Treatment of limbic encephalitis with anti-glioma-inactivated 1 (LGI1) antibodies.

We report a 72-year-old patient who developed acute limbic encephalitis initially considered of uncertain aetiology. Detailed information on clinical presentation, MRI appearance, antibody levels, cognitive impairment assessment, treatment and evolution of the patient is reported here. Since the early 2000s, many antibodies implied in central nervous system autoimmune disorders have been identified. Anti-glioma-inactivated 1 (LGI1) antibodies have been recently identified as associated with limbic encephalitis, as was the case in our patient.

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.

[Progressive multifocal leukoencephalopathy in a non-AIDS patient: high efficiency of combined cytarabine and cidofovir]. / Leucoencéphalite multifocale progressive en dehors du sida: efficacité de l'association cytarabine-cidofovir.

INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the central nervous system, occurring in immunocompromised patients. Treatment, not codified to date, is more often inefficient with a rapid and fatal deterioration. CASE RECORD: A 48-year-old woman, treated with immunosuppressant agents for systemic lupus, presented with PML mimicking neurolupus flare. A complete remission was obtained with cytarabine and cidofovir. CONCLUSION: Combined cytarabine and cidofovir appears a promising therapeutic option in PML associated with autoimmune systemic disorders.

[New trends in progressive multifocal leukoencephalopathy]. / Données récentes sur la leucoencéphalite multifocale progressive.

Infection by Polyomavirus JC is a model of chronic active viral infection, closely controlled by the immune system. Progressive multifocal leucoencephalopathy (PML) is a deadly demyelinating disease of the central nervous system, consecutive to the lytic infection of oligodendrocytes by JC virus. Reactivation of JC virus occurs only in the setting of severe cellular immune deficiency. During the last 25 years, the incidence of PML has significantly increased related to the AIDS pandemic and, more recently, to the growing use of immunosuppressive drugs. There is no specific antiviral treatment for PML. Nevertheless, the availability of highly active antiretroviral therapy has changed the clinical course of PML in HIV-infected individuals. One-year mortality has decreased from 90 percent to approximately 50 percent as a result of reconstitution of the immune system. Recent advances in JC virus biology give new perspectives to the pathogenesis of PML. New trends in the understanding of the cellular immune response against the JC virus have direct implications for patient management and may lead to develop future strategy of immunotherapies for PML.

[Neurospychiatric symptoms in HIV infected patients and the role of efavirenz]. / Troubles neuropsychiatriques chez les patients infectés par le VIH et rôle de l'efavirenz.

Efavirenz has now become commonly used to treat HIV infection. Neuropsychiatric disorders have been reported in patients treated with efavirenz. Several factors often make it hard to determine the cause of these disorders: HIV infected patients take many different drugs, they may suffer from various organ diseases, and may also be heavily affected by problems in their everyday life. The French experts group working on neuropsychiatric side effects of efavirenz has undertaken a review of these disorders with the aim to identify: (1) semiology, (2) epidemiology in the global population, in HIV infected patients, and in patients treated with efavirenz. The expert group suggests recommendations to manage these disorders.

Cidofovir in AIDS-associated progressive multifocal leukoencephalopathy: a monocenter observational study with clinical and JC virus load monitoring.

A monocenter observational study was conducted to determine the clinical and virological effects of cidofovir added to highly active anti-retroviral therapy (HAART) in AIDS-associated progressive multifocal leukoencephalopathy (PML). Exposure to other anti-viral drugs or late initiation of cidofovir were exclusion criteria. Of the 53 consecutive patients with virologically proven PML admitted at the NeuroAIDS Unit of Bicêtre Hospital between May 1996 and July 2000 and having received HAART with or without cidofovir, 46 met the inclusion criteria. Cidofovir was initiated in most cases on compassionate grounds. The 22 patients treated with HAART only (HAART group) were compared to the 24 patients treated with HAART and cidofovir (CDV group). Survival, neurological outcome assessed by the expanded disability status scale (EDSS), and monitoring of the JC virus (JCV) load in CSF were investigated prospectively. At baseline (date of initiation or intensification of HAART), both groups were similar regarding CD4 cell count, plasma HIV load, CSF JCV load, EDSS, and demographic features. Both groups had similar response to HAART in terms of plasma HIV load and CD4 cell count. At month 6, CSF-JCV load was below the detection level in 8 out of 24 (33%) patients from the CDV group and 7 out of 18 (39%) patients from the HAART group (P = 0.71). One-year cumulative probability of being alive was 62% in the CDV group and 53% in the HAART group (P = 0.72). However, an additional benefit with respect to survival was observed in patients who were given cidofovir after adjustment to the following baseline variables (CSF-JCV load, CD4 cell count, and EDSS). Despite the addition of cidofovir to HAART, no significant benefit had been observed in neurological outcome, particularly in patients with an early worsening.

