Anti-HBV DNA vaccination does not prevent relapse after discontinuation of analogues in the treatment of chronic hepatitis B: a randomised trial--ANRS HB02 VAC-ADN.

OBJECTIVE: The antiviral efficacy of nucleos(t)ide analogues whose main limitation is relapse after discontinuation requires long-term therapy. To overcome the risk of relapse and virological breakthrough during long-term therapy, we performed a phase I/II, open, prospective, multicentre trial using a HBV envelope-expressing DNA vaccine. DESIGN: 70 patients treated effectively with nucleos(t)ide analogues for a median of 3 years (HBV DNA <12 IU/mL for at least 12 months) were randomised into two groups: one received five intramuscular injections of vaccine (weeks 0, 8, 16, 40 and 44) and one did not receive the vaccine. Analogues were stopped after an additional 48 weeks of treatment in patients who maintained HBV DNA <12 IU/mL with no clinical progression and monthly HBV DNA for 6 months. The primary endpoint was defined as viral reactivation at week 72 (HBV DNA >120 IU/mL) or impossibility of stopping treatment at week 48. RESULTS: Reactivation occurred in 97% of each group after a median 28 days without liver failure but with an HBV DNA <2000 IU/mL in 33%; 99% of adverse reactions were mild to moderate. Immune responses were evaluated by enzyme-linked immunosorbent spot and proliferation assays: there was no difference in the percentage of patients with interferon-γ secreting cells and a specific T-cell proliferation to HBcAg but not to HBsAg after reactivation in each group. CONCLUSIONS: Although it is fairly well tolerated, the HBV DNA vaccine does not decrease the risk of relapse in HBV-treated patients or the rate of virological breakthrough, and does not restore the anti-HBV immune response despite effective viral suppression by analogues. TRIAL REGISTRATION NUMBER: NCT00536627.

Archived HIV-1 DNA resistance mutations to rilpivirine and etravirine in successfully treated HIV-1-infected individuals pre-exposed to efavirenz or nevirapine.

OBJECTIVES: Efavirenz and nevirapine failure is associated with a rapid selection of resistance-associated mutations (RAMs), which may impact on etravirine or rilpivirine susceptibility. However, RAMs for rilpivirine and etravirine cannot be reported on previous resistance genotypes because these specific RAMs were not analyzed at that time. Therefore, our objective was to determine, in virologically suppressed HIV-1-infected individuals, the presence of RAMs to rilpivirine, etravirine and the combination of tenofovir/emtricitabine/rilpivirine in HIV-1 DNA from individuals previously exposed to efavirenz and/or nevirapine. METHODS: The studied population included 169 treatment-experienced individuals enrolled in the ANRS 138-EASIER trial who previously failed on and/or were intolerant to efavirenz and/or nevirapine and who had plasma HIV-1 RNA<400 copies/mL. Resistance to rilpivirine, etravirine, tenofovir and emtricitabine by bulk sequencing was performed on extracted HIV-1 DNA from whole blood collected at the time of trial inclusion. RESULTS: Reverse transcriptase gene amplification was successful in 128/169 (76%) individuals and 95% of HIV-1 were infected with subtype B. Rilpivirine RAMs were detected in 41 (32%) individuals, with highest frequency for the mutations Y181C/I/V (18%), K101E/P (7%) and E138A/G/K/Q/R/S (6%) and the association L100I+K103N/S (5%). Etravirine RAMs were detected in five (4%) individuals. Resistance to emtricitabine, tenofovir and at least one drug included in the combination of tenofovir/emtricitabine/rilpivirine were detected in 72 (56%), 12 (9%) and 88 (69%), respectively. CONCLUSIONS: In individuals with suppressed viraemia under antiretroviral therapy (ART), but who had been previously exposed to an efavirenz and/or nevirapine-based regimen, rilpivirine RAMs are frequent and etravirine RAMs are rare. This finding suggests that the switch to a rilpivirine-based regimen should not be recommended.

Lymphoma and Epstein-Barr virus DNA in blood during interleukin-2 therapy in antiretroviral-naïve HIV-1-infected patients: a substudy of the ANRS 119 trial.

