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International audience; Objective: Restoring anti-JC virus (JCV) immunity is the only treatment of progressive multifocal leukoencephalopathy (PML). Interleukin-7 is a cytokine that increases number and function of T cells. We analyzed a population of PML patients who received recombinant human IL-7 (rhIL-7) to estimate survival and its determinants.Methods: After exclusion of patients with missing data or receiving other immunotherapies, findings from 64 patients with proven PML who received rhIL-7 between 2007 and 2020 were retrospectively analyzed. Logistic regression was used to analyze variables associated with one-year survival.Results: Underlying conditions were HIV/AIDS (n = 27, 42%), hematological malignancies (n = 16, 25%), primary immunodeficiencies (n = 13, 20%), solid organ transplantation (n = 4, 6%) and chronic inflammatory diseases (n = 4, 6%). One-year survival was 54.7% and did not differ by underlying condition. Survival was not associated with baseline characteristics, but with a >50% increase in blood lymphocytes (OR 4.1, 95%CI 1.2-14.9) and CD4+ T cells (OR 5.9, 95%CI 1.7-23.3), and a > 1 log copies/mL decrease in cerebrospinal fluid JCV DNA (OR 7.6, 95%CI 1.6-56.1) during the first month after rhIL-7 initiation. Side effects were mainly local and flu-like symptoms (n = 8, 12.5%) and PML-immune reconstitution inflammatory syndrome (IRIS) (n = 5, 8%).Interpretation: In this non-controlled retrospective study, survival did not differ from that expected in HIV/AIDS patients, but might have been improved in those with hematological malignancies, primary immunodeficiencies and transplant recipients. RhIL-7 might have contributed to the increase in blood lymphocytes and decrease in CSF JCV replication that were associated with better survival. ANN NEUROL 2022;91:496-505.

Middle-aged persons living with HIV (PLHIV) have a heightened risk of more concomitant age-related comorbidities that are acknowledged as signs of poorer prognosis after deep-brain stimulation of the subthalamic nucleus (STN-DBS) at younger-than-expected ages. To assess the beneficial and adverse effects of STN-DBS in PLHIV with Parkinson's disease (PD).We retrospectively included nine PLHIV with PD who had sustained virological control. Patients were followed up for 7 ± 4 years.Patients' mean ages at PD onset and STN-DBS were 45 ± 15 and 53 ± 16 years, respectively. At STN-DBS, mean HIV infection and PD durations were 15 ± 12 and 8 ± 4 years, respectively. STN-DBS significantly improved 1-year Unified Parkinson's Disease Rating Scale (UPDRS)-III scores (71%), daily off-time (63%), motor fluctuations (75%) and daily levodopa-equivalent dose (68%); mean 5-year UPDRS-III score and motor fluctuation improvements remained ~45%. Impulse control disorders (affecting 6/9 patients) fully resolved after STN-DBS. Postoperative course was uneventful. No serious adverse events occurred during follow-up.Our findings indicate that STN-DBS is a safe and effective treatment for PLHIV with PD.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system due to reactivation of the JC virus (JCV). PML is extremely uncommon despite the high prevalence of the virus in the general population. No specific treatment is available, and the prognosis is bleak. The diagnosis is based on brain imaging findings, detection of the JCV genome in cerebrospinal fluid samples and, in some cases, histological studies of the brain lesions. The pathophysiological mechanisms that drive the development of PML are incompletely understood. However, a consistent feature is the presence of a predisposing factor, most notably immunosuppression. The risk of developing PML varies with the underlying disease (e.g., HIV infection or autoimmune disease) and with the drugs used to treat them. Biologics have been ranked according to the risk of PML during their use. Natalizumab, a monoclonal antibody given to treat multiple sclerosis, is among the drugs associated with a high risk of PML. Patients given natalizumab are now closely monitored based on anti-JCV antibody titers and index values. In rheumatology, the expanding use of biologics has led to an increase in cases of PML, with rituximab being associated with the highest risk. Given the absence of specific recommendations, exhaustive registries and postmarketing observational studies are urgently needed to gauge the risk of PML according to the underlying disease and drug treatments, with the goal of defining optimal monitoring protocols.

Objective:To assess the characteristics and outcomes of patients with AIDS-related primary CNS lymphoma (AR-PCNSL) in the combined antiretroviral therapy (cART) era systematically treated with high-dose methotrexate (HD-MTX).Methods:We retrospectively analyzed (intention-to-treat analysis) 51 consecutive patients with AR-PCNSL (median age 39 years) who were diagnosed from 1996 to 2014 and treated with a median of 6 (range 1–15) infusions of HD-MTX (3 g/m2) combined with cART.Results:Median all-patients' and survivors' follow-up lasted 23 (range 0–186) and 76 (range 23–186) months, respectively. At PCNSL diagnosis, 83% of the patients were on cART, median plasma HIV load was 175,600 copies/mL, and median CD4+ T-cell count was 24/μL. Median Eastern Cooperative Oncology Group performance status was 2 (range 1–4). Median overall survival (OS) was 5.7 years, with 5- and 10-year rates of 48% and 41%. Median time to progression was not reached (69% at 10 months). PCNSL was the direct cause of 14 deaths, all observed within the 10 months after its diagnosis: 6 patients died before HD-MTX could be administered, 4 had refractory disease, and 4 relapsed. Multivariate analyses retained time interval between AIDS diagnosis and PCNSL diagnosis, age at AR-PCNSL diagnosis, and deep brain structure involvement as independent OS-predictive factors. To restore effective immune function, cART tailored to HIV genotypes was started and combined with HD-MTX; no interactions and no immune reconstitution inflammatory syndrome occurred. No patient died of acute treatment-related toxicity, and 21 of 51 (41%) patients experienced grade 3/4 toxicity.Conclusions:Combined short-term HD-MTX monochemotherapy and optimal cART simply and effectively treat AR-PCNSL, achieving long-term survival with few relapses.Classification of evidence:This study provides Class IV evidence that short-term HD-MTX monochemotherapy improves long-term survival of patients with AIDS with primary CNS lymphoma receiving cARTs.

Although human polyomavirus JC (JCV) seroprevalence in the general population is high, its neurological complications are rare and progressive multifocal leukoencephalopathy (PML), a lethal central nervous system (CNS) demyelinating disease, is the most well-known. After an usually asymptomatic primary infection during late childhood, a latent JCV form persists in different sites, notably the kidneys and lymphocytes. Rearrangement of that archetype into the prototypical neurotropic strain can reactivate JCV, thereby enabling its CNS penetration and infection of glial cells. In a context of defective immune defenses (HIV infection, cancer or immunosuppressant therapies) this infection leads to oligodendrocyte death that contributes, via demyelinization, to PML but also, as more recently described, to other CNS complications, e.g., JCV granule cell neuronopathy, meningitis or encephalitis. Clinical manifestations depend on the localization of the lesions. The increasingly widespread use of new immunomodulatory monoclonal antibodies to treat multiple sclerosis and other inflammatory systemic diseases has increased PML frequency in those previously rarely affected entities. Diagnosis relies on magnetic resonance imaging, JCV detection in cerebrospinal fluid and, when necessary, brain histology. PML is often lethal. No specific, evidence-based treatment with clinically relevant efficacy is available. The therapeutic objective is to restore host immune responses to JCV, while avoiding immune-reconstitution inflammatory syndrome.

