Clinical, imaging, and management features of symptomatic carotid web: Insight from CAROWEB registry.

BACKGROUND: Although carotid web (CaW) is increasingly diagnosed as a cause of cryptogenic stroke, data are still limited to monocentric small sample cohort. To broaden knowledge on symptomatic CaW, CAROWEB registry has been recently implemented. AIMS: In a large cohort of symptomatic CaW patients, we described epidemiologic characteristics, admission clinical and imaging features, and the current management including the secondary preventive strategy choice made in comprehensive French Stroke Units. METHODS: CAROWEB is an ongoing French observational multicenter registry enrolling consecutive CaW patients diagnosed after an ipsilateral ischemic stroke (IS) or transient ischemic attack (TIA). Submitted cases were validated by two experienced neurologist and neuroradiologist. Clinical, imaging, and management features were collected for this study. RESULTS: Between June 2019 and December 2021, 244 cases were submitted by 14 centers, 42 rejected, and 202 included (IS, 91.6%; TIA, 7.9%; retinal infarction, 0.5%; mean age, 50.8 ± 12.2 years; female, 62.9%; Caucasian, 47.5%; Afro-Caribbean, 20.3%). IS patients showed median (interquartile range (IQR)) admission National Institutes of Health Stroke Scale (NIHSS) score, 8 (2-15); intracranial artery occlusion, 71.8%; ipsilateral chronic cerebral infarction (CCI), 16.3%; and reperfusion treatment, 57.3%. CaW was not identified during the mechanical thrombectomy procedure in 30 of 85 (35.3%) patients. Secondary prevention was invasive in 55.6% (stenting, n = 80; surgery, n = 30). In multivariable analysis, the invasive therapeutic option was associated with ipsilateral CCI (odds ratio (OR): 4.24 (1.27-14.2), p = 0.019) and inversely associated with risk factors (OR: 0.47 (0.24-0.91), p = 0.025) and admission NIHSS score (OR: 0.93 (0.89-0.97), p = 0.001). CONCLUSION: CaW must be considered in all ethnic groups including Caucasians. Secondary prevention is heterogeneous in large French Stroke Centers. The absence of risk factors, milder severity strokes, and ipsilateral CCI were predictive variables of secondary invasive treatment. The high rate of invasive treatment suggests that medical treatment alone is deemed ineffective to avoid recurrence and emphasize the need of randomized trials.

Dual-layer carotid stenting for symptomatic carotid web: Results from the Caroweb study.

BACKGROUND & PURPOSE: Carotid Web (CaW) is a growingly recognized cause of ischemic stroke, associated with a high recurrence risk. Several therapeutic strategies have been proposed as a tertiary prevention including carotid stenting, endarterectomy and antithrombotic medications. Among these, carotid stenting with dual-layer stent may be promising to adequately cover the focal arterial dysplasia. Our aim was to investigate the safety and efficacy of the Casper stent in the treatment of symptomatic CaW. METHODS: We conducted a retrospective analysis of consecutive patients presenting with a symptomatic CaW and included in the ongoing prospective observational multicenter CAROWEB registry. The study period was January 2015 to December 2021. Inclusion criteria were CaW treated with dual-layer Casper stent. Patients treated with other types of carotid stent, endarterectomy or antithrombotic medication were excluded. Clinical and radiological initial data and outcomes were recorded. RESULTS: twenty-seven patients (with 28 caw) were included. median age was 52 (iqr: 46-68). median delay between index cerebrovascular event and cervical stenting was 9 days (IQR: 6-101). In all cases, the cervical carotid stenting was successfully performed. No major perioperative complication was recorded. No recurrent stroke or transient ischemic attack was observed during a median follow-up time of 272 days (IQR: 114-635). Long-term imaging follow-up was available in 25/28 (89.3%) stented CaW with a median imaging follow-up of 183 days (IQR: 107-676; range: 90-1542). No in-stent occlusion or stenosis was detected. CONCLUSION: In this study, carotid stenting with dual-layer Casper stent in the treatment of symptomatic CaW was effective regarding stroke recurrence prevention and safe, without procedural nor delayed detected adverse event. However, the optimal therapeutic approach of symptomatic CaW still needs to be explored through randomized trials.