OBJECTIVES: Interleukin-2 (IL-2) therapy increased CD4 cell counts and delayed antiretroviral therapy (ART) initiation in HIV-infected patients in the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) 119 trial. However, four cases of lymphoma were reported. Epstein-Barr virus (EBV) replication is associated with an increased risk of lymphoma in immunocompromised patients. We assessed whether IL-2 had an impact on EBV replication and the development of lymphoma. METHODS: A total of 130 ART-naïve patients were randomized to receive IL-2 therapy (n = 66) or no treatment (n = 64). Clinical data for patients with lymphomas were reviewed and tumours assessed for evidence of EBV infection and CD25 (the IL-2 receptor) expression. EBV DNA levels were measured in whole blood and plasma in both arms using real-time polymerase chain reaction (PCR), up to 48 weeks after baseline (BL). RESULTS: Four lymphomas occurred, a median of 61 weeks [range 40-94 weeks] after randomization at a median CD4 cell count of 396 cells/µL (IQR 234-536 cells/µL). In the IL-2 arm, two patients developed EBV-positive Hodgkin's lymphoma, and one developed EBV-negative Burkitt-type lymphoma. One patient in the control group developed EBV-positive non-Hodgkin's lymphoma. CD25 was negative in all cases. Among the 41 of 55 (control arm) and 44 of 58 (IL-2 arm) patients with detectable EBV DNA in whole blood at both BL and week 48, the median change in EBV DNA between BL and week 48 was +0.04 log10 copies/ml in both arms (P = 0.7). In plasma, EBV was detected at least once in 22 of 52 controls and 21 of 54 IL-2-treated patients (P = 0.8). CONCLUSIONS: IL-2 therapy had no significant effect on EBV replication over 48 weeks in these ART-naïve patients. The occurrence of lymphomas did not seem to be associated with IL-2 therapy.

Comparison of resistance mutation patterns in historical plasma HIV RNA genotypes with those in current proviral HIV DNA genotypes among extensively treated patients with suppressed replication.

OBJECTIVES: Heavily treatment-experienced patients with good virological control could be at risk of virological failure on switching to a new regimen if pre-existing drug resistance is not taken into account. We examined whether genotyping based on cellular HIV-1 DNA during controlled viraemia identifies resistance mutations detected in plasma HIV-1 RNA during treatment with previous antiretroviral regimens. PATIENTS AND METHODS: All 169 patients enrolled in the Agence Nationale de Recherche sur le SIDA (ANRS) 138-intEgrase inhibitor MK_0518 to Avoid Subcutaneous Injections of EnfuviRtide (EASIER) trial had already received three antiretroviral drug classes [nucleoside reverse transcriptase inhibitor (NRTI), nonnucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI)] and had plasma HIV-1 RNA<400 copies/ml at baseline. The results of previous resistance genotyping of plasma HIV-1 RNA in individual patients were compared with those of resistance genotyping of whole-blood HIV-1 DNA at randomization. RESULTS: A median of 4 plasma RNA genotypes were available for the 169 patients. The median numbers of resistance mutations in HIV-1 RNA and DNA were, respectively, 5 and 4 for NRTIs, 2 and 1 for NNRTIs, and 10 and 8 for PIs. The difference was significant for all three drug classes (P=0.001). Resistance to at least one antiretroviral drug was detected exclusively in HIV-1 RNA or in DNA in 63% and 13% of patients for NRTI, 47% and 1% of patients for NNRTI, and 50% and 7% of patients for PI, respectively. CONCLUSION: This study shows that, among highly treatment-experienced patients on effective highly active antiretroviral therapy, resistance genotyping of HIV-1 DNA detects fewer resistance mutations than previous analyses of HIV-1 RNA. These results have implications for patient management and for the design of switch studies.

Hyperlactataemia in HIV-infected subjects initiating antiretroviral therapy in a large randomized study (a substudy of the INITIO trial).