Background and purpose Multinodular and vacuolating neuronal tumor (MVNT) of the cerebrum is a rare brain lesion with suggestive imaging features. The aim of our study was to report the largest series of MVNTs so far and to evaluate the utility of advanced multiparametric magnetic resonance (MR) techniques. Methods This multicenter retrospective study was approved by our institutional research ethics board. From July 2014 to May 2019, two radiologists read in consensus the MR examinations of patients presenting with a lesion suggestive of an MVNT. They analyzed the lesions' MR characteristics on structural images and advanced multiparametric MR imaging. Results A total of 64 patients (29 women and 35 men, mean age 44.2 ± 15.1 years) from 25 centers were included. Lesions were all hyperintense on fluid-attenuated inversion recovery and T2-weighted imaging without post-contrast enhancement. The median relative apparent diffusion coefficient on diffusion-weighted imaging was 1.13 [interquartile range (IQR), 0.2]. Perfusion-weighted imaging showed no increase in perfusion, with a relative cerebral blood volume of 1.02 (IQR, 0.05) and a relative cerebral blood flow of 1.01 (IQR, 0.08). MR spectroscopy showed no abnormal peaks. Median follow-up was 2 (IQR, 1.2) years, without any changes in size. Conclusions A comprehensive characterization protocol including advanced multiparametric magnetic resonance imaging sequences showed no imaging patterns suggestive of malignancy in MVNTs. It might be useful to better characterize MVNTs.

Multinodular and vacuolating neuronal tumor of the cerebrum is a rare supratentorial brain tumor described for the first time in 2013. Here, we report 11 cases of infratentorial lesions showing similar striking imaging features consisting of a cluster of low T1-weighted imaging and high T2-FLAIR signal intensity nodules, which we referred to as multinodular and vacuolating posterior fossa lesions of unknown significance. No relationship was found between the location of the lesion and clinical symptoms. A T2-FLAIR hypointense central dot sign was present in images of 9/11 (82%) patients. Cortical involvement was present in 2/11 (18%) of patients. Only 1 nodule of 1 multinodular and vacuolating posterior fossa lesion of unknown significance showed enhancement on postcontrast T1WI. DWI, SWI, MRS, and PWI showed no malignant pattern. Lesions did not change in size or signal during a median follow-up of 3 years, suggesting that multinodular and vacuolating posterior fossa lesions of unknown significance are benign malformative lesions that do not require surgical intervention or removal.

The benefits provided by disease-modifying treatments in multiple sclerosis have been demonstrated in clinical trials, but the extent to which they can be extrapolated to everyday care is less clear, as are the long-term benefits of treatment. The objective of this prospective observational cohort study performed in France was to evaluate the effectiveness and safety of glatiramer acetate in patients with relapsing–remitting multiple sclerosis over a 5-year period. All neurologists in France were invited to participate and enroll adult patients starting a first treatment with brand glatiramer acetate 20 mg. Given the observational nature of the study, no fixed study visits were imposed; consultations took place according to the investigator’s normal practice. Occurrence of disease exacerbations and adverse events was documented and neurological disability evaluated with the EDSS at each consultation. Overall, 852 patients were analysable and 269 took glatiramer acetate continuously for 5 years. Median treatment duration was 3.4 years. Principal reasons for discontinuation were inadequate efficacy (38.9%), local tolerability (22.6%) and personal convenience (21.3%). Age, employment status, baseline EDSS score and number of previous exacerbations were variables associated with treatment persistence. The annualised exacerbation rate (5 years) was 0.41 [95% CI 0.39–0.44]; 316 patients (37.2%) remained exacerbation-free throughout. The risk of confirmed disability worsening (5 years) was 43.8% [95% CI 39.9–47.9%]. The most frequent adverse drug reactions were local injection site reactions (584 patients; 68.5%) and systemic immediate post-injection reactions (168 patients; 19.7%). Overall, these findings are consistent with those of previous clinical trials. Electronic supplementary material The online version of this article (10.1007/s00415-019-09211-5) contains supplementary material, which is available to authorized users.

International audience; Importance: Molecular diagnosis is difficult to achieve in disease groups with a highly heterogeneous genetic background, such as cerebellar ataxia (CA). In many patients, candidate gene sequencing or focused resequencing arrays do not allow investigators to reach a genetic conclusion. Objectives: To assess the efficacy of exome-targeted capture sequencing to detect mutations in genes broadly linked to CA in a large cohort of undiagnosed patients and to investigate their prevalence. Design, Setting, and Participants: Three hundred nineteen index patients with CA and without a history of dominant transmission were included in the this cohort study by the Spastic Paraplegia and Ataxia Network. Centralized storage was in the DNA and cell bank of the Brain and Spine Institute, Salpetriere Hospital, Paris, France. Patients were classified into 6 clinical groups, with the largest being those with spastic ataxia (ie, CA with pyramidal signs [n = 100]). Sequencing was performed from January 1, 2014, through December 31, 2016. Detected variants were classified as very probably or definitely causative, possibly causative, or of unknown significance based on genetic evidence and genotype-phenotype considerations. Main Outcomes and Measures: Identification of variants in genes broadly linked to CA, classified in pathogenicity groups. Results: The 319 included patients had equal sex distribution (160 female [50.2%] and 159 male patients [49.8%]; mean [SD] age at onset, 27.9 [18.6] years). The age at onset was younger than 25 years for 131 of 298 patients (44.0%) with complete clinical information. Consanguinity was present in 101 of 298 (33.9%). Very probable or definite diagnoses were achieved for 72 patients (22.6%), with an additional 19 (6.0%) harboring possibly pathogenic variants. The most frequently mutated genes were SPG7 (n = 14), SACS (n = 8), SETX (n = 7), SYNE1 (n = 6), and CACNA1A (n = 6). The highest diagnostic rate was obtained for patients with an autosomal recessive CA with oculomotor apraxia-like phenotype (6 of 17 [35.3%]) or spastic ataxia (35 of 100 [35.0%]) and patients with onset before 25 years of age (41 of 131 [31.3%]). Peculiar phenotypes were reported for patients carrying KCND3 or ERCC5 variants. Conclusions and Relevance: Exome capture followed by targeted analysis allows the molecular diagnosis in patients with highly heterogeneous mendelian disorders, such as CA, without prior assumption of the inheritance mode or causative gene. Being commonly available without specific design need, this procedure allows testing of a broader range of genes, consequently describing less classic phenotype-genotype correlations, and post hoc reanalysis of data as new genes are implicated in the disease.

Background Silent cerebral small-vessel disease (CSVD) is defined as white matter hyperintensities, silent brain infarction, or microbleeds. CSVD is responsible for future vascular events, cognitive impairment, frailty, and shorter survival. CSVD prevalence among middle-aged people living with well-controlled human immunodeficiency virus (HIV) infection (PLHIV) is unknown. Methods The French National Agency for Research on AIDS and Viral Hepatitis (ANRS) EP51 Microvascular Brain Retina and Kidney Study (MicroBREAK; NCT02082574) is a cross-sectional study with prospective enrollment of treated PLHIV, ≥50 years old with viral load controlled for ≥12 months, and frequency age- and sex-matched HIV-uninfected controls (HUCs). It was designed to estimate CSVD prevalence on 3T magnetic resonance imaging (3D fluid-attenuated inversion recovery, transversal T2-weighted gradient-echo imaging and diffusion-weighted imaging), as diagnosed by 2 blinded neuroradiologists. A logistic regression model was used to assess the impact of HIV on CSVD after adjustment for traditional risk factors. Results Between June 2013 and May 2016, 456 PLHIV and 154 HUCs were recruited. Median age was 56 and 58 years, respectively (P = .001), among whom 84.9% and 77.3%, respectively (P = .030), were men. CSVD was detected in 51.5% of PLHIV and 36.4% of HUCs with an adjusted odds ratio (aOR) of 2.3. The HIV impact differed according to age, with aOR values of 5.3, 3.7, and 1.0 for age groups 60 years, respectively (P = .022). Older age, hypertension, and lower CD4 cell count nadir were independently associated with a higher risk of CSVD among PLHIV. Conclusions HIV is an independent risk factor for CSVD. Despite sustained immunovirological control, the CSVD prevalence was twice as high among middle-aged PLHIV than HUCs. Clinical Trials Registration NCT02082574.