Case-Fatality and Functional Outcome after Subarachnoid Hemorrhage (SAH) in INternational STRoke oUtComes sTudy (INSTRUCT).

BACKGROUND: There are few large population-based studies of outcomes after subarachnoid hemorrhage (SAH) than other stroke types. METHODS: We pooled data from 13 population-based stroke incidence studies (10 studies from the INternational STRroke oUtComes sTudy (INSTRUCT) and 3 new studies; N=657). Primary outcomes were case-fatality and functional outcome (modified Rankin scale score 3-5 [poor] vs. 0-2 [good]). Harmonized patient-level factors included age, sex, health behaviours (e.g. current smoking at baseline), comorbidities (e.g.history of hypertension), baseline stroke severity (e.g. NIHSS >7) and year of stroke. We estimated predictors of case-fatality and functional outcome using Poisson regression and generalized estimating equations using log-binomial models respectively at multiple timepoints. RESULTS: Case-fatality rate was 33% at 1 month, 43% at 1 year, and 47% at 5 years. Poor functional outcome was present in 27% of survivors at 1 month and 15% at 1 year. In multivariable analysis, predictors of death at 1-month were age (per decade increase MRR 1.14 [1.07-1.22]) and SAH severity (MRR 1.87 [1.50-2.33]); at 1 year were age (MRR 1.53 [1.34-1.56]), current smoking (MRR 1.82 [1.20-2.72]) and SAH severity (MRR 3.00 [2.06-4.33]) and; at 5 years were age (MRR 1.63 [1.45-1.84]), current smoking (MRR 2.29 [1.54-3.46]) and severity of SAH (MRR 2.10 [1.44-3.05]). Predictors of poor functional outcome at 1 month were age (per decade increase RR 1.32 [1.11-1.56]) and SAH severity (RR 1.85 [1.06-3.23]), and SAH severity (RR 7.09 [3.17-15.85]) at 1 year. CONCLUSION: Although age is a non-modifiable risk factor for poor outcomes after SAH, however, severity of SAH and smoking are potential targets to improve the outcomes.

Stroke Recurrence in First-Ever Symptomatic Carotid Web: A Cohort Study.

BACKGROUND AND PURPOSE: Carotid web (CaW) is an intimal variant of fibromuscular dysplasia responsible for ipsilateral cerebral ischemic events (CIE). Symptomatic CaW likely has a high risk of recurrent CIE, but no salient prospective data are available. We aimed to assess recurrence rate and its predictors after a first-ever CIE. METHODS: Consecutive Afro-Caribbean patients who had cryptogenic first-ever CIEs (ischemic stroke [IS] or transient ischemic attack [TIA]) associated with ipsilateral CaW were included in this multicenter observational cohort study. The follow-up (January 2008 to March 2019) focused on CIE recurrences. Kaplan-Meier method assessed rates of recurrences and Cox proportional hazards regression analyzed risk factors. RESULTS: Ninety-two patients (79 first-ever ISs and 13 TIAs; mean age±standard deviation, 49.8±9.9 years; 52 [56.5%] women) were included. During a mean follow-up of 50.5±29.6 months, 19 (20.7%) patients experienced recurrent ipsilateral CIEs (16 ISs and three TIAs). Of 23 patients receiving surgery/stenting treatment, no recurrence occurred after the intervention (median follow-up, 39.8 months [interquartile range, 27.6 to 72.4]). Under medical treatment alone, the annual recurrent CIE rate was 6.9%, and the cumulative rate was 4.4% at 30-day, 10.8% at 1-year, 19.8% at 2-year, 23.2% at 3-year, and 27.3% at 5-year. Presence of silent cerebral infarctions was the only independent risk factor of CIE recurrences (hazard ratio, 6.99; 95% confidence interval, 2.4 to 20.4; P=0.004). CONCLUSIONS: Under medical treatment alone, symptomatic CaW was associated with a high rate of recurrence that reached 27.3% at 5-year. Surgery/stenting seems to be efficient, and randomized control trials are required to confirm the benefit of these interventions.

