Highly Effective Therapies as First-Line Treatment for Pediatric-Onset Multiple Sclerosis.

Importance: Moderately effective therapies (METs) have been the main treatment in pediatric-onset multiple sclerosis (POMS) for years. Despite the expanding use of highly effective therapies (HETs), treatment strategies for POMS still lack consensus. Objective: To assess the real-world association of HET as an index treatment compared with MET with disease activity. Design, Setting, and Participants: This was a retrospective cohort study conducted from January 1, 2010, to December 8, 2022, until the last recorded visit. The median follow-up was 5.8 years. A total of 36 French MS centers participated in the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort. Of the total participants in OFSEP, only treatment-naive children with relapsing-remitting POMS who received a first HET or MET before adulthood and at least 1 follow-up clinical visit were included in the study. All eligible participants were included in the study, and none declined to participate. Exposure: HET or MET at treatment initiation. Main Outcomes and Measures: The primary outcome was the time to first relapse after treatment. Secondary outcomes were annualized relapse rate (ARR), magnetic resonance imaging (MRI) activity, time to Expanded Disability Status Scale (EDSS) progression, tertiary education attainment, and treatment safety/tolerability. An adapted statistical method was used to model the logarithm of event rate by penalized splines of time, allowing adjustment for effects of covariates that is sensitive to nonlinearity and interactions. Results: Of the 3841 children (5.2% of 74 367 total participants in OFSEP), 530 patients (mean [SD] age, 16.0 [1.8] years; 364 female [68.7%]) were included in the study. In study patients, both treatment strategies were associated with a reduced risk of first relapse within the first 2 years. HET dampened disease activity with a 54% reduction in first relapse risk (adjusted hazard ratio [HR], 0.46; 95% CI, 0.31-0.67; P < .001) sustained over 5 years, confirmed on MRI activity (adjusted odds ratio [OR], 0.34; 95% CI, 0.18-0.66; P = .001), and with a better tolerability pattern than MET. The risk of discontinuation at 2 years was 6 times higher with MET (HR, 5.97; 95% CI, 2.92-12.20). The primary reasons for treatment discontinuation were lack of efficacy and intolerance. Index treatment was not associated with EDSS progression or tertiary education attainment (adjusted OR, 0.51; 95% CI, 0.24-1.10; P = .09). Conclusions and Relevance: Results of this cohort study suggest that compared with MET, initial HET in POMS was associated with a reduction in the risk of first relapse with an optimal outcome within the first 2 years and was associated with a lower rate of treatment switching and a better midterm tolerance in children. These findings suggest prioritizing initial HET in POMS, although long-term safety studies are needed.

Lumbar Spinal Stenosis Treatment: Is Surgery Better than Non-Surgical Treatments in Afro-Descendant Populations?

(1) Background: Limited data are available on lumbar spine stenosis management in sub-Saharan African populations and Afro-descendant patients are underrepresented in European and US clinical trials. We aimed to compare the clinical response between decompressive surgery and conservative treatments in a population of self-reported Afro-Caribbean patients with lumbar spine stenosis over a 2-year follow-up period. (2) Methods: Prospective cohort of 137 self-reported Afro Caribbeans with lumbar spine stenosis based on clinical and radiological criteria. Patients were assigned to decompression surgery or to conservative treatments according to their outcome after a first course of steroid epidural injection and their preferences. The primary outcome was evolution of the Oswestry disability index at 3 months (3 M), 12 M, 18 M and 24 M follow-up. (3) Results: Decrease of ODI was significantly more important in the "decompression surgery" arm compared to "conservative treatment" arm at 3 M, 12 M and 18 M: −17.36 vs. 1.03 p < 10−4; −16.38 vs. −1.53 p = 0.0059 and −19.00 vs. −4.52 p = 0.021, respectively. No difference was reported at 24 M. (4) Conclusions: In this first comparative study between surgery and conservative treatments in an exclusively afro-descendant lumbar spine stenosis cohort, we report long term superiority of decompression surgery versus conservative treatments over an 18-month period.

Marburg Multiple Sclerosis Variant: Complete Remission with Very Early Administration of Mitoxantrone-A Case Report.