OBJECTIVE: The aim of the study was to evaluate the predictive value of clinical and molecular risk factors, including peripheral blood mononuclear cell (PBMC) mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA), for the development of lactic acidosis (LA) and symptomatic hyperlactataemia (SHL). METHODS: In a substudy of a large multicentre, randomized trial of three antiretroviral regimens, all containing didanosine (ddI) and stavudine (d4T), in antiretroviralnaïve, HIV-1-infected patients, patients with LA/SHL ('cases') were compared with those without LA/SHL in a univariate analysis, with significant parameters analysed in a multivariate model. In a molecular substudy, PBMC mtDNA and mtRNA from cases and matched controls at baseline and time of event were examined. RESULTS: In 911 subjects followed for a median of 192 weeks, 24 cases were identified (14 SHL and 10 LA). In univariate analysis, cases were more likely to be female (P=0.05) and to have a high body mass index (BMI) (P=0.02). In multivariate analyses, only BMI remained an independent predictor of the development of LA/SHL (P=0.03). Between cases and controls there was no significant difference in mtDNA copy number at baseline (389 vs. 411 copies/cell, respectively; P=0.60) or at time of event (329 vs. 474 copies/cell, respectively; P=0.21), in the change in mtDNA copy number from baseline to event (-65 vs. +113 copies/cell, respectively; P=0.12), in mtRNA expression at baseline or time of event, or in the change in mtRNA expression from baseline to event. CONCLUSION: The development of LA/SHL was associated with increased BMI, but PBMC mtDNA and mtRNA did not predict LA/SHL. This demonstrates the ineffectiveness of routine measurement of PBMC mtDNA in patients on ddI and d4T as a means of predicting development of LA/SHL.

Gag mutations can impact virological response to dual-boosted protease inhibitor combinations in antiretroviral-naïve HIV-infected patients.

ANRS 127 was a randomized pilot trial involving naïve patients receiving two dual-boosted protease inhibitor (PI) combinations. Virological response, defined as a plasma HIV RNA level of <50 copies/ml at week 16, occurred in only 41% patients. Low baseline plasma HIV RNA level was the only significant predictor of virological response. The purpose of this study was to investigate the impact on virological response of pretherapy mutations in cleavage sites of gag, gag-pol, and the gag-pol frameshift region. The whole gag gene and protease-coding region were amplified and sequenced at baseline and at week 16 for 48 patients still on the allocated regimen at week 16. No major PI resistance-associated mutations were detected either at baseline or in the 26 patients who did not achieve virological response at week 16. Baseline cleavage site substitutions in the product of the gag open reading frame at positions 128 (p17/p24) (P = 0.04) and 449 (p1/p6(gag)) (P = 0.01) were significantly more frequent in those patients not achieving virological response. Conversely, baseline cleavage site mutation at position 437 (TFP/p6(pol)) was associated with virological response (P = 0.04). In multivariate analysis adjusted for baseline viral load, these 3 substitutions remained independently associated with virological response. We demonstrated here, in vivo, an impact of baseline polymorphic gag mutations on virological response in naïve patients receiving a combination of two protease inhibitors. However, it was not possible to link the substitutions selected under PI selective pressure with virological failure.

Virological and immunological outcomes at 3 years after starting antiretroviral therapy with regimens containing non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or both in INITIO: open-label randomised trial.