Association between neurological outcome and poststroke comorbid mood and anxiety disorders: A real-life experience.

INTRODUCTION: Poststroke depression (PSD) and anxiety (PSA) are prevalent and have a strong impact on functional outcome. Beside stroke severity, little is known on their clinical determinants. This study investigated the association between stroke mechanism, neurological poststroke complications and remaining vascular risk factors and the presence of comorbid PSD and PSA, termed poststroke emotional distress (PSED). METHODS: This was a retrospective analysis of a prospectively compiled medical records database of consecutive patients evaluated during a follow-up visit 3- to 4-month poststroke. HAD scale was used to define PSED category (PSD+PSA vs. NoPSD+NoPSA). Stroke mechanism and poststroke complications were identified clinically or using appropriate scales. Their association with PSED was tested using a multivariate logistic regression model. RESULTS: The sample included 2,300 patients (male: 64.8%); 19% had a PSED and 56.39% were free of any depression or anxiety. The most frequent poststroke complications were fatigue/fatigability (58.4%), sleep problems (26.7%), and pain (20.4%). While no association was observed between PSED and stroke mechanism, higher functional disability (OR:1.572), lower cognitive abilities (OR:0.953), sleep problems (OR:2.334), pain (OR:1.478), fatigue/fatigability (OR:2.331), and abnormal movements (OR:2.380) were all independent risk factors. Persisting tobacco consumption (OR:1.360) was the only vascular significant risk factor. CONCLUSIONS: The frequency of comorbid PSED remains high (1/5 patient) despite improved awareness of these conditions. The association between poststroke complications and the presence of PSED emphasizes the need for standardized neurological and psychological evaluations at follow-up. These results foster the need to improve the management of addictive behaviors to reduce the burden of PSED.

Temporal trends in Human T-Lymphotropic virus 1 (HTLV-1) associated myelopathy/tropical spastic paraparesis (HAM/TSP) incidence in Martinique over 25 years (1986-2010).

BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1) has been discovered in 1980 and has been linked to tropical spastic paraparesis (HAM/TSP) in 1985 in Martinique. There is no data on HAM/TSP incidence trends. We report, in the present work, the temporal trends incidence of HAM/TSP in Martinique over 25 years. METHODS: Martinique is a Caribbean French West Indies island deserved by a unique Neurology Department involved in HAM/TSP diagnosis and management. A registry has been set up since 1986 and patients diagnosed for a HAM/TSP were prospectively registered. Only patients with a definite HAM/TSP onset between 1986 and 2010 were included in the present study. The 25-year study time was stratified in five-year periods. Crude incidence rates with 95% confidence interval (95%CI) were calculated using Poisson distribution for each period. Age-standardized rates were calculated using the direct method and the Martinique population census of 1990 as reference. Standardized incidence rate ratios with 95% CIs and P trends were assessed from simple Poisson regression models. Number of HTLV-1 infection among first-time blood donors was retrospectively collected from the central computer data system of the Martinique blood bank. The HTLV-1 seroprevalence into this population has been calculated for four 5-year periods between 1996 and 2015. RESULTS: Overall, 153 patients were identified (mean age at onset, 53+/-13.1 years; female:male ratio, 4:1). Crude HAM/TSP incidence rates per 100,000 per 5 years (95%CI) in 1986-1990, 1991-1995, 1996-2000, 2001-2005 and 2006-2010 periods were 10.01 (6.78-13.28), 13.02 (9.34-16.70), 11.54 (8.13-14.95), 4.27 (2.24-6.28) and 2.03 (0.62-3.43). Age-standardized 5-year incidence rates significantly decreased by 69% and 87% in 2001-2005 and 2006-2010 study periods. Patients characteristics did not differ regarding 1986-2000 and 2001-2010 onset periods. Between 1996-2000 and 2011-2015 study periods, the HTLV-1 seroprevalence significantly decreased by 63%. CONCLUSION: Martinique faces a sudden and rapid decline of HAM/TSP incidence from 2001 in comparison to 1986-2000 periods. Reduction of HTLV-1 seroprevalence, that may result from transmission prevention strategy, could account for HAM/TSP incidence decrease.