Marburg variant is a severe and fulminant pseudotumor form of multiple sclerosis (MS) with high morbidity and mortality rates. Because of its scarcity, it remains incompletely characterized and physicians' experiences will influence the treatment. We report the inflammatory explosive case of a 31-year-old woman presenting with rapid neurological degradation of histology proven Marburg's disease, successfully treated with early administration of Mitoxantrone (MITX). To our knowledge, it is the first case describing complete remission after MITX in a biopsy-proven condition.

Risk Factors and Time to Clinical Symptoms of Multiple Sclerosis Among Patients With Radiologically Isolated Syndrome.

Importance: Younger age, oligoclonal bands, and infratentorial and spinal cord lesions are factors associated with an increased 10-year risk of clinical conversion from radiologically isolated syndrome (RIS) to multiple sclerosis (MS). Whether disease-modifying therapy is beneficial for individuals with RIS is currently unknown. Objectives: To evaluate the 2-year risk of a clinical event (onset of clinical symptoms of MS) prospectively, identify factors associated with developing an early clinical event, and simulate the sample size needed for a phase III clinical trial of individuals with RIS meeting 2009 RIS criteria. Design, Setting, and Participants: This cohort study used data on prospectively followed-up individuals with RIS identified at 1 of 26 tertiary centers for MS care in France that collect data for the Observatoire Français de la Sclérose en Plaques database. Participants were aged 10 to 80 years with 2 or more magnetic resonance imaging (MRI) scans after study entry and an index scan after 2000. All diagnoses were validated by an expert group, whose review included a double centralized MRI reading. Data were analyzed from July 2020 to January 2021. Exposure: Diagnosis of RIS. Main Outcomes and Measures: Risk of clinical event and associated covariates at index scan were analyzed among all individuals with RIS. Time to the first clinical event was compared by covariates, and sample size estimates were modeled based on identified risk factors. Results: Among 372 individuals with RIS (mean [SD] age at index MRI scan, 38.6 [12.1] years), 354 individuals were included in the analysis (264 [74.6%] women). A clinical event was identified among 49 patients (13.8%) within 2 years, which was associated with an estimated risk of conversion of 19.2% (95% CI, 14.1%-24.0%). In multivariate analysis, age younger than 37 years (hazard ratio [HR], 4.04 [95% CI, 2.00-8.15]; P < .001), spinal cord lesions (HR, 5.11 [95% CI, 1.99-13.13]; P = .001), and gadolinium-enhancing lesions on index scan (HR, 2.09 [95% CI, 1.13-3.87]; P = .02) were independently associated with an increased risk of conversion to MS. Having 2 factors at the time of the index MRI scan was associated with a risk of 27.9% (95% CI, 13.5%-39.9%) of a seminal event within 2 years, increasing to 90.9% (95% CI, 41.1%-98.6%) for individuals with all 3 factors (3 risk factors vs none: HR, 23.34 [95% CI, 9.08-59.96]; P < .001). Overall, with 80% power to detect an effect size of 60% within 24 months, a total of 160 individuals with RIS were needed assuming an event rate of 20%. Conclusions and Relevance: This study found that age younger than age 37 years, spinal cord involvement, and gadolinium-enhancing lesions on index MRI scan were associated with earlier clinical disease and relevant to the number of enrolled patients needed to detect a potential treatment effect.

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.

Untreated patients with multiple sclerosis: A study of French expert centers.