International audience; Background: Cerebral small-vessel disease (CSVD) is a chronic disease accounting for one-third of strokes and the second etiology of dementia. Despite sustained immunovirological control, CSVD prevalence is doubled in middle-aged persons living with HIV (PLHIVs), even after adjustment for traditional cardiovascular risk factors. We aimed to investigate whether exposure to any antiretroviral drug class could be associated with an increasing risk of CSVD.Methods: The MicroBREAK-2 case-control study (NCT02210130) enrolled PLHIVs aged 50 years and older, treated with combined antiretroviral therapy for ≥5 years, with plasma HIV load controlled for ≥12 months. Cases were PLHIVs with radiologically defined CSVD, and controls were CSVD-free PLHIVs matched for age (±5 years), sex, and year of HIV diagnosis (±5 years). Multivariable conditional logistic regression analyses focused on cumulative exposure to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and/or exposure to integrase inhibitors (yes or no), adjusted for hypertension, CD4 nadir, current CD4/CD8 ratio, and HIV transmission group.Results: Between May 2014 and April 2017, 77 cases and 77 controls (85.7% males) were recruited. PLHIVs' median age was 57.6 years, and median HIV diagnosis year was 1992. The increasing risk of CSVD was not associated with exposure to any ART class.Conclusion: No deleterious effect of ART class exposure on the risk of CSVD was found for middle-aged treated PLHIVs.

Progressive multifocal leukoencephalopathy. Progressive multifocal leukoencephalopathy (PML) is a lethal central nervous system (CNS) demyelinating disease caused by the human polyomavirus JC. Primary infection is asymptomatic and occurs in late childhood. JC virus persists in a latent state in different organs, notably kidney. Immunosuppression (including persons with HIV infection, receiving therapeutic immunomodulatory monoclonal antibodies to treat conditions such as multiple sclerosis, and transplant recipients) plays a key role in the viral reactivation leading to PML but also to other more recently described CNS complications. Clinical presentation depends on the localization of the lesions. Diagnosis is based on magnetic resonance imaging, the identification of JC virus in the cerebrospinal fluid, and when necessary on brain pathology. PML natural evolution is lethal. As no specific treatment with clinically relevant efficacy is available, the treatment goal is to restore host immune response to JC virus.Leucoencéphalopathie multifocale progressive. La leucoencéphalopathie multifocale progressive (LEMP) est une affection démyélinisante du système nerveux central due au polyomavirus JC. Ce virus infecte l’homme de façon asymptomatique au cours de l’enfance et persiste dans l’organisme, au moins dans le tissu rénal. À l’occasion d’un déficit de l’immunité cellulaire principalement (infection par le VIH ou traitements immunosuppresseurs comme certains anticorps monoclonaux utilisés dans la sclérose en plaques, greffe d’organe par exemple), la réactivation du virus est responsable de la LEMP mais aussi d’autres atteintes du système nerveux central plus récemment décrites. Le tableau clinique de ces différentes encéphalopathies varie selon le siège des lésions. Le diagnostic repose sur l’imagerie par résonance magnétique, la présence du génome viral dans le liquide cérébrospinal et quand elle est nécessaire sur l’analyse anatomopathologique du tissu cérébral. Son évolution naturelle est le plus souvent mortelle, et aucun traitement spécifique n’est encore disponible. En revanche, la restauration du système immunitaire peut enrayer la progression des lésions et conduire à des survies prolongées.

Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance.

Purpose To use and test a new method of inducing endogenously generated pupillary oscillations (POs) in patients with unilateral optic neuritis (ON), to describe a signal analysis approach quantifying pupil activity and to evaluate the extent to which POs permit to discriminate patients from control participants. Method Pupil size was recorded with an eye-tracker and converted in real time to modulate the luminance of a stimulus (a 20° disk) presented in front of participants. With this biofeedback setting, an increasing pupil size transforms into a high luminance, entraining a pupil constriction that in turn decreases the stimulus luminance, and so on, resulting in endogenously generated POs. POs were recorded for 30 seconds in the affected eye, in the fellow eye and in binocular conditions with 22 patients having a history of unilateral ON within a period of 5 years, and with 22 control participants. Different signal analysis methods were used to quantify the power and frequency of POs. Results On average, pupil size oscillated at around 1 Hz. The amplitude of POs appears not to be a reliable marker of ON. In contrast, the frequency of POs was significantly lower, and was more variable over time, in the patients’ affected eye, as compared to their fellow eye and to the binocular condition. No such differences were found in control participants. Receiver operating characteristic analyses based on the frequency and the variability of POs to classify patients and control participants gave an area under the curve of 0.82, a sensitivity of 82% (95%CI: 60%-95%) and a specificity of 77% (95%CI: 55%-92%). Conclusions The new method used to induce POs allowed characterizing the visual afferent pathway defect in ON patients with encouraging accuracy. The method was fast, easy to use, only requiring that participants look ahead, and allows testing many stimulus parameters (e.g. color, stimulus location, size, etc).

International audience; This work aims at describing the diversity of osteomyelitis of the jaw (OJ) and at assessing the relevance of a new method designed to avoid salivary contamination during bone sampling in order to improve microbiological analysis and clinical decision-making. We reviewed medical and microbiological data of patients with a suspected OJ based on clinical and/or CT-scan signs and at least one bone sample made for microbiological analysis. During the study period, a new procedure for intraoral bone sampling was elaborated by surgeons and infectious diseases specialists authoring this article (based on stratified samples, cleaning of the surgical site and change of instruments between each sample). A comparison of the microbiological analyses between the two procedures was performed. From 2012 to 2017, 56 patients were included. Median age was 58 years (11-90), sex ratio: 1.24. Main risk factors were having a dental disease (n = 24) or cancer (n = 21). Nineteen patients with the new sample procedure were compared to 37 patients with standard procedure, especially non-cancer patients (n = 16 and 19, respectively). With the new procedure, a median of 3 (1-7) microorganisms per sample was recovered, vs. 7 (1-14) with the former (p

Progressive multifocal leucoencephalopathy (PML), a devastating demyelinating disease caused by John Cunningham virus (JCV) reactivation, affects patients with severe immune deficiencies.1 Despite having tested numerous molecules over the last 25 years, their benefits have often been overstated based on isolated case reports or small series.1 Because those therapies offered patients with PML some, although limited, hope, the desire to try an inaccurately tested but potentially lifesaving treatment surpasses rigorous clinical trial evaluation before widespread use. Notably, cidofovir’s alleged promise, based on case reports, largely evaporated when prospective cohort studies demonstrated that it had no influence on AIDS-related PML (AR-PML) overall survival (OS) or residual disability.2 That story might be repeating itself with maraviroc (MVC) use, also based on only a few favourable case reports.3 Restoring JCV-specific immune responses is the most effective way to improve survival of patients with PML.1 Immune recovery is not always beneficial and a subset of patients with PML may worsen due to immune reconstitution inflammatory syndrome (PML-IRIS), mediated by CD8+ T cells strongly expressing CC chemokine receptor-5 (CCR5). MVC is a non-competitive CCR5 antagonist approved in the HIV armamentarium. Histological findings and some case reports inferred that MVC might work as a mediating double-edged sword by enhancing CD4+ T-cell reconstitution and its potential immunomodulatory properties to improve AR-PML and AR-PML-IRIS survival in various conditions (idiopathic CD4+ T-cell lymphocytopaenia, sarcoidosis and natalizumab-treated patients with multiple sclerosis).4 But, MVC had no beneficial effect on OS of patients with PML in one-third of reports (online supplementary …

