMS foram calculadas com base nos dados populacionais do IBGE/2010. A determinação do tipo capsular foi realizada através da técnica de Multiplex-PCR e/ou reação de Quellung. A sensibilidade a nove antimicrobianos foi testada através das técnicas disco-difusão,microdiluição e E-test. Para caracterizar o perfil molecular foram aplicadas as técnicas de genotipagem de PFGE e MLST. RESULTADOS: Um total de 939 casos de meningite pneumocócica foram identificados no período de 1996-2013, sendo que 70 casos ocorrem entre 2011 a 2013 (período pós-vacinal). A incidência de meningite pneumocócica em todas as faixas etárias na RMS reduziu de 0,70 casos/100.000 habitantes para 0,59 casos/100.000 habitantes considerando o período de três anos antes e após a vacinação com PCV10 [p<0,05; RR IC 95%: 1,46 (1,03-2,05)]. Esta redução foi significativa na faixa etária de 0-2 anos e nos casos por sorotipos relacionados à PCV10. Não houve aumento significativo de casos por sorotipos não vacinais nesta casuística,apesar do surgimento de casos por sorotipos não-vacinais não detectados anteriormente na série histórica de MP (10F, 21, 22F, 15A e 24F). Os isolados resistentes à penicilina analisados na série histórica se restringiram a 13 sorotipos, entre os quais: 14 (45,1 %; 78/173), 23F (19,1%; 33/173), 6B (14,4 %; 25/173), 19F (9,2 %; 16/173) e 19A (5,2 %; 9/173). 94% dos casos nãosusceptíveis à penicilina (PNSSP) foram de sorotipos vacinais. Os grupos clonais caracterizados pelo PFGE/MLST predominantes ao longo dos anos foram representados pelo sorotipo 14, denominado grupo A/ST 66 [35,3 %(61/173)] e grupo GK/ST 156 [4.6 % (8/173)], este último associado com níveis elevados de resistência a penicilina e ceftriaxona. Não foram detectados grupos clonais emergentes associados a tipos capsulares não-vacinais.CONCLUSÕES: Estes achados sugerem que a introdução da PCV10 modificou a epidemiologia da meningite pneumocócica na população estudada.

INTRODUCTION: In 2010, the 10-valent pneumococcal conjugate vaccine (PCV10) was introduced into the Brazilian national immunization program (NIP). This immunobiological provides immunization against the main ten capsular types of Streptococcus pneumoniae, the pathogen responsible for different clinical manifestations and high contribution in the incidence and mortality from meningitis, which is the most severe clinical condition. OBJECTIVE: This study aimed to evaluate the impact of PCV10 in the epidemiology of pneumococcal meningitis in the metropolitan area of Salvador (RMS) Bahia, comparing the previous (2008-2010) and after (2011-2013) periods its use, as well as conduct a thorough molecular characterization from a historical series (1996-2012) among isolates resistant to penicillin (PNSSP with CIM≥ 0.125 g / ml) and nonvaccine serotypes (2008-2012). MATERIAL AND METHODS: We included all cases of pneumococcal meningitis laboratory confirmed for the period 1996 to 2013. Incidence rates for Salvador and RMS were calculated based on population data from IBGE/2010. The capsular type determination was performed by multiplex PCR and/or Quellung reaction. Isolates Nine antibiotics were tested by disk-diffusion test, broth micro-dilution and E-test. To characterize the molecular profiling techniques were applied genotyping PFGE and MLST...

Pneumonia and malnutrition are highly predictive of mortality among African children hospitalized with human immunodeficiency virus infection or exposure in the era of antiretroviral therapy.