BACKGROUND: Antiretroviral therapy has greatly reduced HIV mortality and morbidity. However, the best sequence of regimens and implications of initial regimen for long-term therapeutic success are not well defined. METHODS: In INITIO, a large international randomised trial, we compared antiretroviral therapy with two nucleoside analogue reverse transcriptase inhibitors (didanosine+stavudine) plus either a non-nucleoside reverse transcriptase inhibitor (efavirenz, EFV) or a protease inhibitor (nelfinavir, NFV), or both (EFV/NFV), in patients with HIV-1 infection who had not previously received antiretroviral drugs. Primary outcomes were proportion with undetectable HIV RNA in plasma, and change in CD4 count from baseline at 3 years. Analyses were by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN44582462. FINDINGS: We followed up 911 participants (297 EFV, 311 NFV, 303 EFV/NFV). At 3 years, the proportion with HIV RNA less than 50 copies per mL was highest in the EFV group (188 [74%] EFV, 162 [62%] NFV, 155 [62%] EFV/NFV; p=0.004). Mean (95% CI) increases in CD4 count were 316x10(6) cells per L (288-343) for EFV, 289x10(6) cells per L (262-316) for NFV, and 274x10(6) cells per L (231-291) for EFV/NFV (p=0.1). Fewer participants in the EFV group than in the other groups stopped adequate antiretroviral therapy for more than 30 days (p=0.005). Participants in the EFV/NFV group had shorter time to stopping the initial regimen (p<0.0001) and to a treatment modifying adverse event (p=0.04) than those in the other groups. INTERPRETATION: Starting antiretroviral therapy with a three-drug/two-class regimen including efavirenz was better than starting with regimens including nelfinavir or efavirenz plus nelfinavir in terms of virological suppression and durability of the initial regimen. The shorter time on adequate antiretroviral therapy or to a treatment-modifying adverse event might explain the absence of additional benefit for the four-drug regimen.

Toxoplasma gondii infection in advanced HIV infection.

OBJECTIVE: To study Toxoplasma encephalitis (TE) in advanced HIV infection, including predictive factors, possible prophylactic regimens and impact on survival. DESIGN: Epidemiological analysis of data collected prospectively during the Alpha study, a double-blind, randomized clinical trial, comparing two doses of dideoxyinosine in patients with advanced HIV disease. PATIENTS: First episode of TE occurred in 75 out of 499 patients participating in the trial. METHODS: Kaplan-Meier estimates and semi-parametric Cox's model were used. RESULTS: A low CD4 cell count and a positive Toxoplasma serology were strongly predictive of the occurrence of TE. In patients with CD4 counts < 100 x 10(6)/l and a positive Toxoplasma serology at entry to the study, the 12-month TE incidence was 25.4%. Patients who were receiving at entry any of the following potentially antitoxoplasmic drugs: trimethoprim-sulphamethoxazole, pyrimethamine, dapsone, pyrimethamine-sulphadoxine or sulphadiazine, had a lower TE incidence than those who were not; 6.2 versus 18.8%, respectively (P < 0.001). The rate of survival 12 months after TE was 29.6%. Even after adjusting the major prognostic covariates, TE was predictive of death (P < 0.001; relative risk, 1.8). CONCLUSIONS: The high HIV incidence, morbidity and mortality in high-prevalence areas suggests that primary prophylaxis should be given in patients at high risk for toxoplasmic reactivation.

A prospective study of criteria for the diagnosis of toxoplasmic encephalitis in 186 AIDS patients. The BIOTOXO Study Group.

OBJECTIVE: To define the factors associated with diagnosis of toxoplasmic encephalitis (TE) in AIDS patients; and to establish a rational procedure for the clinician faced with a decision concerning empiric antitoxoplasma therapy. DESIGN: A 15-month prospective multicentre cohort study in France. METHODS: One hundred and eighty-six consecutive HIV-positive inpatients undergoing empiric antitoxoplasma therapy for a first episode of presumed TE were monitored. The clinician's initial estimation of the probability of response to antitoxoplasma therapy was recorded. In addition, a validation committee classified cases as TE or non-TE. RESULTS: Among the 186 patients, the following variables were significantly more frequent in TE (n = 113) than non-TE (n = 73) patients: fever (59% versus 40%). headache (55% versus 33%), seizures (22% versus 11%), suggestive lesions on the brain scan (98% versus 76%), positive Toxoplasma serology (97% versus 71%). Median CD4+ lymphocyte count was significantly higher in TE than in non-TE (27 x 10(6)/l versus 11 x 10(6)/l). The rate of TE in patients on systemic antiprotozoal prophylaxis at entry was 43% as compared with 75% in patients without previous prophylaxis. Pre-therapy estimation of response to empiric therapy was highly correlated with final diagnosis. Multivariate logistic regression analysis showed that the following variables contributed independently to the diagnosis of TE: clinician's estimation of response to treatment at entry > 75%; absence of systemic antiprotozoal prophylaxis; seizures; headache; suggestive lesions on CT or MRI brain scan; and positive Toxoplasma serology. CONCLUSIONS: A linear logistic model is proposed which uses significant variables, which are readily available. This model gives good accuracy to classify suspected cases of TE.