Purpose To compare peripapillary retinal nerve-fiber-layer (pRNFL) thickness, total retina macular volume, and ganglion-cell-layer (GCL) macular volume and thickness between persons living with HIV (PLHIVs) with well-controlled infections and good immune recovery, and sex- and age-matched HIV-uninfected controls (HUCs). Methods This prospective cross-sectional study (www.clinicaltrials.gov identifier: NCT02003989) included 56 PLHIVs, infected for ≥10 [median 20.2] years and with sustained plasma HIV-load suppression on combined antiretroviral therapy (cART) for ≥5 years, and 56 matched HUCs. Participants underwent spectral-domain optical coherence tomography (SD-OCT) with thorough ophthalmological examinations and brain magnetic resonance imaging (MRI). Their overall and quadrant pRNFL thicknesses, total macular volumes, and GCL macular volumes and thicknesses were compared. Cerebral small-vessel diseases (CSVD) complied with STRIVE criteria. Results Median [interquartile range, IQR] ages of PLHIVs and HUCs, respectively, were 52 [46-60] and 52 [44-60] years. Median [IQR] PLHIVs' nadir CD4+ T-cell count and current CD4/CD8 T-cell ratio were 249/μL [158-350] and 0.95 [0.67-1.10], respectively; HIV-seropositivity duration was 20.2 [15.9-24.5] years; cART duration was 16.8 [12.6-18.6] years; and aviremia duration was 11.4 [7.8-13.6] years. No significant between-group pRNFL thickness, total macular volume, macular GCL-volume and -thickness differences were found. MRI-detected CSVD in 21 (38%) PLHIVs and 14 (25%) HUCs was associated with overall thinner pRNFLs, and smaller total retina and GCL macular volumes, independently of HIV status. Conclusions SD-OCT could not detect pRNFL thinning or macular GCL-volume reduction in well-sustained, aviremic, cART-treated PLHIVs who achieved good immune recovery. However, CSVD was associated with thinner pRNFLs and GCLs, independently of HIV status.

Background Despite its overall efficacy, combined antiretroviral therapy (cART) has failed to control human immunodeficiency virus (HIV) infection of the central nervous system (CNS). New acute and chronic neurological complications continue to be reported. Methods We conducted a retrospective study of 14 HIV-infected patients with documented encephalitis, which was initially attributed to an undetermined origin. Brain magnetic resonance imaging (MRI) uniformly revealed unusual, multiple linear gadolinium-enhanced perivascular lesions. Results All patients had manifested acute or subacute neurological symptoms; the brain MRIs indicating diffuse brain damage. The mean duration of HIV infection was approximately 10 years, and 8 patients were immunovirologically stable. Cerebrospinal fluid abnormalities with mildly elevated protein and pleocytosis with >90% lymphocytes, predominantly CD8, were found in all but 1 patient. The mean cerebral spinal fluid HIV load was 5949 copies/mL. Six patients reported a minor infection a few days prior to neurological symptoms, 2 patients presented criteria for the immune reconstitution inflammatory syndrome of the CNS, 2 were in virological escape, and 1 developed encephalitis after interruption of cART. Brain biopsies revealed inflammatory encephalitis associated with astrocytic and microglial activation as well as massive perivascular infiltration by polyclonal CD8(+) lymphocytes. All patients had been treated with glucocorticosteroids. The long-term therapeutic response varied from excellent, with no sequalae (n = 5), to moderate, with cognitive disorders (n = 4). The mean survival time was 8 years; however, 5 patients died within 13 months of initiation of treatment. Conclusions CD8 encephalitis in HIV-infected patients receiving cART is a clinical entity that should be added to the list of HIV complications.

Objective To characterise recurrence of multiple sclerosis (MS) inflammatory activity during the year following natalizumab (NTZ) cessation. Methods Thirty-two patients with MS were included in a monocentric cohort study. Data were collected prospectively during and after NTZ, with serial clinical and MRI evaluations. The first relapse occurring after interrupting NTZ was the primary outcome measure. The numbers of gadolinium-enhancing lesions before, during and after NTZ treatment, were compared. Results During the year following NTZ cessation, the cumulative probability of relapses was estimated at 52.9% and an unusually high MRI inflammation was noticed. It was defined by a number of gadolinium-enhancing lesions >5 and exceeding the gadolinium lesions existing before NTZ initiation. Rebound of MS activity after NTZ cessation was characterised by association of relapses and unusual MRI inflammation. Cumulative probability of rebound was estimated at 39% and mostly occurring between 3 months and 9 months after interrupting NTZ. Risk of rebound appears related with a higher annualised relapse rate and a lower Expanded Disability Status Scale score before NTZ initiation. Rebound was associated with severe recurring relapses in 9% of the patients. Conclusions This study identifies rebound after NTZ cessation as an association of relapses and high MRI activity.

Background and Objective: This study aimed to assess the value of cerebrospinal fluid (CSF) findings for predicting conversion to clinically definite multiple sclerosis (CDMS). Methods: From a database of 447 patients with a first demyelinating event, the records of 208 patients less than 51 years old who had baseline magnetic resonance imaging (MRI) and CSF examinations and a follow-up of at least 1 year were included. A multivariable Cox model was used to assess the short-term risk of CDMS according to baseline CSF findings after adjustment for prognostic factors (including brain MRI) and to provide a simple classification for predicting CDMS. Results: During a median follow-up of 3.5 years, 141 (67.8%) patients converted to CDMS. In multivariate analysis, younger age (hazard ratio [HR]: 1.44 [95% CI 1.02–2.01]), spatial dissemination on brain MRI (HR: 2.07 [95% CI 1.47–2.91]) and more than 4 WBC/mm3 in CSF (HR: 1.44 [95% CI 1.03–2.02]) were independently associated with CDMS. The Cox score obtained from these three predictors enabled patients to be divided into three groups with significant increased risks of CDMS at 1, 2 and 3 years; groups were classified as high-risk (64.7%, 77.4%, 96.1%), intermediate-risk (33.3%, 51.5%, 61.5%), and low-risk (11.1%, 18.3%, 40.3%). Conclusions: Age at onset, spatial dissemination on brain MRI and CSF white blood cell count are independently associated with short-term conversion to CDMS. The three proposed risk group classifications could be a useful tool to select patients for early therapeutic intervention.

We report data on 11 patients with neurological symptoms and human immunodeficiency virus (HIV) cerebrospinal fluid (CSF) viremia contrasting with suppressed plasma HIV RNA during receipt of combined antiretroviral therapy.We retrospectively identified instances of central nervous system (CNS) symptoms in patients who had been receiving stable combination antiretroviral therapy. Discordance between plasma and CSF HIV RNA levels was defined by any detectable CSF HIV RNA level200 copies/mL while plasma levels were50 copies/mL or by a CSF HIV RNA level that was 1 log greater than the plasma HIV RNA level.Eleven patients had experienced acute or subacute neurological symptoms. All but one patient had CSF pleocytosis and/or elevated protein levels. The median CSF HIV RNA level was 880 copies/mL (range, 558-12,885 copies/mL). Patients had been receiving stable combination antiretroviral therapy for a median of 13 months (range, 10-32 months). Eight of 11 patients had a plasma HIV RNA level50 copies/mL, and 3 had plasma HIV RNA blips with their CSF HIV RNA level1 log higher than their plasma HIV RNA level. Resistance-associated mutations were detected in 7 of 8 CSF HIV RNA genotypic strains. The median number of resistance-associated mutations was 6 (range, 2-8) to nucleoside reverse-transcriptase inhibitors and 3 (range, 1-9) to protease inhibitors. One patient had a virus harboring nonnucleoside reverse-transcriptase inhibitor mutations. The median central nervous system penetration-effectiveness (CPE) rank was 2 (range, 1-3), and 5 patients had a CPE 1.5. After antiretroviral therapy optimization based on genotypes and CPE, all patients clinically improved, with normalization of CSF.Despite successful suppression of plasma viremia with antiretroviral therapy, HIV may replicate in CSF, with development of CSF HIV resistance resulting in acute or subacute neurological manifestations.