OBJECTIVE: To identify clinical characteristics predicting death among inpatients who are infected with or exposed to human immunodeficiency virus (HIV) during a period of pediatric antiretroviral therapy scale-up in sub-Saharan Africa. STUDY DESIGN: Retrospective review of medical records from every child with HIV infection (n = 834) or exposure (n = 351) identified by routine inpatient testing in Kamuzu Central Hospital, Lilongwe, Malawi, September 2007 through December 2008. RESULTS: The inpatient mortality rate was high among children with HIV infection (16.6%) and exposure (13.4%). Clinically diagnosed Pneumocystis pneumonia or very severe pneumonia independently predicted death in inpatients with HIV infection (OR 14; 95% CI 8.2 to 23) or exposure (OR 21; CI 8.4 to 50). Severe acute malnutrition independently predicted death in children who are HIV infected (OR 2.2; CI 1.7 to 3.9) or exposed (OR 5.1; CI 2.3 to 11). Other independent predictors of death were septicemia, Kaposi sarcoma, meningitis, and esophageal candidiasis for children infected with HIV, and meningitis and severe anemia for inpatients exposed to HIV. CONCLUSIONS: Severe respiratory tract infections and malnutrition are both highly prevalent and strongly associated with death among hospitalized children who are HIV infected or exposed. Novel programmatic and therapeutic strategies are urgently needed to reduce the high mortality rate among inpatients with HIV infection and HIV exposure in African pediatric hospitals.

Incidência das meningites no Estado do Rio de Janeiro no período de 2000 a 2006 / Incidence of meningitis in the state of Rio de Janeiro, in the period of 2000 to 2006

As meningites são um importante problema de saúde pública, em particular as de origem bacteriana, devido à maior chance de evolução com sequelas neurológicas ou óbito. No Estado do Rio de Janeiro, no entanto, existem poucos estudos sobre o tema. O objetivo deste trabalho foi realizar um estudo descritivo sobre a incidência das meningites ocorridas no Estado do Rio de Janeiro, no período de 2000 a 2006. Os dados foram extraídos do banco de dado do Sistema de Informações de Agravos de Notificação (SINAN). Foram calculadas as taxas de incidência padronizada de meningite e a variação percentual relativa no período. A taxa de incidência padronizada de meningite para o Estado do Rio de Janeiro variou de 14,5 em 2000 a 11,1 por 100 mil em 2006, com uma variação percentual relativa de 23,3%. A maior taxa média de incidência ocorreu no município de Carapebus (25,3 por 100 mil). Observou-se uma queda na taxa de incidência por meningite no Estado do Rio de Janeiro, no último ano do período estudado.

Meningitis is an important public health problem, particularly those of bacterial origin, due to higher chance of evolve with neurological sequelae or death. In the State of Rio de Janeiro, however, there are few studies about the issue. The objective of this work was to perform a descriptive study of the incidence of meningitis that occurred in State of Rio de Janeiro, Brazil, in the period of 2000 to 2006. Data were obtained from the Information System Notification Diseases (SINAN) Database.The meningitis incidence rates were calculated, in standard way, and the percentage change in the period. The standardized incidence rate of meningitis in the State of Rio de Janeiro ranged from 14.5 in 2000 to 11.1 per 100 000 in 2006, with a relative percentage change of 23,3%. The highest average incidence rate occurred in the municipality of Carapebus (25.3 per 100,000). There was a decrease in the incidence rate of meningitis in the State of Rio de Janeiro, in the last year of the studied period.

Survival after neuroAIDS: association with antiretroviral CNS Penetration-Effectiveness score.