Clinical Predictors of Stroke Mimics in Patients Treated with Recombinant Tissue Plasminogen Activator according to a Normal Multimodal Computed Tomography Imaging.

BACKGROUND: Multimodal computed tomography imaging (MCTI) is increasingly used for rapid assessment of acute stroke. We investigated characteristics and final diagnoses of patients treated with recombinant tissue plasminogen activator (rt-PA) while admission imaging was unremarkable. METHODS: From our prospectively collected stroke database (2013-2016), we identified consecutive patients treated with rt-PA on the basis of an unremarkable brain MCTI and assessed with a 24-hour follow-up brain magnetic resonance imaging (MRI). Demographic data, medical history, score on the 15-item National Institute of Health Stroke Scale, and final diagnosis were considered. Absence of MRI infarction and alternate diagnosis defined stroke mimics (SMs). Univariable and multivariable logistic regression analyses identified factors predictive of SMs. RESULTS: Sixty-eight (47.9%) SMs, 63 (44.4%) strokes, and 11 (7.7%) aborted strokes were found. SMs had more often aphasia (P = .003) and hemianopia (P = .0008), whereas upper limb weakness (ULW) (P = .03) and limb ataxia (P = .002) were more prevalent in strokes. Headache (adjusted odds ratio [Adj. OR], 3.89 [95% confidence interval {CI} 1.44-10.47]), relevant history of epilepsy, migraine, dementia or depression (Adj. OR 3.66 [95% CI 1.31-10.18]), unilateral sensory loss (Adj. OR 2.60 [95% CI 1.05-6.45]), and hemianopia (Adj. OR 4.94 [95% CI 1.46-16.77]) were independent predictors of SMs whereas ULW (Adj. OR 3.16 [95% CI 1.28-7.82]) and ataxia (Adj. OR 3.81 [95% CI 1.43-10.13]) predicted stroke. Sensitivity of hemianopia or aphasia for SMs was 52.9%, with specificity of 84.1%, positive predictive value of 78.3%, and negative predictive value of 62.4%. CONCLUSIONS: Hemianopia and/or aphasia with normal MCTI suggest SMs. Diffusion-weighted MRI might be discussed before rt-PA administration in patients with such a clinical pattern.

Retinal Nerve Fiber Layer Thickness in Human T-cell Lymphotropic Virus Type 1 Patients.

PURPOSE: To determine whether there is an optic neuropathy (ON) in patients with human T-cell lymphotropic virus type 1 (HTLV-1) infection. METHODS: We included HTLV-1 asymptomatic carriers (a.c.HTLV-1) and tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM) patients between January 1st, 2014 and March 31st, 2015. All patients had complete eye examination. The visual acuity (VA) and retinal nerve fiber layer (RNFL) thickness were measured and compared to age- and sex-matched control groups including patients seen in our refraction clinic with no previous medical or surgical history. RESULTS: Thirty-one a.c.HTLV-1 (group 1) and 29 TSP/HAM patients (group 2) were included. The average RNFL thickness was 99.9 ± 14.3 µm in group 1 and 87.8 ± 19.2 µm in group 2. The average RFNL thicknesses were lower in both groups, when compared to controls. The difference was significant in patients with TSP/HAM (87.8 ± 19.2 µm vs. 97 ± 7.8 µm; p = 0.003) who also had significantly decreased VA. CONCLUSIONS: We report here the first study about the RNFL thickness in patients with TSP/HAM. In these patients, there is decrease of the RNFL thickness with subtle but definite decrease of VA. This suggests that subclinical ON occurs in the natural history of the disease. The diagnosis of TSP/HAM must be evoked as a differential of primary progressive multiple sclerosis in a population at risk. Moreover, RNFL thinning with no evidence of glaucoma should raise suspicion for HTLV-1 infection and TSP/HAM in a population at risk.