International audience; INTRODUCTION:Cerebral punctate and curvilinear gadolinium enhancements (PCGE) correspond to opacification of small vessel lumen or its perivascular areas in case of blood-brain barrier (BBB) disruption. We will discuss the possible causes of intra-parenchymal central nervous system PCGE.METHODS:Our review is based on French database including patients presenting with central nervous system PCGE and literature search using PubMed database with the following keywords: punctate enhancement, linear enhancement, and curvilinear enhancement. Disorders which displayed linear leptomeningeal or periventricular enhancements without intra-parenchymal PCGE are excluded of this review.RESULTS:Among our 39 patients with PCGE, 16 different diagnoses were established. After combining our PCGE causes with those described in the literature, we propose a practical approach. Besides physiologic post-contrast enhancement of small vessels, three pathologic conditions may exhibit PCGE: (1) small collateral artery network seen in Moyamoya syndrome, (2) small veins congestions related to developmental or acquired venous outflow disturbance, and (3) disorders causing small vessels BBB disruption indicated by T2 and FLAIR hyperintensities in the corresponding areas of PCGE. Disruption of the BBB could be caused by a direct injury of the endothelial cell, as in posterior reversible encephalopathy syndrome, Susac syndrome, and radiochemotherapy-induced injuries, or by an angiocentric cellular infiltrate, as in inflammatory disorders, demyelinating diseases, host immune responses fighting against infections, prelymphoma states, lymphoma, and in CLIPPERS.CONCLUSION:PCGE may conceal several causes, including physiological and pathological conditions. Nevertheless, a practical approach could improve its management and limit the indications of brain biopsy to very specific situations

OBJECTIVE To describe the clinical features, treatment(s), and outcomes of 15 HIV-infected patients with idiopathic Parkinson disease (PD) and sustained virus suppression and immunologic reconstitution, from a reference cohort of 9847 persons living with HIV (PLH). METHODS This retrospective, single-center matched case-control 1:2 study included PLH-PD patients evaluated over a 12-year period (2002-2013) with mean follow-up of 6.5 years. PD clinical features and dopamine replacement therapy (DRT) were compared, and biologically relevant HIV data were assessed. RESULTS PD prevalence in PLH was similar to that of the general population. At onset, clinical presentations and therapeutic management were similar for both groups. Rapidly effective DRT was well tolerated without combined antiretroviral therapy interactions or virus escape. At the end of the follow-up, compared with HIV-negative PD, PLH had a significantly lower median Unified Parkinson's Disease Rating Scale motor score (4 vs 14; P < 0.001), median Hoehn and Yahr stage (1 vs 2; P = 0.0005), and median Handipark scale score (2 vs 3; P = 0.0036) under the same daily DRT. One PLH underwent highly successful deep brain stimulation of the subthalamic nucleus. CONCLUSIONS HIV-associated PD is similar to idiopathic PD with some features suggesting an HIV-induced functional adaptation of dopaminergic neurons that might counterbalance the PD-induced neuronal loss. Concurrent HIV infection does not compromise the outcome of idiopathic PD.

Highly active antiretroviral therapy (HAART)-induced immune restoration has been very beneficial for acquired immunodeficiency syndrome (AIDS) patients. In rare instances, HAART may induce a paradoxical clinical deterioration due to an immune reconstitution inflammatory syndrome (IRIS). This syndrome has been described with a wide variety of systemic infections and, in the central nervous system, with Cryptococcus neoformans infection, cytomegalovirus retinitis, and progressive multifocal leukoencephalopathy (PML). The authors have examined brain tissue in eight cases of IRIS: two autopsy cases and three biopsy cases of HIV encephalitis with IRIS and one autopsy case and two biopsy cases of PML with IRIS. All the patients presented with clinical deterioration following initiation of HAART and imaging showed contrast enhancement of the lesions. The symptoms regressed in four patients whereas the other four patients died. Neuropathological examination revealed severe inflammatory and demyelinating lesions with marked intraparenchymal and perivascular infiltration by macrophages and T lymphocytes. In some cases abundant viral proliferation was identified by immunocytochemistry or in situ hybridization, but in others the infectious agent could only be detected using PCR. T lymphocytes were predominantly CD8(+). In those cases with the more favorable course, inflammation was less severe with marked macrophage activation and a number of CD4(+) lymphocytes; in contrast, in the lethal cases inflammation was severe and mostly composed of CD8(+) cytotoxic lymphocytes. We conclude that HAART-induced paradoxical aggravation of HIV encephalitis or AIDS-related PML due to IRIS is reversible in most cases but may be lethal in others. In fatal cases, fulminant viral infection and/or acute perivenous leukoencephalitis may result from a dysregulation of the CD8(+)/CD4(+) T-cell balance.

International audience; BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disorder, which in over 90% of cases is due to one of three primary mitochondrial DNA (mtDNA) point mutations (m.11778G>A, m.3460G>A and m.14484T>C, respectively in MT-ND4, MT-ND1 and MT-ND6 genes). However, the spectrum of mtDNA mutations causing the remaining 10% of cases is only partially and often poorly defined. METHODOLOGY/PRINCIPAL FINDINGS: In order to improve such a list of pathological variants, we completely sequenced the mitochondrial genomes of suspected LHON patients from Italy, France and Germany, lacking the three primary common mutations. Phylogenetic and conservation analyses were performed. Sixteen mitochondrial genomes were found to harbor at least one of the following nine rare LHON pathogenic mutations in genes MT-ND1 (m.3700G>A/p.A132T, m.3733G>A-C/p.E143K-Q, m.4171C>A/p.L289M), MT-ND4L (m.10663T>C/p.V65A) and MT-ND6 (m.14459G>A/p.A72V, m.14495A>G/p.M64I, m.14482C>A/p.L60S, and m.14568C>T/p.G36S). Phylogenetic analyses revealed that these substitutions were due to independent events on different haplogroups, whereas interspecies comparisons showed that they affected conserved amino acid residues or domains in the ND subunit genes of complex I. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that these nine substitutions are all primary LHON mutations. Therefore, despite their relative low frequency, they should be routinely tested for in all LHON patients lacking the three common mutations. Moreover, our sequence analysis confirms the major role of haplogroups J1c and J2b (over 35% in our probands versus 6% in the general population of Western Europe) and other putative synergistic mtDNA variants in LHON expression.

Combined antiretroviral therapy (cART) has led to considerable improvement in the spectrum of disorders affecting the central nervous system (CNS). The majority of focal brain presentations are due to toxoplasmosis, non-Hodgkin's lymphoma, and progressive multifocal leukoencephalopathy. Other causes are much rarer (Moulignier et al. 1994, 1996; Saravanan and Turnbull 2009). A growing number of severe, acute inflammatory leukoencephalopathies, whose causes remain to be identified, have been recently reported (Tavazzi et al. 2010). These include highly destructive forms of HIVassociated leukoencephalopathy (Langford et al. 2002), “burnt out” forms of HIV encephalitis (Scaravilli et al. 2007), immune reconstitution inflammatory syndrome (IRIS) (Venkataramana et al. 2006), brain tumefactive demyelination (Saravanan and Turnbull 2009; Solomon et al. 2013), and discordant HIV diseases (Canestri et al. 2010). A series of cases of diffuse encephalitis with marked perivascular infiltration by CD8 T lymphocytes with corticosteroid-responsive brain inflammation have been described as CD8 encephalitis (Lescure et al. 2013; Gray et al. 2013). Brain MRI shows characteristic perivascular punctuate or linear gadolinium-enhanced lesions, better seen in T1 spin echo with magnetic transfer, that are poorly delineated in T2weighted images (Lescure et al. 2013). We describe the first biopsy-proven focal CD8 encephalitis (CD8-E) mimicking a brain tumor in a HIV+ patient.