OBJECTIVE: We examined if the CNS Penetration-Effectiveness (CPE) score of antiretroviral drugs was associated with survival after a diagnosis of HIV-related encephalopathy, progressive multifocal leukoencephalopathy (PML), cerebral toxoplasmosis, or cryptococcal meningitis. METHODS: Using data from the FHDH-ANRS CO4, we compared the survival of 9,932 HIV-infected patients diagnosed with a first neurologic AIDS-defining event in the pre-combination antiretroviral therapy (cART) (1992-1995), early cART (1996-1998), or late cART (1999-2004) periods. Follow-up was subdivided (CPE < 1.5 and CPE ≥ 1.5), and relative rates (RR) of death were estimated using multivariable Poisson regression models. RESULTS: In the pre-cART and early cART periods, regimens with CPE ≥ 1.5 were associated with lower mortality after HIV-related encephalopathy (RR 0.64; 95% confidence interval [CI] 0.47-0.86 and RR 0.45; 95% CI 0.35-0.58) and after PML (RR 0.79; 95% CI 0.55-1.12 and RR 0.45; 95% CI 0.31-0.65), compared to regimens with CPE < 1.5, while in the late cART period there was no association between the CPE score and the mortality. A higher CPE score was also associated with a lower mortality in all periods after cerebral toxoplasmosis (RR 0.68, 95% CI 0.56-0.84) or cryptococcal meningitis (RR 0.50, 95% CI 0.34-0.74). Whatever the neurologic event, these associations were not maintained after adjustment on updated plasma HIV-RNA (missing, <500, ≥500 copies/mL) with RR ranging from 0.82 (95% CI 0.36-1.91) to 1.02 (0.69-1.52). CONCLUSION: At the beginning of the cART era, the CPE score was of importance for survival after severe neurologic event, while in the late cART period, the additional effect of CPE score vanished with more powerful antiretroviral regimens associated with plasma viral load control.

One thousand endoscopic skull base surgical procedures demystifying the infection potential: incidence and description of postoperative meningitis and brain abscesses.

BACKGROUND: Endonasal endoscopic skull base surgery (ESBS) is perceived as having a high risk of infection because it is performed through the sinuses, which are not sterile. OBJECTIVE: To identify the bacteriological characteristics, incidence, mortality, and risk factors for intracranial infection after ESBS. METHODS: A retrospective analysis of the first 1,000 ESBS procedures performed at the University of Pittsburgh Medical Center from 1998 to 2008. RESULTS: In 18 cases (1.8%), the patient developed meningitis. In 2 cases, the patient died within 2 months after surgery, of noninfectious causes. In 11 cases, cerebrospinal fluid (CSF) cultures had positive results. There were no predominant pathogens. Male sex (odds ratio [OR], 3.97 [95% confidence interval {CI}, 1.21-13.03]; P = .02), history of a craniotomy or endonasal surgery (OR, 4.77 [95% CI, 1.68-13.56]; P = .02), surgery with higher levels of complexity (OR, 6.60 [95% CI, 1.77-24.70]; P = .003), the presence of an external ventricular drain or ventriculoperitoneal shunt at the time of surgery (OR, 6.38 [95% CI, 1.07-38.09]; P = .005), and postoperative CSF leak (OR, 12.99 [95% CI, 4.24-39.82]; P < .001) were risk factors for infection. CONCLUSION: The incidence of infection of 1.8% in ESBS is comparable to that in open craniotomy. The most important risk factor was a postoperative CSF leak. All patients recovered from their infection.

Prolonged survival of neoplastic meningitis from breast cancer with letrozole and intrathecal methotrexate: a case report.

Neoplastic meningitis from breast cancer has a dismal prognosis and short survival. Treatment is based on the intrathecal administration of chemotherapeutic agents, cranial or craniospinal radiotherapy, and systemic chemotherapy. In this report we describe the case of a woman with neoplastic meningitis from breast carcinoma who developed an excellent response to letrozole combined with intrathecal methotrexate, resulting in long-term survival of more than 36 months. Based on the findings of this case report, we suggest that addition of letrozole to the standard therapeutic approach may be beneficial for some patients.