Induction and maintenance therapy of cytomegalovirus central nervous system infection in HIV-infected patients.

OBJECTIVE: To evaluate the efficacy and safety of the foscarnet-ganciclovir combination in induction therapy (IT) and maintenance therapy (MT) for cytomegalovirus (CMV) central neurological disorders in HIV-infected patients. DESIGN: An open pilot non-comparative multicentre study. METHODS: Thirty-one patients with acute CMV encephalitis (CMVe) (n = 17) or CMV myelitis (CMVm) (n = 14) during the era before highly active antiretroviral therapy (HAART) received intravenous IT with foscarnet 90 mg/kg plus ganciclovir 5 mg/kg twice a day followed by MT. The primary endpoint was clinical efficacy, assessed at the end of the induction phase. RESULTS: The foscarnet-ganciclovir combination in IT resulted in a 74% (23 out of 31 patients) clinical improvement or stabilization. Eight patients did not respond clinically. Side-effects leading to drug discontinuation occurred in 10 patients during IT. Among the 23 patients who qualified for the maintenance phase, CMV disease progressed in 10, with a median time to the first relapse of 126 days (range 64-264 days). Overall, the median survival time was 3 months [95% confidence interval (CI), 2-4 months]. CONCLUSION: The combination of foscarnet and ganciclovir can safely be used for CMV central nervous system (CNS) infection, with an improvement or stabilization in 74% of patients. Life-long MT with this combination is recommended as long as the immune system is profoundly impaired.

Survival improvement of AIDS-related progressive multifocal leukoencephalopathy in the era of protease inhibitors. Clinical Epidemiology Group. French Hospital Database on HIV.

OBJECTIVE: To estimate the change in survival of patients with AIDS-related progressive multifocal leukoencephalopathy (PML), in relation to the introduction of protease inhibitors (PI). DESIGN: The French Hospital Database on HIV (FHDH) is a prospective cohort of 70 224 HIV-infected subjects. This study included the patients diagnosed with PML between 1 July 1995 and 30 June 1997. PML diagnosis was both presumptive and confirmed. We compared the survival probability according to the diagnosis period (period 1 or 2, before or after introduction of PI in France on 1 April 1996). Cox's model was used to calculate the relative hazards of death according to the antiretroviral regimen. RESULTS: The study included 246 patients, 109 diagnosed during period 1 and 137 during period 2. In all, 131 patients received an antiretroviral combination that included PI. By 31 December 1997, a total of 131 deaths had been reported. The probability of survival at 6 months for patients from period 2 was nearly twice as high as for patients from period 1 (60.5 versus 34.5%). In comparison with patients receiving no treatment, the risk of death in patients on combination therapy not including PI was reduced by 38% [relative hazard (RH) 0.62, 95% confidence interval (CI) (0.41; 0.95), P = 0.026] and in patients on combination therapy with PI, by 63% [RH 0.37, 95% CI (0.22; 0.64), P = 0.0004]. CONCLUSION: This study of a large cohort of patients diagnosed with PML (n = 246), provides evidence that a combination antiretroviral regimen, especially one including PI, confers marked survival benefits.

Prolonged survival without neurological improvement in patients with AIDS-related progressive multifocal leukoencephalopathy on potent combined antiretroviral therapy.

To evaluate the benefit of combined antiretroviral therapy including protease inhibitors (CART) on survival time and neurological progression in patients with AIDS-related progressive multifocal leukoencephalopathy (PML), 81 consecutive PML cases, collected between January 1990 and June 1998, were reviewed. Fifteen patients were neuropathologically proven. JC virus detection in CSF was positive in 59 patients. At PML diagnosis, median CD4 cell count was low (median, 35 cells/microL) and plasma HIV load, determined in 41 patients, was high (median, 4.8 log10 copies/ml). Following PML diagnosis, there was a significant difference (P<10(-4)) in survival between patients who were untreated or treated with nucleoside analogs (n=50, median: 80 days) and patients who were started early on CART (n=23, median: 246 days). A third group of eight patients who received CART late during the course of PML was considered separately. At the study endpoint, 18 of all the CART-treated patients (n=31) were still alive. Plasma HIV load was undetectable in 67% of them. The median increase in CD4 cell count was 112 cells/microL from CART onset. In contrast, no significant improvement in neurological status was observed. Our results demonstrate a benefit of CART on survival of AIDS-related PML patients and suggest the need for an early, specific anti-JC virus treatment to limit the neurological deterioration.