BACKGROUND AND PURPOSE: Disease-modifying therapies (DMTs) have an impact on relapses and disease progression. Nonetheless, many patients with multiple sclerosis (MS) remain untreated. The objectives of the present study were to determine the proportion of untreated patients with MS followed in expert centers in France and to determine the predictive factors of nontreatment. METHODS: We conducted a retrospective cohort study. Data were extracted from the 38 centers participating in the European Database for Multiple Sclerosis (EDMUS) on December 15, 2018, and patients with MS seen at least once during the study period (from June 15, 2016 to June 14, 2017) were included. RESULTS: Of the 21,189 patients with MS (age 47.1 ± 13.1 years; Expanded Disability Status Scale (EDSS) score 3.4 ± 2.4), 6,631 (31.3%; 95% confidence interval [CI] 30.7-31.9) were not receiving any DMT. Although patients with a relapsing-remitting course (n = 11,693) were the most likely to receive DMT, 14.8% (95% CI 14.2-15.4) were still untreated (6.8% never treated). After multivariate analysis among patients with relapsing-remitting MS, the main factors explaining never having been treated were: not having ≥9 lesions on brain magnetic resonance imaging (odds ratio [OR] 0.52 [95% CI 0.44-0.61]) and lower EDSS score (OR 0.78 [95% CI 0.74-0.82]). Most patients with progressive MS (50.4% for secondary and 64.2% for primary progressive MS) did not receive any DMT during the study period, while 11.6% of patients with secondary and 34.0% of patients with primary progressive MS had never received any DMT. CONCLUSION: A significant proportion of patients with MS did not receive any DMT, even though such treatments are reimbursed by the healthcare system for French patients. This result highlights the unmet need for current DMTs for a large subgroup of patients with MS.

Progressive Multifocal Leukoencephalopathy Incidence and Risk Stratification Among Natalizumab Users in France.

Importance: Risk of developing progressive multifocal leukoencephalopathy (PML) is the major barrier to using natalizumab for patients with multiple sclerosis (MS). To date, the association of risk stratification with PML incidence has not been evaluated. Objective: To describe the temporal evolution of PML incidence in France before and after introduction of risk minimization recommendations in 2013. Design, Setting, and Participants: This observational study used data in the MS registry OFSEP (Observatoire Français de la Sclérose en Plaques) collected between April 15, 2007, and December 31, 2016, by participating MS expert centers and MS-dedicated networks of neurologists in France. Patients with an MS diagnosis according to current criteria, regardless of age, were eligible, and those exposed to at least 1 natalizumab infusion (n = 6318) were included in the at-risk population. A questionnaire was sent to all centers, asking for a description of their practice regarding PML risk stratification. Data were analyzed in July 2018. Exposures: Time from the first natalizumab infusion to the occurrence of PML, natalizumab discontinuation plus 6 months, or the last clinical evaluation. Main Outcomes and Measures: Incidence was the number of PML cases reported relative to the person-years exposed to natalizumab. A Poisson regression model for the 2007 to 2016 period estimated the annual variation in incidence and incidence rate ratio (IRR), adjusted for sex and age at treatment initiation and stratified by period (2007-2013 and 2013-2016). Results: In total, 6318 patients were exposed to natalizumab during the study period, of whom 4682 (74.1%) were female, with a mean (SD [range]) age at MS onset of 28.5 (9.1 [1.1-72.4]) years; 45 confirmed incident cases of PML were diagnosed in 22 414 person-years of exposure. The crude incidence rate for the whole 2007 to 2016 period was 2.00 (95% CI, 1.46-2.69) per 1000 patient-years. Incidence significantly increased by 45.3% (IRR, 1.45; 95% CI, 1.15-1.83; P = .001) each year before 2013 and decreased by 23.0% (IRR, 0.77; 95% CI, 0.61-0.97; P = .03) each year from 2013 to 2016. Conclusions and Relevance: The results of this study suggest, for the first time, a decrease in natalizumab-associated PML incidence since 2013 in France that may be associated with a generalized use of John Cunningham virus serologic test results; this finding appears to support the continuation and reinforcement of educational activities and risk-minimization strategies in the management of disease-modifying therapies for multiple sclerosis.

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.

Treatment of neuromyelitis optica with rituximab: a 2-year prospective multicenter study.