Epidemiología de la meningitis Venezuela 2010 / Epidemiology of meningitis in Venezuela 2010

Las meningitis en Venezuela constituyen un importante problema de salud pública, que afecta de manera especial a los niños menores de 5 años. Las vacunas antineumocócicas, antimeningocócicas, contra Haemophilus influenzae tipo b, así como la BCG, obligan a revisar la dinámica de la morbi-mortalidad en nuestro país. La etiología más frecuente es viral, seguida de las meningitis bacterianas y las tuberculosas, mientras que se conoce poco de la micótica y otras causas. Los sistemas de vigilancia epidemiológica muestran cifras altas de la incidencia de las meningitis que ameritan acciones más enérgicas de salud pública para vigilar, prevenir y mejorar los Programas Nacionales de Inmunizaciones y sus coberturas, además de tratar médicamente las meningitis en cualquiera de sus causas infecciosas

Meningitis constitutes an important public health problem in Venezuela that affects children, specially under 5 years of age. Antimeningococcal, anti-pneumococcal, vaccines against Haemophilus influenzae type b and BCG induce pediatricians to review the dynamics of the morbidity and mortality of these diseases. The most common etiology is the viral followed by bacterial meningitis followed by tuberculosis, while little is known of the fungal or other causes. Epidemiological surveillance systems show high figures of the incidence which warrant a more intense public health action to monitor, prevent and improve national programs of immunization and their vaccine coverage, and to treat medically any infectious cause of meningitis

Neoplastic meningitis in patients with acute myeloid leukemia scheduled for allogeneic hematopoietic stem cell transplantation.

We analyzed the frequency of neoplastic meningitis in patients with acute myeloid leukemia prior to allogeneic hematopoietic stem cell transplantation at our institution. Between 1996 and 2009, cerebrospinal fluid samples of 204 adult patients were examined during pre-transplant work-up for cell counts and, if abnormal, morphologically. We found blasts in cerebrospinal fluid samples of 17 patients with either persistent (n=9) or newly diagnosed (n=8) neoplastic meningitis. All patients proceeded to transplant. The proportion of patients with central nervous system involvement was significantly higher in patients with refractory disease at the time of transplantation compared with patients responding to prior systemic therapy (19% vs. 4.6%; P=0.003). Since most of the patients with central nervous system involvement were asymptomatic, cerebrospinal fluid evaluation should be considered at least in patients with refractory acute myeloid leukemia.

Neurologic complications associated with intrathecal liposomal cytarabine given prophylactically in combination with high-dose methotrexate and cytarabine to patients with acute lymphocytic leukemia.

Central nervous system (CNS) prophylaxis has led to a significant improvement in the outcome of patients with acute lymphocytic leukemia (ALL). Liposomal cytarabine (Enzon Pharmaceuticals, Piscataway, NJ; Skye Pharma, San Diego, CA), an intrathecal (IT) preparation of cytarabine with a prolonged half-life, has been shown to be safe and effective in the treatment of neoplastic meningitis. Liposomal cytarabine was given for CNS prophylaxis to 31 patients with newly diagnosed ALL. All patients were treated concurrently with hyper-CVAD chemotherapy (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) including high-dose methotrexate (MTX) and cytarabine on alternating courses. Liposomal cytarabine 50 mg was given intrathecally on days 2 and 15 of hyper-CVAD and day 10 of high-dose MTX and cytarabine courses until completion of either 3, 6, or 10 IT treatments, depending on risk for CNS disease. Five patients (16%) experienced serious unexpected neurotoxicity, including seizures, papilledema, cauda equina syndrome (n = 2), and encephalitis after a median of 4 IT administrations of liposomal cytarabine. Toxicities usually manifested after the MTX and cytarabine courses. One patient died with progressive encephalitis. After a median follow-up of 7 months, no isolated CNS relapses have been observed. Liposomal cytarabine given via intrathecal route concomitantly with systemic chemotherapy that crosses the blood-brain barrier such as high-dose MTX and cytarabine can result in significant neurotoxicity.

Granulomatous cutaneous centrofacial and meningocerebral amebiasis.

A 7-year-old, otherwise healthy Peruvian boy presented with a 3-month history of an indurated centrofacial plaque. Histologic examination revealed a granuloma containing free-living amebae tentatively identified as Balamuthia mandrillaris. The patient failed to respond to tentative treatment. He was admitted to the intensive care unit 7 months later with neurologic manifestations of granulomatous amebic encephalitis, which proved fatal. The difficulty in diagnosing this rare presentation of cutaneous amebiasis, the challenge of treating the condition, and the morbidity and high mortality associated with cerebral involvement are discussed.