Association Between Carotid Bulb Diaphragm and Ischemic Stroke in Young Afro-Caribbean Patients: A Population-Based Case-Control Study.

BACKGROUND AND PURPOSE: Carotid bulb diaphragm (CBD) has been described in young carotid ischemic stroke (CIS) patients, especially in blacks. However, the prevalence of CBD in CIS patients is unknown, and whether CBD is a risk factor for CIS remains unclear. We assessed the association between CBD and incident CIS in a population-based study. METHODS: We selected all young (<55 years) CIS patients from a 1-year population-based cohort study in the Afro-Caribbean population of Martinique in 2012. All patients had a comprehensive work-up including a computed tomographic angiography. We calculated CIS associated with ipsilateral CBD incidence with 95% confidence intervals using Poisson distribution. We then selected age- and sex-matched controls among young (<55 years) Afro-Caribbean stroke-free patients admitted for a road crash who routinely had computed tomographic angiography. Odds ratio (ORs) were calculated by conditional logistic regression adjusted for hypertension, dyslipidemia, diabetes and smoking. RESULTS: CIS associated with ipsilateral CBD incidence was 3.8 per 100 000 person-years (95% confidence interval, 1.4-6.1). Prevalence of ipsilateral CBD was 23% in all CIS and 37% in undetermined CIS patients. When restricted to undetermined CIS, CBD prevalence was 24 times higher than that in controls (adjusted OR, 24.1; 95% confidence interval, 1.8-325.6). CONCLUSIONS: CBD is associated with an increased risk of ipsilateral CIS in young Afro-Caribbean population.

MRI characteristics of carotid bulb atypical fibromuscular dysplasia in black stroke patients.

BACKGROUND AND PURPOSE: In black stroke patients, a particular form of fibromuscular dysplasia (FMD), called atypical FMD (aFMD), is involved in stroke mechanism. The high rate of stroke recurrence under medical treatment leads to propose surgery in such patients. Regarding its location level on the carotid bulb, aFMD is often confused with atherosclerosis or free-floating thrombus. Nowadays, only histology can confirm the diagnosis. MRI of aFMD has never been assessed. MATERIALS AND METHODS: The constitution of a black patient's cohort with aFMD-related ischemic stroke is currently in progress in the French West Indies, Martinique. In patients scheduled for surgery, MRI of the carotid bifurcation was analyzed preoperatively, with subsequent histological examination of the excised specimen. The first four black stroke patients with MRI and histological findings are described. RESULTS: On imaging, aFMD lesion was homogeneous with isosignal on T2-weighted sequences and slight hypersignal on T1-weighted sequences with mild gadolinium enhancement of the inner layer. Histological findings confirmed the aFMD mainly located in the intima. CONCLUSIONS: aFMD generates a particular MRI pattern in our four patients, which could increase the diagnosis accuracy. Carotid bulb lesion in black stroke patients should suggest aFMD and MRI analysis may contribute to rule out differential diagnoses.

Carotid-bulb atypical fibromuscular dysplasia in young Afro-Caribbean patients with stroke.

BACKGROUND AND PURPOSE: An atypical form of fibromuscular dysplasia located in the internal carotid-bulb (CaFMD) is thought to be uncommon and is poorly described as a cause of ischemic stroke in the young. This study aimed to obtain a better description of CaFMD in Afro-Caribbean population, who could be particularly affected by it. METHODS: This study included consecutive patients <55 years consulting at Fort-de-France University Hospital Stroke Center (Martinique, FWI) found to have CaFMD as the only cause after a comprehensive work-up. CaFMD was diagnosed when computed tomographic angiography showed a bulbar spur without calcification. RESULTS: Twenty-five patients with stroke and CaFMD were identified. Computed tomographic angiography showed 2 CaFMD patterns: a thin (n=15) or thick (n=10) spur. Three patients initial computed tomographic angiography images showed a mural thrombus overlying the CaFMD. CaFMD was surgically removed from 7 of 25 and 20 of 25 patients who received antiplatelet therapy; after mean follow-up of 25.3±19.5 months, their respective recurrence rates were 0% and 30%. CONCLUSIONS: CaFMD could be a common condition in young Afro-Caribbeans with carotid-territory ischemic stroke. Recurrences were frequent under antiplatelet treatment, while surgical CaFMD removal seemed more effective.