We report the neuropathological findings in 10 HIV‐infected patients treated by combination antiretroviral therapy who developed subacute encephalopathy of rapidly progressive onset. Brain biopsy showed encephalitic lesions variably associated with myelin loss and slight axonal damage. There was inconstant, weak expression of HIV protein p24; tests for other pathogens were negative. The most striking feature was diffuse, perivascular and intraparenchymal infiltration by CD8+ T‐lymphocytes. Six patients improved after the treatment. Four had an unfavorable outcome and died within a year. Post‐mortem in one case confirmed HIV leukoencephalitis with p24‐positive multinucleated giant cells, associated with acute demyelinating encephalomyelitis (ADEM) in the cerebellum. There was diffuse infiltration by CD8+ lymphocytes; CD4+ cells were virtually absent. These cases may represent a specific clinicopathological entity, of which a few comparable cases have been already described. They can be included in the wide framework of immune reconstitution disease. Such syndromes have been described with opportunistic infections, but only seldom with HIV infection of the central nervous system (CNS). Our findings support the hypothesis that CD8+ cytotoxic lymphocytes can be harmful in immune reconstitution disease, particularly in the absence of CD4+ lymphocytes. CD8 cytotoxicity produces an acutization of a smoldering infection and/or an immunopathological reaction similar to ADEM.

Idiopathic intracranial hypertension (IH) occurs most commonly in women and overweight subjects. It must be reported associated to general diseases, like systemic lupus erythematosus (SLE).We report an observation of a patient with lupus complicated by glomerulonephritis and IH.A 29 years old woman, without overweight, was followed for a SLE with skin and arthritic involvement . Four years after onset, a renal complication appeared with severe nephrotic syndrome. Six weeks after, bilateral papillar oedema was discovered, revealing an IH, as the patient was treated by oral steroids at 1mg/kg/d and bimonthly intravenous cyclophosphamide. The patient was completely asymptomatic. Brain MRI with veino-RMN was normal, without cerebral venous thrombosis. Lumbar punction showed an elevated opening pressure of 30,5 cmH(2)0 but with normal cerebrospinal fluid (CSF) contents. Evacuation of 30 mL of CSF and immunosuppressive treatment allowed symptoms regression.Twenty-seven cases of IH associated to SLE with nephritis have been reported in literature. Young women are more frequently involved with in half of cases a diffuse proliferative glomerulonephritis. Predisposing factors, like anaemia, must be associated. IH allows SLE diagnose in more than the third of the cases. Then, SLE has to be searched as an etiology of IH, in particular in non-obese patients and when nephritis is associated.

The SENTINEL study showed that the addition of natalizumab improved outcomes for patients with relapsing multiple sclerosis (MS) who had experienced disease activity while receiving interferon beta-1a (IFNbeta-1a) alone. Previously unreported secondary and tertiary magnetic resonance imaging (MRI) measures are presented here. Patients received natalizumab 300 mg (n=589) or placebo (n=582) intravenously every 4 weeks plus IFNbeta-1a 30 microg intramuscularly once weekly. Annual MRI scans allowed comparison of a range of MRI end points versus baseline. Over 2 years, 67% of patients receiving natalizumab plus IFNbeta-1a remained free of new or enlarging T2-lesions compared with 30% of patients receiving IFNbeta-1a alone. The mean change from baseline in T2 lesion volume over 2 years decreased in patients receiving natalizumab plus IFNbeta-1a and increased in those receiving IFNbeta-1a alone (-277.5mm(3) versus 525.6mm(3); p0.001). Compared with IFNbeta-1a alone, add-on natalizumab therapy resulted in a smaller increase in mean T1-hypointense lesion volume after 2 years (1821.3mm(3) versus 2210.5mm(3); p0.001), a smaller mean number of new T1-hypointense lesions over 2 years (2.3 versus 4.1; p0.001), and a slower rate of brain atrophy during the second year of therapy (-0.31% versus -0.40%; p=0.020). Natalizumab add-on therapy reduced gadolinium-enhancing, T1-hypointense, and T2 MRI lesion activity and slowed brain atrophy progression in patients with relapsing MS who experienced disease activity despite treatment with IFNbeta-1a alone.

Syphilis has been a public health problem for centuries. Syphilis and HIV form a dangerous combination: syphilis significantly increases the risk of contracting HIV infection, and HIV can alter the natural course of syphilis. Despite a better understanding of the interaction between these two diseases, many controversies persist. The incidence of syphilis has increased among HIV-infected patients both in Europe and in the USA, and especially in the homosexual/bisexual transmission group. We discuss the interaction between HIV/AIDS and syphilis in a review of the most recent literature, focusing particularly on the diagnosis, treatment, and follow-up of HIV-infected patients with syphilis. Early diagnosis of syphilis in HIV-infected patients requires awareness among both patients and clinicians. Early treatment of syphilis is crucial as it reduces the risk of transmission.

Susac syndrome is a rare microangiopathy, responsible for small cerebral, retinal and cochlear infarcts. The classic clinical triad includes multiple neurologic signs (from headaches to coma), retinal branch occlusions and sensorineural hearing loss.We report a series of five patients with Susac syndrome followed in our department from 1997 to 2007.There were four women and one man (mean age at onset: 35.2 years). Clinical symptoms at onset were neurological (n=1), ophthalmological (n=1), auditory (n=1) and clinical triad (n=2). Neurologic symptoms included encephalopathy (n=2), headache (n=5), transient ischemic attacks (n=1). Brain MRI showed T2 lesions in the white and grey matter, corpus callosum and gadolinium-enhanced punctiform lesions. Cerebrospinal fluid contained an elevated protein level in three cases. Immunologic treatments (steroids [n=4], cylophosphamid [n=3], intravenous immunoglobulins [n=5]) associated with aspirin and/or oral anticoagulants, despite early relapses (n=2), led to dramatic clinical improvement (n=5).Due to its polymorphism the SS is difficult to diagnose when the clinical triad is lacking. In the absence of clinical trial and consensus treatment is empiric and based on supposed pathogenesis.

The epidemiology of human immunodeficiency virus (HIV) infection has changed in recent years. New infections in persons over the age of 50 have increased and seropositive individuals are aging due to the widespread use of highly active antiretroviral therapies in Western countries. HIV-associated dementia remains one of the commonest neurological disorders associated with AIDS, but its progression has been modified by HAART and immune reconstitution. We review in details the epidemiology, pathogenesis, clinical features, diagnosis, and management of the HIV dementia and related cognitive disorders, and their relationship with aging.

Objective: To determine the incidence and clinical effects of antibodies that develop during treatment with natalizumab. Methods: In two randomized, double-blind, placebo-controlled studies (natalizumab safety and efficacy in relapsing remitting multiple sclerosis [MS, AFFIRM] and safety and efficacy of natalizumab in combination with interferon β-1a [INFβ1a] in patients with relapsing remitting MS [SENTINEL]) of patients with relapsing multiple sclerosis, blood samples were obtained at baseline and every 12 weeks to determine the presence of antibodies against natalizumab. Antibodies to natalizumab were measured using an ELISA. Patients were categorized as “transiently positive” if they had detectable antibodies (≥0.5 μg/mL) at a single time point or “persistently positive” if they had antibodies at two or more time points ≥6 weeks apart. Results: In the AFFIRM study, antibodies were detected in 57 of 625 (9%) of natalizumab-treated patients: Twenty (3%) were transiently positive and 37 (6%) were persistently positive. Persistently positive patients showed a loss of clinical efficacy as measured by disability progression ( p ≤ 0.05), relapse rate ( p = 0.009), and MRI ( p ≤ 0.05) compared with antibody-negative patients. In transiently positive patients, full efficacy was achieved after approximately 6 months of treatment, the time when patients were becoming antibody negative. The incidence of infusion-related adverse events was significantly higher in persistently positive patients. Results of SENTINEL were similar to AFFIRM, except with regard to sustained disability progression; differences between persistently positive and antibody-negative patients were not statistically significant. Conclusions: The incidence of persistent antibody positivity associated with natalizumab is 6%. Reduced clinical efficacy is apparent in persistently positive patients. Patients with a suboptimal clinical response or persistent infusion-related adverse events should be considered for antibody testing. GLOSSARY: BLQ = below the limit of quantification; EDSS = Expanded Disability Status Scale; Gd+ = gadolinium enhancing; IFNβ1a = interferon β-1a; MS = multiple sclerosis; MSFC = multiple sclerosis functional composite; OD = optical density.