OBJECTIVE: Neuromyelitis optica (NMO) is a very severe autoimmune disorder of the central nervous system. It affects young subjects and has a poor prognosis both on a functional and vital level. Therefore, it is imperative to reduce the frequency of relapses. The purpose of this study was to evaluate the clinical and neuroradiological effectiveness of rituximab (RTX) on active forms of NMO. METHODS: We conducted a 2-year open prospective multicenter study that included 32 patients treated with RTX at a dose of 375 mg/m2/week for 1 month. When the number of circulating CD19+ B cells reached 1%, a maintenance therapy was started, consisting of two infusions of 1 g of RTX, administered at a 15-day interval. The primary objective was to reduce the annual relapse rate (ARR), in comparison to that observed in the 2 years before treatment onset. RESULTS: Rituximab administration reduced the ARR from 1.34 to 0.56 (p = 0.0005). The average Expanded Disability Status Scale (EDSS) score significantly improved by 1.1 point, from 5.9 (2-9) to 4.8 (0-9) after 2 years (p = 0.03). Anti-aquaporin-4 antibodies' level predicted treatment failure (p = 0.03). Frequency of Gad+ lesions in spinal cord decreased from 23.3 to 14.2%. RTX treatment did not prevent the death of three patients (treatment failure in two patients and acute myeloid leukemia in a patient previously treated with mitoxantrone). CONCLUSION: Rituximab is clinically effective in active forms of NMO, although few patients are resistant to the treatment.

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.

Blood products use in France: a nationwide cross-sectional survey.

BACKGROUND: Blood products use has increased in France between 2000 and 2011. To understand the reasons for this increase, data about transfused patients and transfusion practices needed to be updated. STUDY DESIGN AND METHODS: A nationwide cross-sectional survey was performed with health care establishments. Diagnoses and indication for the transfusion, pretransfusion laboratory results, and blood products used were collected during a randomly selected 24-hour period in 2011. All patients who received at least one blood product delivered on the survey day were included. RESULTS: A total of 10,794 blood products were requested for 4720 patients: 8688 red blood cell (RBC) units, 842 platelet (PLT) concentrates, and 1264 fresh-frozen plasma (FFP) units. Hematologic and cancer pathologies included 46% of transfused patients, 34% of the patients had transfusions in a surgical context, and 32.4% of transfused patients were receiving medication with an impact on transfusion. Nearly half of RBC transfusions were performed with hemoglobin levels of less than 8 g/dL. PLT transfusions for prophylactic indication were prescribed with PLT counts of less than 20 × 109 and 50 × 109 /L in 56.9 and 86.6% of patients, respectively. RBCs and PLTs transfusion practices were in agreement with national guidelines. FFP units were involved in 8.0% of all prescriptions. Among these, 57.4% were requested in the context of an acute hemorrhage and 8.4% for plasma exchange. The median of FFP use (n = 2) in a nonsurgical context, excluding plasma exchange, suggests an insufficient dosing of FFP. CONCLUSION: Except for insufficient FFP dosing per patient and limitations on assessment of indications for prescribing, transfusion practices were in agreement with national guidelines.

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.

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.

Ocular oscillations in the neuromyelitis optica spectrum.

Four French West Indian women complained of oscillopsia and were found to have an acquired eye movement disorder. In 3 of them, different types of nystagmus were found, including upbeat, downbeat, and central form of vestibular nystagmus. One developed opsoclonus-myoclonus syndrome. Three patients had neuromyelitis optica antibodies, and 3 had brainstem abnormalities detected on MRI. Two patients had definite NMO, while the other 2 were considered to be at high risk for developing NMO. Treatment with high-dose systemic corticosteroids, with plasma exchanges, or in combination led to resolution of oscillopsia. We propose that eye movement disorders be added to the neurological manifestations of NMO.

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.

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.

NMO-IgG and Devic's neuromyelitis optica: a French experience.

BACKGROUND: A serum autoantibody biomarker, NMO-IgG has been recently described in patients with Devic's neuromyelitis optica (DNMO) and so called ;high-risk' patients for this disease. Our objectives were to replicate the test and to assess its usefulness. METHODS: Indirect immunofluorescence with a substrate of adult rat cerebellum and midbrain was used to identify the distinctive NMO-IgG staining pattern. We tested masked sera from 26 patients with DNMO (group 1), 21 patients with idiopathic acute transverse myelitis (ATM) (group 2), 21 patients with bilateral and/or recurrent idiopathic optic neuritis (group 3), 52 patients with classical multiple sclerosis (MS) (group 4), 36 patients with HTLV-1 infection (group 5) and 7 patients with miscellaneous disorders (group 6). RESULTS: We identified a vascular staining pattern typical of NMO-IgG. This particular staining was observed in 14/26 samples in group 1, 7/21 in group 2 (positive only in longitudinally extensive acute transverse myelitis: 7/13), 4/21 in group 3 (with bilateral loss of vision in all seropositive cases), 5/52 in group 4 (none of them suggestive of DNMO), 0/36 in group 5 and 0/7 in group 6. Sensitivity of the test was 54% considering detection of DNMO (group 1), and specificity was respectively 94% and 90% when considering groups 4, 5 and 6 altogether or group 4 of MS patients only. CONCLUSION: Detection of NMO-IgG is contributory to the distinction of DNMO and 'DNMO high-risk' syndromes from MS. This test may allow earlier diagnosis and help therapeutic decisions.