Discrepant responses to triple combination antiretroviral therapy in advanced HIV disease.

OBJECTIVES: To determine the clinical, virological and immunological outcome in a cohort of unselected patients receiving triple combination therapy for more than 1 year. METHODS: Prospective follow-up of a cohort of 162 unselected, protease inhibitor-naive, antiretroviral-experienced patients with advanced HIV disease, treated with indinavir combined with two nucleoside analogues. RESULTS: The mean CD4 cell count and plasma HIV RNA level in the study group at baseline were 69+/-5 x 10(6)/l and 4.75+/-0.07 log10 copies/ml, respectively. Five per cent of patients died prematurely or were lost to follow-up. Fifty-seven per cent of patients responded to therapy, as assessed by a sustained increase in CD4 cell counts above 50 x 10(6)/l and a decrease in plasma HIV RNA greater than 1 log10 copies/ml, throughout 12.1 months of follow-up. Seventeen per cent of patients were immunological and virological non-responders. Twenty-one per cent of patients exhibited discrepant virological and immunological responses to treatment, of whom one-half failed to exhibit significant increases in CD4 cells despite a virological response to therapy and one-half exhibited increased CD4 cell counts in the absence of significant decrease in plasma viral load. The incidence of AIDS-defining events in the latter group of patients was similar to that of responder patients, whereas their incidence was higher in patients who failed to exhibit a virological and immunological response and those who failed to increase CD4 cells despite a significant decrease in viral load. CONCLUSION: Our observations of discrepant immunological and virological responses to treatment raise the issue of the significance of persistent elevated levels of plasma HIV RNA and of the relevance of measurements of plasma viral load for assessing the efficacy of antiretroviral therapy in patients whose CD4 cell counts increase despite the absence of significant decrease in plasma HIV viral load.

Highly active antiretroviral therapy started in infants under 3 months of age: 72-week follow-up for CD4 cell count, viral load and drug resistance outcome.

OBJECTIVE: To assess the feasibility and impact of highly active antiretroviral therapy (HAART) started in vertically HIV-1-infected infants less than 3 months of age. DESIGN: A multicentre, phase I/II, non-randomized, open-label study (PENTA 7). METHODS: Adverse events, plasma HIV-1 RNA, CD4 cell counts, CD4 cell percentage (CD4%) and clinical progression were recorded at baseline and prospectively to 72 weeks in order to assess the toxicity, tolerability and efficacy of a combination of stavudine, didanosine and nelfinavir. Selection of genotypic resistance was also investigated. RESULTS: Twenty infants, of whom only three had Centers for Disease Control and Prevention stage B, initiated HAART at median age 2.5 months (range, 0.9-4.7) with median HIV-1 RNA concentration 5.5 log10 copies/ml (range, 3.2-6.8) and CD4% 33% (range, 11-66). Median follow-up was 96 weeks (range, 60-144). At week 72, 11 infants were still taking the original treatment. Few adverse events were reported related to treatment, all minor and causing treatment interruption in only three infants. No AIDS-defining events occurred; one child died of non-HIV-related causes (prematurity). All but two had CD4% > 25% at 72 weeks; however, 14 infants had virological failure and six acquired resistance mutations. CONCLUSIONS: Early treatment with stavudine, didanosine and nelfinavir was well tolerated and associated with good clinical and immunological outcomes at week 72. However, a high rate of virological failure with emergence of genotypic resistance is of great concern. More palatable drug combinations for infants and closer drug monitoring are required.

Zidovudine resensitization and dual HIV-1 resistance to zidovudine and lamivudine in the delta lamivudine roll-over study.