Trends in incidence and early outcomes in a Black Afro-Caribbean population from 1999 to 2012: Etude Réalisée en Martinique et Centrée sur l'Incidence des Accidents Vasculaires Cérébraux II Study.

BACKGROUND AND PURPOSE: Seldom studies are available on trends in stroke incidence in blacks. We aimed to evaluate whether stroke risk prevention policies modified first-ever stroke incidence and outcomes in the black Afro-Caribbean population of Martinique. METHODS: Etude Réalisée en Martinique et Centrée sur l'Incidence des Accidents Vasculaires Cérébraux (ERMANCIA) I and II are 2 sequential prospective population-based epidemiological studies. There have assessed temporal trends in first-ever stroke incidence, risk factors, pathological types, and early outcomes in the black Afro-Caribbean population of Martinique comparing two 12-month periods (1998-1999 and 2011-2012). Crude and age-standardized incidence and 30-day outcomes for stroke in the 2 study periods were compared using Poisson regression. RESULTS: We identified 580 and 544 first-ever strokes in the 2 studies. World age-standardized incidence rates decreased by 30.6% in overall (111 [95% confidence interval, 102-120] versus 77 [95% confidence interval, 70-84]). Rate decline was greater in women than in men (34% versus 26%) particularly in women aged 65 to 74 years (-69%) and 75 to 84 years (-43%). Frequencies of hypertension and diabetes mellitus were unchanged, whereas dyslipidemia, smoking, and atrial fibrillation significantly increased. Only ischemic stroke types showed significant rate reduction in overall and in women, incidence rate ratio (95% confidence intervals) of 0.69 (0.50-0.97) and 0.61 (0.42-0.88), respectively. The overall 30-day case-fatality ratio remained stable (19.3%/17.6%), whereas a better 30-day outcome was found (modified Rankin Score, ≤2 in 47%/37.6%; P=0.03). CONCLUSIONS: Over 13 years, there has been a significant decrease (30.6%) in the age-specific first-ever stroke incidence in our Afro-Carribean population. Although prevention policies seem effective, we need to focus on new risk factors limitation and on male population adherence to prevention program.

Increased osteopontin expression in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patient cells is associated with IL-17 expression.

BACKGROUND: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological inflammatory disease associated with a predominant infiltration of CD4+ T lymphocytes, which are the main subset of HTLV-1-infected cells. It has been demonstrated that in cell line the viral Tax protein transcriptionnally regulate expression of osteopontin, an inflammatory cytokine associated with Th17-related pathologies. OBJECTIVES: The aim of the study was to explore osteopontin expression in HTLV-1 asymptomatic carriers and in HAM/TSP patients and consequences on IL17 expression. STUDY DESIGN: We quantified Tax, osteopontin, RORγ, IL17 and IL22 mRNA expressions in cells from 10 HAM/TSP patients, 6 asymptomatic HTLV-1 carriers (ASY) and 4 HTLV-1-negative healthy donors during ex vivo culture. RESULTS: We observed that the expression of osteopontin was higher in HAM/TSP patients and correlated with Tax expression levels. Positive regulation of RORγ, IL17 and IL22 were also observed during cell culture. CONCLUSIONS: Our results propose a new mechanism which could contribute to HAM/TSP pathogenesis.

Efficacy of mitoxantrone in neuromyelitis optica spectrum: clinical and neuroradiological study.