Prognostic value of JC virus load in cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy.

JC virus (JCV) load was determined by using quantitative polymerase chain reaction in cerebrospinal fluid (CSF) of 12 patients with AIDS-associated progressive multifocal leukoencephalopathy (PML) and compared with clinical outcome. JCV loads varied widely (3-7 log10 JCV equivalents/mL of CSF) and were apparently not related to absolute CD4 cell counts or CSF and plasma human immunodeficiency virus type 1 loads. A significant correlation was observed between JCV load and survival time (Spearman's rank correlation, -0.83; P<. 01). Moreover, CSF JCV load decreased and then became undetectable in 1 PML patient receiving cidofovir treatment, and this was associated with clinical improvement. These results show that CSF JCV load may be useful as a prognostic parameter and in monitoring the effectiveness of anti-JCV therapies in PML patients.

[Spinal tuberculous arachnoiditis]. / Arachnoïdites tuberculeuses spinales.

Tuberculous arachnoiditis of the spine is a rare complication of tuberculous meningitis and can occur despite correct treatment. We report two cases of arachnoiditis in patients with tuberculous meningitis. In both cases, clinical signs included flaccid paraparesia and sphincter dystonia. Evidence for diagnosis was obtained with magnetic resonance imaging of the lombosacral spine after a 3 or 11 week course. Adding corticosteroids to the anti-tuberculosis therapy provided spectacular clinical improvement within 8 days in both cases. The diagnosis of tuberculous arachnoiditis of the spine is often made late but can be confirmed easily with magnetic resonance imaging. Our cases emphasize the importance of oral corticosteroid therapy to avoid severe sequellae.

[Lesions of the spinal cord in HIV infection]. / Atteintes de la moelle épinière au cours de l'infection par le VIH.

Neurological lesions are frequent complications of human immunodeficiency virus (HIV) infections. Organs involved include the brain, peripheral nerves and muscles. Since the widespread use of immunodepressive agents, spinal cord complications have also appeared although poorly documented in the literature. We observed six cases of spinal cord involvement which help indicate the modalities of practical management. In the first case, a 45-year old HIV1 + male presented dysesthesia evolving progressively over the T10 to L2 zones leading to the diagnosis of spinal cord toxoplasmosis. A gait disorder was the first sign in the second case, a 60-year old HIV1 + male. Neurological involvement progressed and the patient developed paraparesia, decreased muscular force with hypoesthesia and impaired proprioception of the lower limbs. Further complications led to coma and death and on autopsy, the patient was found to have cytomegalovirus myeloencephalitis. A 21 HIV1 + haemophiliac was our third case. Here paraplegia resulted from epidural compression due to Burkitt malignant lymphocytosis. The aggravation of paresthesia of the lower limbs, complicated by painful dysesthesia and proximal motor deficiency led to the suspected diagnosis of HIV-related myelitis in a particularly complicated case in a 52-year old seropositive male. In the fifth case, HIV infection led to major demelinization of the cervical and dorsal spinal cord due to toxoplasmosis and vacuolar myelopathy. In the sixth case, acute myelitis in an HIV2 positive male regressed spontaneously in 15 days. In clinical practice, spinal cord complications would appear to be frequent but less so than brain involvement. In the future, a better understanding of these complications should lead to specific identification of spinal cord signs in the neurological symptomatology of patients with HIV infection and allow adapted specific management.

[The possible endometrial risk of ovarian stimulation. Apropos of 3 cases]. / Du risque endométrial de la stimulation ovarienne. A propos de trois cas.

Three cases of adenomatous hyperplasia of the endometrium--one of them degenerated--have been reported in young women provided with ovulation stimulation. The association between these hormonal therapies and the adenocarcinoma or its antecedents signs, is particularly disturbing. However, it's difficult to establish a relationship between cause and effect. Indeed the women who suffer from an ovarian sterility are a group exposed to a cancer of the endometrium independently of any other iatrogenic agent. The method of detection is yet to be found, as is the mode of conduct which can reconcile the risk of a carcinoma and the desire of pregnancy.