OBJECTIVE: To study zidovudine resensitization and dual resistance to zidovudine/lamivudine in HIV-1 isolates from nucleoside reverse transcriptase (RT) inhibitor-experienced patients during selective pressure exerted by zidovudine/lamivudine combination therapy. DESIGN AND METHODS: HIV-1 isolates from 29 patients receiving zidovudine/lamivudine combination therapy in the Delta roll-over study were analysed at entry and during a 1 year follow-up period for phenotypic susceptibility to zidovudine and lamivudine in the ANRS PBMC assay. The RT gene from codon 20 to 230 and at codon 333 was analysed by nucleotide sequencing of the corresponding isolates. RESULTS: HIV-1 isolates from 23 of the 29 patients were phenotypically resistant to zidovudine at baseline; 61% of these patients showed significant zidovudine resensitization during follow-up. The zidovudine IC50 value correlated positively with log10 plasma HIV-1 RNA (P = 0.02) and negatively with the CD4 cell count (P = 0.004). Zidovudine resensitization (related to acquisition of the M184V mutation) was transient, with evolution towards dual resistance to zidovudine and lamivudine in 20 of the 29 patients. The phenotype of certain dually resistant isolates coincided with the emergence of multiple mutations in the 5' part of the RT gene. CONCLUSIONS: M184V-mediated zidovudine resensitization of HIV-1 is transient in most patients who are given zidovudine/lamivudine combination therapy when zidovudine resistance has already emerged. The subsequent evolution towards dual phenotypic resistance to zidovudine/lamivudine corresponds to complex genotypic profiles.

Consistency of routine measurements of CD4+, CD8+ peripheral blood lymphocytes.

In order to evaluate the reliability of CD4 and CD8 T lymphocyte counts in large scale studies, a quality control study was performed in 12 French laboratories. CD4 and CD8 counts, assessed by various haematological and immunological techniques, were compared in order to assess possible differences between the laboratories and the techniques used. Our data showed that (a) the consistency of CD4 measurements was satisfactory since the between-laboratory coefficient of variation for absolute CD4 cell numbers above 200/mm3 was around 15% instead of 5-10% for all laboratories but one; (b) the major sources of variability arose from the use of automatic devices in the two-step measurement procedure: immunophenotyping and haematological counting. These data suggest that multicentre assays of CD4 and CD8 counts result in some increase in their variability. Nevertheless the results of large multicentric trials can be extrapolated with confidence in the routine care of HIV+ patients. Together, the results justified the involvement of several experienced laboratories in a clinical trial of HIV-related disease.

Specific anti-toxoplasmic IgG antibody immunoblot profiles in patients with AIDS-associated Toxoplasma encephalitis.

Among 186 suspected cases of Toxoplasma encephalitis (TE) in HIV-infected patients, 113 were classified as TE and 73 as non-TE. Serum Toxoplasma gondii (T.g.) antibodies were detected by ELISA in 97% of TE vs 71% of non-TE cases (p < 0.001). In the 164 patients positive for T. g. antibodies, the IgG 27 and 32 bands were more frequently present in TE than in non-TE (p = 0.003, p = 0.002, respectively). Among patients with positive T.g. serology, multivariate analysis showed that the presence of an IgG 32 (OR 3.1) or IgG 27 band (OR 2.7) on Western blot was highly indicative of TE independently of each other. Positive T.g. serology, but not anti-T.g. IgG antibody titres, was predictive. Thus, the positivity of IgG 27 and 32 bands on Western blot analysis provides useful data for improving the diagnosis of presumptive TE in HIV-infected patients with suspected TE and positive Toxoplasma serology.

[Computer tomography changes in multiple sclerosis (author's transl)]. / Aspects tomodensitométriques évolutifs de la sclérose en plaques.