Objective To report the relationship between disease activity and health-related quality of life (HRQoL) in relapsing multiple sclerosis, and the impact of natalizumab. Methods HRQoL data were available from 2,113 multiple sclerosis patients in natalizumab clinical studies. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study, patients received natalizumab 300mg (n = 627) or placebo (n = 315); in the Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) study, patients received interferon beta-1a (IFN-β-1a) plus natalizumab 300mg (n = 589), or IFN-β-1a plus placebo (n = 582). The Short Form-36 (SF-36) and a subject global assessment visual analog scale were administered at baseline and weeks 24, 52, and 104. Prespecified analyses included changes from baseline to week 104 in SF-36 and visual analog scale scores. Odds ratios for clinically meaningful improvement or worsening on the SF-36 Physical Component Summary (PCS) and Mental Component Summary were calculated. Results Mean baseline SF-36 scores were significantly less than the general US population and correlated with Expanded Disability Status Scale scores, sustained disability progression, relapse number, and increased volume of brain magnetic resonance imaging lesions. Natalizumab significantly improved SF-36 PCS and Mental Component Summary scores at week 104 in AFFIRM. PCS changes were significantly improved by week 24 and at all subsequent time points. Natalizumab-treated patients in both studies were more likely to experience clinically important improvement and less likely to experience clinically important deterioration on the SF-36 PCS. The visual analog scale also showed significantly improved HRQoL with natalizumab. Interpretation HRQoL was impaired in relapsing multiple sclerosis patients, correlated with severity of disease as measured by neurological ratings or magnetic resonance imaging, and improved significantly with natalizumab. Ann Neurol 2007

Central nervous system complications are common in HIV-1 infected patients and occur either as a result of concomitant immunosuppression (opportunistic infections, lymphoma and tumors), as a primary manifestation of HIV infection, or as an adverse effect of therapy (immune restoration and toxicity). These complications contribute largely to patient morbidity and mortality. In the era of highly active antiretroviral therapy (HAART) these disease states have changed in presentation, outcome and incidence. We review in detail the epidemiology, pathogenesis, clinical features, diagnosis, and management of these disorders.

Background Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an α 4 integrin antagonist, appeared to be safe and effective alone and when added to interferon beta-1a in preliminary studies. Methods We randomly assigned 1171 patients who, despite interferon beta-1a therapy, had had at least one relapse during the 12-month period before randomization to receive continued interferon beta-1a in combination with 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks. The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years. Results Combination therapy resulted in a 24 percent reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P = 0.02). Kaplan–Meier estimates of the cumulative probability of progression at two years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone. Combination therapy was associated with a lower annualized rate of relapse over a two-year period than was interferon beta-1a alone (0.34 vs. 0.75, P

A human immunodeficiency virus (HIV) type 2 (HIV-2)-infected African patient developed inflammatory demyelinating lesions of the optic nerves, spinal cord, and brain, which coincided with a decreasing CD4 cell count and with active HIV-2 replication. This case provides evidence that HIV-2 is neurotropic, extends the range of known HIV-2-associated neurological complications, and confirms the overlap between the neurological complications of HIV type 1 and HIV-2 infection.

A 38-year-old man living near Phnom Penh (Cambodia) was admitted to a hospital in Paris in June 2001 for a single episode of a generalized grand mal seizure. This episode was preceded by a 9-month history of headaches. Magnetic resonance imaging (MRI) of the head revealed a rounded lesion immediately ahead of the left central sulcus. The resected lesion was about 20 mm in diameter. Histologic examination revealed an elongated but unsegmented metacestode at the center of the lesion. Polymerase chain reaction (PCR) analysis was inconclusive due to formalin-based histologic processing of the tissue. Morphologic analysis based on the histologic sections revealed that the metacestode was a tetra-acetabulate plerocercoid of the order Cyclophyllidea, with a distinct rostellum and pseudosegmentation of the dorsoventrally flattened hindbody. This is the first report of a tetra-acetabulate plerocercoid from a human host and the first report of any cyclophyllidean plerocercoid from the human brain. After 6 weeks, the patient was asymptomatic, neurologic examination was normal, and the brain MRI showed only surgical cavitation. The patient returned to Cambodia.

Spontaneous episodic hypothermia (SEH), defined as periodic, centrally mediated hypothermic episodes in a patient free of systemic disease and brain lesions, has not previously been attributed to HIV infection in a recent review.1 We report the case of an HIV-1-infected man who had recurrent episodes of marked hypothermia related to active viral replication. A 47-year-old Guinean man diagnosed with HIV-1 infection in 1991 had 21 stereotyped attacks of hypothermia (mean body temperature 28.4 °C), starting in October 1998. At that time, his CD4 cell count dropped from 700 to 480/mm3 with a plasma viral load (pVL) rising at 115,000 copies/mL, attesting to an active viral replication, before any antiretroviral treatment (ART). Except for HIV infection, his personal and familial history were unremarkable. In April 1998, he had erectile dysfunction, thoracic allodynia, and no skin rash. Onset of hypothermia was usually accompanied by transient confusion. Body temperature always fell within a few hours to a nadir of between 25 and 34.9 °C. Shivering was absent, but profuse …

Interferon (IFN)-alpha is associated with central nervous system (CNS) side effects such as depression and suicide ideation, somnolence, confusion, drowsiness, psychomotor slowing, memory impairment and visual disorientation. More severe complications are uncommon and include frank paranoia, dementia, coma, seizures and neuropathy. With the increasing long-term and extensive use of interferon (IFN)-alpha several new neurologic adverse effects have been recognized. We report on two patients who developed severe subcortico-frontal impairment, associated in one case with choreic movements, after a long-term treatment with IFN-alpha 2b for hematologic malignancies. Our patients rapidly and completely recovered from their cognitive and motor symptoms after the discontinuation of the drug. The same neurologic symptoms reappeared when we attempted to reintroduce lower doses of IFN-alpha in one case. Although little is known regarding IFN-alpha actions in the CNS, several possible mechanisms may underlie its neurotoxicity and might result from complex direct and indirect effects involving brain vasculature, neuroendocrine system, neurotoxic secondary cytokines'release and neurotransmitters.

Objective: To describe the clinical features, treatment, and outcome of six cases of HIV-1-associated ALS-like disorder. Methods: The authors reviewed patients with HIV infection with neurologic symptoms seen over a 13-year period. Patients were identified by using the El Escorial research diagnostic criteria defining three categories of certainty for definite, probable, or possible ALS. Clinical features, EMG, CSF, serum analyses, and imaging and virological studies were assessed. Results: Six patients with immunodepression (mean CD4 + cells = 86.2/mm 3 ; mean age = 34 years) developed distal motor weakness mimicking a monomelic amyotrophy that subacutely progressed regionally or assumed a symmetric distribution on more than one region. EMG was characteristic of motor neuron disease with no multifocal conduction block. Causes other than HIV-1 were ruled out. The unusual rapid extension of the disease and the positive response to antiretroviral therapy suggest that ALS syndrome and HIV infection are etiologically related. HIV-1 might cause an ALS-like disorder by several mechanisms—via neuronal infection, by secretion of toxic viral substance, by inducing the immune system to secrete cytokines, or by inducing an autoimmune disease. Conclusion: These cases suggest that the association between some motor neuron diseases and HIV infection is not coincidental but pathogenetically related and that ALS-like disorder should be considered an HIV-related neurologic complication.