Phase II trial of intracerebrospinal fluid etoposide in the treatment of neoplastic meningitis.

BACKGROUND: The purpose of the current study was to determine the toxicity and response of a fixed dose intracerebrospinal fluid (CSF) etoposide in the treatment of patients with newly diagnosed neoplastic meningitis (NM). NM reportedly occurs in 1% to 5% of patients with known cancer. Currently available treatment options are limited and provide only modest benefit. METHODS: Twenty-seven patients (median age, 55 yrs) with clinically and cytologically documented NM received intra-CSF etoposide. Tumor histologies included lung (8 patients), breast (5 patients), primary brain tumor (4 patients), non-Hodgkin lymphoma (4 patients), melanoma (4 patients), colon (1 patient), and prostate (1 patient). Concurrent involved-field radiotherapy (19 of 27 patients) or systemic chemotherapy (17 of 27 patients) was administered based on clinical indications. Etoposide was administered at a fixed dose (0.5 mg every day given 5 days per week every other week for 8 weeks [induction]). Patients were evaluated by CSF cytology and neurologic examination at the conclusion of induction therapy. Responding patients continued to receive etoposide (5 consecutive days every 4 weeks) with monthly evaluations. RESULTS: Seven of 27 patients (26%) treated with etoposide had a cytologic response and either stable or improved neurologic status at the conclusion of induction. Eight patients (30%) developed disease progression during induction therapy and did not complete the 8-week induction course of therapy. At the conclusion of induction therapy, 12 patients (44%) had persistently positive CSF cytology, although they were clinically stable. In responding patients, time to neurologic disease progression ranged from 8 weeks to 40 weeks (median, 20 wks). Toxicity manifested as transient chemical arachnoiditis (5 of 27 patients; 13% of all treatment cycles). The 6-month neurologic disease progression-free survival was 11%. CONCLUSIONS: Etoposide appears to have modest activity against NM and easily managed toxicity.

[Predictive value of the Knosp classification in grading the surgical resection of invasive pituitary macroadenomas. A prospective study of 23 cases]. / Valor predictivo de la clasificación de Knosp en el grado de resección quirúrgica de los macroadenomas invasivos. Estudio prospectivo de una serie de 23 casos.

OBJECTIVE: To evaluate our experience regarding the treatment of pituitary macroadenomas with cavernous sinus invasion in a series of 23 cases of transphenoidal resection. MATERIALS, METHODS AND RESULTS: Twenty two patients, fifteen males and seven females, with ages ranging from 27 to 75 (mean of 48), were operated under protocol by a single surgeon between May of 2002 and December of 2004. Preoperatively all lesions were diagnosed by MRI and staged according to the Knosp classification. All tumors had extension to one or both cavernous sinuses. Four patients were considered to be grade 1, two grade 2, one grade 3 and sixteen grade 4. Twenty three operations were performed on twenty-two patients. Twenty cases were the standard transsphenoidal approach, and three were endoscopic. Postoperatively, the excision was classified as Complete or Total, Subtotal or Partial. Mean follow up was 15 months. The variables considered for analysis include invasion and resection grades. All six patients with graded 1 and 2 lesions and two patients with grade 4 lesions underwent a complete resection. Subtotal (greater than 80%) excision was achieved in one patient with a grade 3 tumor and six patients with grade 4 tumors. The remaining seven patients with grade 4 adenomas had a Partial (less than 80%) excision. We compare de resection grade versus invasion grade with exact Fisher test. And there is not estadistical difference (p=0.12). CONCLUSION: The Knosp classification alone cannot predict the behavior of these tumors. In our experience, despite tumor extension to the cavernous sinus, pituitary macroadenomas can be safely resected with low morbidity and mortality.

Neoplastic meningitis-related encephalopathy.