OBJECTIVE: To evaluate the efficacy of mitoxantrone (MTX) on clinical and neuroradiological parameters of patients who had a relapse of neuromyelitis optica spectrum (NMOS) within the 12 previous months. METHODS: MTX (12 mg/m(2)) combined with methylprednisolone 1 g as three monthly courses followed by three quarterly courses was administered during an observational multicentre open study including 51 consecutive patients (28 NMO, 23 limited forms of NMO) of the French Caribbean and Guyana. The main outcome measure was the reduction of the annualised relapse rate (ARR), and the secondary outcome measures were alteration of disability measured by expanded disability status scale (EDSS) score, the time to onset of the first relapse, and the progression of neuroradiological lesions at 1 year of treatment. RESULTS: At 1 year of treatment, the ARR dropped from 1.82 to 0.37 (p<0.0001). The mean EDSS score improved by 1.3 points, going from 5.8 at baseline to 4.5 at 1 year (p<0.0001). The number of patients showing gadolinium (Gad)+ spinal cord lesions at baseline, that is, 46.9%, dropped to 10.6% (a 77.4% reduction; p=0.02). The median time to onset of the first relapse was 18 months. IgG-NMO seropositivity was a predictive factor of relapse (p=0.006). A case of acute myeloid leukaemia was observed after a mean time span of 4.8 years. CONCLUSIONS: In this observational NMO study, MTX decreased dramatically the frequency of relapses, which is directly related to progression of disability or even death in this disorder.

Safety of long-term treatment of HAM/TSP patients with valproic acid.

HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease of the central nervous system induced by human T-lymphotropic virus type 1. As a potential therapeutic approach, we previously suggested reducing the proviral load by modulating lysine deacetylase activity using valproic acid (VPA) and exposing virus-positive cells to the host immune response. We conducted a single-center, 2-year, open-label trial, with 19 HAM/TSP volunteers treated with oral VPA. Proviral load, CD38/HLA-DR expression, and CD8(+) lysis efficiency were not significantly affected by VPA. Mean scores of HAM/TSP disability did not differ between baseline and final visit. Walking Time Test increased significantly (> 20%) in 3 patients and was in keeping with minor VPA side effects (drowsiness and tremor). Walking Time Test improved rapidly after VPA discontinuation. We conclude that long-term treatment with VPA is safe in HAM/TSP.

Effects of valproate on Tax and HBZ expression in HTLV-1 and HAM/TSP T lymphocytes.

A determinant of human T-lymphotropic virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) development is the HTLV-1-infected cell burden. Viral proteins Tax and HBZ, encoded by the sense and antisense strands of the pX region, respectively, play key roles in HTLV-1 persistence. Tax drives CD4(+)-T cell clonal expansion and is the immunodominant viral antigen recognized by the immune response. Valproate (2-n-propylpentanoic acid, VPA), a histone deacetylase inhibitor, was thought to trigger Tax expression, thereby exposing the latent HTLV-1 reservoir to immune destruction. We evaluated the impact of VPA on Tax, Gag, and HBZ expressions in cultured lymphocytes from HTLV-1 asymptomatic carriers and HAM/TSP patients. Approximately one-fifth of provirus-positive CD4(+) T cells spontaneously became Tax-positive, but this fraction rose to two-thirds of Tax-positive-infected cells when cultured with VPA. Valproate enhanced Gag-p19 release. Tax- and Gag-mRNA levels peaked spontaneously, before declining concomitantly to HBZ-mRNA increase. VPA enhanced and prolonged Tax-mRNA expression, whereas it blocked HBZ expression. Our findings suggest that, in addition to modulating Tax expression, another mechanism involving HBZ repression might determine the outcome of VPA treatment on HTLV-1-infected-cell proliferation and survival.

HTLV-1 evades type I interferon antiviral signaling by inducing the suppressor of cytokine signaling 1 (SOCS1).

Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of Adult T cell Leukemia (ATL) and the neurological disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the majority of HTLV-1-infected individuals remain asymptomatic carriers (AC) during their lifetime, 2-5% will develop either ATL or HAM/TSP, but never both. To better understand the gene expression changes in HTLV-1-associated diseases, we examined the mRNA profiles of CD4+ T cells isolated from 7 ATL, 12 HAM/TSP, 11 AC and 8 non-infected controls. Using genomic approaches followed by bioinformatic analysis, we identified gene expression pattern characteristic of HTLV-1 infected individuals and particular disease states. Of particular interest, the suppressor of cytokine signaling 1--SOCS1--was upregulated in HAM/TSP and AC patients but not in ATL. Moreover, SOCS1 was positively correlated with the expression of HTLV-1 mRNA in HAM/TSP patient samples. In primary PBMCs transfected with a HTLV-1 proviral clone and in HTLV-1-transformed MT-2 cells, HTLV-1 replication correlated with induction of SOCS1 and inhibition of IFN-α/ß and IFN-stimulated gene expression. Targeting SOCS1 with siRNA restored type I IFN production and reduced HTLV-1 replication in MT-2 cells. Conversely, exogenous expression of SOCS1 resulted in enhanced HTLV-1 mRNA synthesis. In addition to inhibiting signaling downstream of the IFN receptor, SOCS1 inhibited IFN-ß production by targeting IRF3 for ubiquitination and proteasomal degradation. These observations identify a novel SOCS1 driven mechanism of evasion of the type I IFN antiviral response against HTLV-1.

Absence of consistent association between human leukocyte antigen-I and -II alleles and human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis risk in an HTLV-1 French Afro-Caribbean population.

OBJECTIVES: Human T-cell lymphotropic virus type 1 (HTLV-1) infection leads to the risk of developing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in less than 5% of cases. The mechanism of disease progression in HAM/TSP remains unknown. A significant role of certain human leukocyte antigen (HLA) genotypes in determining the risk of HAM/TSP has been reported in Japan, where the HLA-A*02 gene has been found to be associated with a lower HTLV-1 provirus load and with protection from HAM/TSP, whereas HLA-DRB1*0101 has been found to be associated with an increased susceptibility to HAM/TSP. The aim of the present case-control study was to investigate the HLA class I and class II allele distribution in HTLV-seropositive French Afro-Caribbean individuals, originating from the French West Indies. METHODS: Associations with HLA class I (A and B) and class II (DRB1 and DQB1) alleles were tested in 123 HAM/TSP patients and 85 asymptomatic HTLV-1 carriers. HLA typing was undertaken on genomic DNA extracted from peripheral blood leukocytes. RESULTS: In our cohort, no significant effect on either the risk of developing HAM/TSP or HTLV-1 provirus load was found for HLA class I or class II, including HLA-A*02 (p=0.43). CONCLUSIONS: Our findings are in contrast to those in the Japanese population, however the literature on HLA associations in HTLV-1 infections across different populations over the past decade have reported conflicting results and this suggests strong ethnic disparities.

Intracranial hypertension caused by a meningioma compressing the transverse sinus.

We report a 55-year-old woman with intracranial hypertension due to unilateral extrinsic compression of the left transverse sinus by a meningioma. Because of the high risk of the conventional neurosurgical intervention, she underwent an endovascular procedure consisting of a transstenotic stent placement in the left transverse sinus. One month after stenting, her ophthalmological examination revealed complete regression of the bilateral papilledema, with persistent improvement at 1 year. Cerebral venous-stenting could be a safe alternative for patients suffering from intracranial hypertension caused by extrinsic sinus compression.

Neuromyelitis optica associated with subacute human T-lymphotropic virus type 1 infection.

Although human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy, or tropical spastic paraparesis (HAM/TSP), is usually considered as a progressive myelopathy, a subacute variant has been described. It is unusual for optic neuritis (ON) to be associated with an HTLV-1 infection. Neuromyelitis optica (NMO) is characterised by severe attacks of acute transverse myelitis and ON of unknown aetiology. We report a 61-year-old Afro-Caribbean male patient with subacute HAM/TSP associated with bilateral ON that occurred 5years previously. To our knowledge this is the first report of recurrent NMO syndrome associated with HTLV-1 infection.