An attempt is made to evaluate the semiological data supplied by computer tomography, following its use on several occasions in 4 patients with multiple sclerosis. Three known signs in the encephalic forms are defined: cerebral atrophy, low density plates of sclerosis that do not take up the contrast medium, and those that do. These localized lesions are distinguished by their frequent multiplicity, often periventricular location, and absence of a mass effect. The semiological value of these signs involves discussion on the poor results of statistical evaluation, the significance of histology examination results, which are still being studied, and more particularly the variability, the best evidence of which seems to be the beginning and/or the changes occurring in contrast medium uptake. To this major diagnostic argument can be added the discovery of multilocular lesions which are sometimes present without clinical manifestations. Computer tomography is an essential procedure for establishing the differential diagnosis of multiple sclerosis, avoiding numerous valueless arteriographies, is a fundamental method for early positive diagnosis, and perhaps an element for establishing prognosis.

[Responsibility of the left renal vein and inferior vena cava in certain cases of myelitis and syringomyelia. Value of ligation of the venous reno-spinal trunk. Apropos of 30 cases]. / Responsabilité de la veine rénale gauche et de la veine cave inférieure dans certains cas de myélites et de syringomyélie. Intérêt de la ligature du tronc veineux réno-rachidien. A propos de trente cas.

Certain diffuse forms of myelitis may be due to raised intra-spinal venous pressure resulting in veritable "varicose veins of the spinal cord". The origin of this increased pressure is often multifactorial, but may be due to venous reflux of blood from the left kidney into the intraspinal plexuses via the reno-spinal trunk. Ligation of this trunk results in a considerable and often complete improvement in the neurological syndrome. This operation was performed for the first time by our team in 1973 and since then has been successfully performed on 30 occasions for 21 cases of myelopathy and 9 cases of syringomyelia.

[Multiple intracranial aneurysms associated with coarctation of the aorta. Apropos of a case surgically treated under controlled hypotension]. / Anévrysmes intracrâniens multiples associés à une coarctation de l'aorte. A propos d'un cas opéré sous hypotension contrôlée.

A 17 year old girl presenting with multiple intracranial aneurysms and coarctation of aorta was treated surgically under controlled hypotension. Blood pressure distal to the stenosis was monitored to avoid risk of medullary ischemia.

[Extra-intracranial arterial bypasses. Evaluation of their permeability by use of the Doppler effect]. / Les anastomoses extra-intracraniennes: controle de leur perméabilité par effet Doppler.

40 temporo-sylvian anastomoses were controlled using Doppler ultrasonic examination. The results are compared to post-operative arteriograms. The Doppler examination has proved to be highly accurate when compared to contrast arteriography in the survey of extra-intracranial anastomosis. This non invasive procedure can easily be repeated. However the size of the revascularized area cannot be estimated. The simultaneous isotopic studies of regional cerebral blood flow could provide a means of quantifying the results of the anastomoses.

[Anatomical study of different modes of anastomosis between the facial artery and ophthalmological artery at the medial angle of the orbit (author's transl)]. / étude anatomique des différents modes d'anastomose entre l'artère faciale et l'artère ophtalmique à l'angle interne de l'orbite.

In 21 autopsy specimens, we performed latex injection, and studied the rate and the diameter of the anastomosis between the ophthalmic artery and the facial artery: we find 26 cases in 42 face-sides, 60 %; which can supply rapidly a circulatory insufficiency. The anastomosis which go to the ophthalmic artery from the others branches of the external carotid are less frequent.

[Should the aneurysms of Osler's disease be investigated and operated on prior to hemorrhage?]. / Faut-il rechercher et opérer les anévrismes de la maladie d'Osler avant l'hémorragie?

Neurologic accidents are today the first cause of mortality following bacterial endocarditis through ischemia or mycotic aneurysm rupture. Authors propose a protocol management by complete cerebral angiography and CT scan as soon as the least neurologic sign appears. A headache is the most frequent of these signs. 35 patients were explored during 3 years and 10 treated surgically. These authors conclude that: mycotic aneurysm must be detected aneurysm with subarachnoid haemorrhage must be operated on as soon as possible. With unruptured aneurysm, surgical decision is more difficult: sequential angiography after excision of the most dangerous aneurysm, demonstrates that an aneurysm can appear, enlarge, diminish or spontaneously resolve. Carrying on with this protocol should allow an answer to this question.