BACKGROUND: A retrospective comparison evaluating survival in two well-matched cohorts of patients with cytologically positive neoplastic meningitis (NM) presenting with or without encephalopathy. METHODS: Two cohorts were studied: 20 with and 20 without of NM-related encephalopathy defined as a confusional syndrome. Cohorts were matched with respect to age, primary tumor, performance status, absence of CSF compartmentalization and absence of neuroradiographic bulky CNS disease. Primary tumor histology included the following: breast(10 patients); non-small cell lung cancer (8); non-Hodgkin's lymphoma (8); colorectal cancer (6); melanoma (4); small cell lung cancer (2); prostate cancer (2). NM at presentation revealed: encephalopathy (20 patients); spinal cord dysfunction (18); and cranial neuropathy (15). Radiotherapy was administered to 31 patients (whole brain only in 17 patients; restricted spine only in 8 patients; whole brain and restricted spine in 6 patients). All patients received intraventricular chemotherapy and 16 patients received concurrent tumor-specific systemic chemotherapy. RESULTS: Median survival was 2.5 months (range 1.5-5 months) in the cohort with NM-related encephalopathy compared to 6 months (range: 2-10 months) in the cohort without NM-related encephalopathy (p < 0.001). No treatment-related deaths were observed. All patients demonstrated progressive disease and died of either NM or systemic cancer. CONCLUSIONS: NM-related encephalopathy is a clinical variable that predicts for poor survival in patients with NM. As a consequence, patients with NM-related encephalopathy may be best served by offering supportive care.

Neoplastic meningitis.

Neoplastic meningitis (NM) is a common problem in neuro-oncology occurring in approximately 5% of all patients with cancer, and is the third most common site of CNS metastases. NM is a disease affecting the entire neuraxis, and therefore clinical manifestations are pleomorphic affecting the spine, cranial nerves, and cerebral hemispheres. Because of craniospinal disease involvement, staging and treatment need to encompass all CSF compartments. Treatment of NM utilizes involved-field radiotherapy of bulky or symptomatic disease sites and intra-CSF drug therapy. The inclusion of concomitant systemic therapy may benefit patients with NM and may obviate the need for intra-CSF chemotherapy. At present, intra-CSF drug therapy is confined to three chemotherapeutic agents (ie, methotrexate, cytarabine, and thiotepa) administered by a variety of schedules either by intralumbar or intraventricular drug delivery. Although treatment of NM is palliative with an expected median patient survival of 2 to 6 months, it often affords stabilization and protection from further neurologic deterioration in patients with NM.

Vigilância epidemiológica e avaliação da assistência às meningites / Epidemiologic surveillance and evaluation of meningitis hospital care

OBJETIVO: Analisar o perfil clínico-epidemiológico dos casos de meningite internados em hospital público e os fatores associados à evolução hospitalar. MÉTODOS: Foram analisados 694 casos confirmados, notificados e investigados pelo serviço de epidemiologia de um hospital público de 1986 a 2002. Os dados foram coletados do Sistema de Informação de Agravos de Notificação (Sinan), como parte da rotina local de vigilância epidemiológica. Foi realizada análise multivariada por regressão logística. RESULTADOS: Etiologias mais freqüentes: criptocócica (12,3 por cento; letalidade =37,7 por cento); meningocócica (8,7 por cento; letalidade =13,3 por cento); pneumocócica (7,2 por cento; letalidade =46 por cento); tuberculosa (6,1 por cento; letalidade =40,5 por cento); estafilocócica (5,2 por cento; letalidade =38,9 por cento), viral (5,5 por cento; letalidade =7,9 por cento); hemófilo (2,9 por cento; letalidade =20 por cento). 38,8 por cento dos casos apresentavam etiologia não especificada (letalidade =36 por cento) e 17,3 por cento estavam associados à infecção pelo HIV. Observou-se meningite hospitalar em 27,1 por cento e seqüelas em 9,2 por cento dos casos com alta hospitalar. Variáveis associadas a uma maior chance de óbito: etiologia (referência viral) - tuberculose, criptococo, estafilococo, meningococo, não especificada, outros gram negativos, cândida e pneumococo; infecção pelo HIV; coma. A tríade febre, vômitos e rigidez de nuca associou-se a uma menor chance de óbito. CONCLUSÕES: A elevada proporção de etiologia não especificada e letalidade alta podem refletir problemas de processo de assistência e/ou seleção dos casos relacionada ao perfil do hospital. A vigilância epidemiológica operante no nível hospitalar foi capaz de retro-alimentar os serviços com indicadores da assistência, sendo pertinente o uso do Sinan neste nível.