We report a case of Susac's syndrome characterized by subacute encephalopathy, bilateral hearing loss and multiple bilateral branch retinal artery occlusions in a forty-year-old-white-woman. Brain Magnetic Resonance Imaging showed on T2-weighted images multiple, punctate areas of increased signal intensity in periventricular white matter, gray matter and brainstem most of them being enhanced by gadolinium. Cerebrospinal fluid was acellular but with an increased protein level (1.66 g/l). Treatment with cyclophosphamid and intravenous immmunoglobulin resulted in dramatic improvement of the clinical status over the following months and CSF normalization.

Background and Purpose —We report a case of facial diplegia complicating a bilateral internal carotid artery dissection. Case Description —A 49-year-old patient presented with unilateral headache and oculosympathetic paresis. Cerebral angiography revealed a bilateral internal carotid artery dissection. A few days later, the patient developed a facial diplegia that regressed after arterial recanalization. An arterial anatomic variation may explain this ischemic complication of carotid dissection. Conclusions —Double carotid dissection should be included among the causes of bilateral seventh nerve palsy.

Objective: To determine whether CD8 lymphoid infiltrates in nerves of patients with HIV-associated diffuse infiltrative lymphocytosis syndrome (DILS) corresponds to a lymphomatous neoplastic process or to a proliferation of T cells reactional to HIV. Background: DILS is characterized by persistent CD8 hyperlymphocytosis and multivisceral CD8 T-cell infiltration, which may affect peripheral nerves. Methods: Presence of monoclonal T cells and HIV-1 proviral load were evaluated by polymerase chain reaction (PCR) techniques in frozen peripheral nerve samples from six patients with DILS neuropathy and 22 patients with other HIV-associated peripheral neuropathies, including mononeuritis multiplex(MM:6), inflammatory demyelinating polyneuropathies (IDP:6), distal sensory polyneuropathy (DSP:5), and toxic distal sensory polyneuropathy (TDSP:5). Results: Five of six patients with DILS showed no detectable monoclonal T-cell clones in their nerves. Nerve proviral load in DILS (6.8 ± 0.2 log/105 cells) was much higher than in MM (p Conclusions: DILS neuropathy represents a separate entity among HIV-associated neuropathies. It is associated with massive HIV proviral load in nerve and must not be confused with a peripheral nerve T-cell lymphoma.

CD8 T-cell neurological complications are a new HIV-driven condition caused by an unusually intense inflammatory reaction with influx of CD8 lymphocytes in the nervous system. Encephalitis and neuropathies have been described. We report the first case of spinal cord involvement. A 52-year-old African woman with HIV infection not profoundly immunosuppressed, and with a low plasmatic viral replication, without antiretroviral therapy, presented with transverse myelitis. Spinal MRI revealed inflammatory intraspinal gadolinium-enhanced lesions. Exhaustive workup was negative and brain biopsy revealed a significant inflammatory reaction with abundant CD8 T cells. Intravenous pulse methylprednisolone treatment led to rapid, disease-free recovery. CD8 T cells transverse myelitis in patients with HIV infection receiving antiretroviral therapy is a clinical entity that should be added to the list of HIV complications.

A subset of human immunodeficiency virus (HIV)-infected patients develop persistent CD8 hyperlymphocytosis and a Sjogren's syndrome-like syndrome associated with multivisceral CD8 T-cell infiltration, known as the diffuse infiltrative lymphocytosis syndrome (DILS). Patients with DILS tend to have higher CD4 cell counts, fewer opportunistic infections, and longer survival times than other HIV-infected patients. Peripheral nerve involvement in DILS has been poorly documented. We studied 12 HIV-infected patients with CD8 hyperlymphocytosis, DILS, and clinical signs of peripheral neuropathy. Two of 4 patients who were HLA typed were HLA-DR5 and 1 was HLA-DR6. All patients had the sicca syndrome and multivisceral involvement. The neuropathy was acute or subacute, always painful, and symmetrical in 8 cases. Electrophysiology was consistent with axonal neuropathy in 10 of 12 patients. Nerve biopsy showed marked angiocentric CD8 infiltrates without mural necrosis (12 of 12), and abundant expression of HIV p24 protein in macrophages (12 of 12). The HIV genome was detected by polymerase chain reaction in nerve homogenates. Zidovudine therapy was associated with improvement in 6 of 6 patients and steroid therapy was beneficial in 4 of 5 patients. No T-cell lymphoma was observed during follow-up, but 2 patients developed a primary B-cell lymphoma. We conclude that DILS neuropathy represents HIV-associated neuropathy, characterized by marked CD8 infiltration and abundant HIV in nerve, that improves with zidovudine or steroid therapy, and probably reflects a systemic host-determined and antigen-driven response to HIV.

Viral infections are observed with increasing frequency in HIV patients and one of the commonest viruses is cytomegalovirus. Clinical features of cytomegalovirus (CMV) encephalitis are non specific and radiology is rarely helpful. Polymerase chain reaction in cerebrospinal fluid has been shown to be useful for diagnosis of CMV encephalitis. CMV lesions in the nervous system are subdivided into six groups: Nodular encephalitis, myeloradiculitis, isolated inclusion-bearing cells, focal parenchymal necrosis, ventriculo-encephalitis and peripheral neuropathy. Clinicopathological aspects are only subdivided into four groups: Encephalitis, myelitis, myeloradiculitis and polyneuropathy. Diagnosis of cytomegalovirus encephalitis should be considered in patients with a CD4 count less than 100 cells/mm3. Recent developments in diagnostic techniques allow early recognition and more aggressive therapeutic approaches.

We reviewed cases of cytomegalovirus (CMV) infection of the central nervous system (CNS) that initially masqueraded as tumors in 37 of 543 consecutive patients infected with human immunodeficiency virus (HIV) and CMV who were seen at the Pasteur Institute Hospital and Saint-Louis Hospital (Paris) between 1992 and 1994. We detail the clinical features of three patients who presented with ring-enhanced space-occupying lesions mimicking CNS tumors. They were all profoundly immunodepressed (mean CD4 cell count, 13/mm3). Magnetic resonance imaging (MRI) showed enlargement of the spinal cord in one case, consistent with a space-occupying lesion and showing gadolinium enhancement; in the other two cases, ring-enhanced mass lesions were seen in the cerebral hemispheres. In all three cases marked edema and a mass effect were present. Image-guided stereotactic biopsies confirmed the diagnosis of CMV infection. The three patients' conditions improved with specific therapy. MRI showed enhanced focal intraparenchymal lesions consistent with marked focal necrosis, probably related to the severity of immunodepression, as HIV infection had been diagnosed several years previously. CMV infection should be considered as a cause of ring-enhanced space-occupying mass lesions in patients with HIV-1 infection. Earlier identification of these unusual tumorlike forms of CMV infection by means of MRI should result in improved outcome.

PURPOSE : To describe the clinical features of new-onset seizures in HIV-1-infected persons with progressive multifocal leukoencephalopathy (PML), and to discuss potential mechanisms. PATIENTS AND METHODS : Forty-nine consecutive HIV-1-infected patients with PML attended our institutions between January 1988 and September 1993. We retrospectively analyzed cases with seizures as the presenting symptom of PML. RESULTS : Twenty percent of the HIV-1-infected patients with PML presented with new-onset seizures of various types, generalized or partial. None of them met the criteria of the AIDS dementia complex or had a concomitant opportunistic infection. Their mean CD4 cell count was