Increased diffusion of soluble adhesion molecules in meningitis, severe sepsis and systemic inflammatory response without neurological infection is associated with intrathecal shedding in cases of meningitis.

OBJECTIVE: Sepsis and systemic inflammatory response syndrome (SIRS) result in the release in plasma of inflammatory cytokines and soluble forms of adhesion molecules in relation to endothelial activation. This study was designed to compare cerebrospinal fluid (CSF) concentrations of adhesion molecules in meningitis and SIRS without neurological infection and to evaluate in meningitis whether they originate from passive diffusion through damaged blood-CSF barrier or from local production. DESIGN: Prospective observational study. SETTING: University hospital medical intensive care unit. PATIENTS: Nineteen patients with meningitis and 41 patients with sepsis or SIRS without cerebrospinal infection consecutively admitted to the critical care unit over an 18-month period. INTERVENTIONS: Soluble forms of adhesion molecules (ICAM-1, VCAM-1, E-selectin) and cytokines (interleukin (IL)-1beta and TNF-alpha) were measured in paired CSF and blood samples. RESULTS: Serum concentrations of soluble adhesion molecules and cytokines were increased in the two groups, without significant differences. The CSF concentrations were elevated in both cases, whereas patients with meningitis demonstrated significantly higher CSF concentrations of soluble ICAM-1, VCAM-1, E-selectin, and TNF-alpha ( p<0.001), with higher corresponding CSF/serum ratios. Correlations between CSF and serum concentrations were found only in meningitis. These correlations were strong for soluble ICAM-1 (r(2)=0.7, p<0.001) and E-selectin (r(2)=0.9, p<0.001), but weaker for VCAM-1. VCAM-1 CSF/serum ratios were increased, in comparison with ICAM-1 and E-selectin CSF/serum ratios, despite similar molecular weights. Serum and CSF levels of cytokines and adhesion molecules were not predictive of death for the whole population, except concentrations of ICAM-1 significantly increased in non-surviving patients ( p<0.05). CONCLUSIONS: The CSF soluble adhesion molecules are increased in sepsis, SIRS and meningitis. In meningitis, the correlation between CSF and serum concentrations of adhesion molecules and the presence of a discrepancy of CSF/serum ratios for molecules of the same molecular weight may suggest intrathecal shedding in addition to diffusion through blood-CSF barrier.

Carcinomatous meningitis: are surgeryand gamma knife radiosurgery treatment risk factors?

OBJECT: The purpose of this study was to identify possible risk factors leading to carcinomatous meningitis in patients with a known brain metastasis and who were treated with gamma knife radiosurgery (GKS). METHODS: Two hundred eighty lesions in 101 patients were treated during 121 GKS procedures. The clinical and neuroimaging history, tumor histology, and follow-up studies were reviewed for all patients. Evidence as demonstrated by magnetic resonance imaging criteria and/or cerebrospinal fluid (CSF) cytology of carcinomatous meningitis was evaluated. The data were then analyzed to identify potential risk factors for the development of CSF dissemination. CONCLUSIONS: It appears that carcinomatous meningitis is exclusively identified in patients with adenocarcinoma, in particular with primary lung cancer. Furthermore, the incidence is higher if surgery is performed and the interval to subsequent GKS is prolonged.