Natural history of human T-lymphotropic virus 1-associated myelopathy: a 14-year follow-up study.

BACKGROUND: The progression of neurological disability in human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) remains undefined. OBJECTIVES: To determine the time course of disability scores and to identify predictors of outcome among patients with HAM/TSP. DESIGN: Clinical 14-year follow-up study. SETTING: University hospital. Patients One hundred twenty-three patients with HAM/TSP. MAIN OUTCOME MEASURES: We determined time from onset to the following 4 Kurtzke Disability Status Scale (DSS) end points: scores of 6 (unilateral aid required), 6.5 (bilateral aid required), 8 (wheelchair confinement), and 10 (death related to the disease). Times to reach selected DSS scores were estimated using the Kaplan-Meier method. Univariate and multivariate analyses identified variables related to the rate of progression to DSS 8. The HTLV-1 proviral loads were also assessed. RESULTS: The disability of the cohort progressed throughout the follow-up period. The median times from onset to DSS 6, 6.5, and 8 were 6, 13, and 21 years, respectively. The median time from DSS 6 to DSS 8 was 8 years; DSS 10 was reached by one fourth of the patients within 20 years. Age at onset of 50 years or older and high HTLV-1 proviral load were associated with a shorter time to DSS 8 (P = .01 and P = .02, respectively). A shorter time to DSS 6 significantly adversely affected the time to progression from DSS 6 to DSS 8. CONCLUSIONS: Human T-lymphotropic virus 1-associated myelopathy/tropical spastic paraparesis is a rapidly disabling disease. Monitoring for HTLV-1 proviral load is recommended in future therapeutic trials.

Symptomatic ossification of the ligamentum flavum: a clinical series from the French Antilles.

STUDY DESIGN: A series of 14 patients from the French Antilles treated for ossification of the ligamentum flavum (OLF). OBJECTIVES: To describe the clinical and radiologic aspects, as well as disease course in a group of Caribbean patients. Also describe the use of sagittal computerized tomography (CT) reconstructions to distinguish OLF from calcification of the ligamenta flava. SUMMARY OF BACKGROUND DATA: OLF is a rare disease described almost exclusively in Japanese patients. Only rarely are patients of African descent affected. No series of OLF in African American or African Caribbean subjects has previously been published. METHODS: A retrospective study of 14 consecutive patients, including 7 men and 7 women (mean age, 66.8 years), was conducted from 1996 to 2003. Diagnosis in each case was established using CT. Magnetic resonance imaging was also performed in every case. For the 11 patients treated surgically, pathology studies were performed. RESULTS: Walking difficulties were the most common presenting complaint. A picture of spastic paraparesis associated with sphincter dysfunction was the most common finding on initial examination. In each case, CT provided sufficient information to establish a diagnosis of OLF, while magnetic resonance imaging was helpful for showing spinal cord involvement. In most of the patients, OLF was located in the lower thoracic spine. Surgical decompression through a posterior approach resulted in regression of symptoms in all 11 patients treated surgically. CONCLUSIONS: This study is the first reported series of OLF in a group of Caribbean patients. The disease appears to be underreported in the African Caribbean population. OLF can lead to debilitating thoracic myelopathy. Surgery is frequently indicated and achieves favorable results.

HTLV-1 proviral load in peripheral blood mononuclear cells quantified in 100 HAM/TSP patients: a marker of disease progression.

A high proviral load of human T cell lymphotropic virus type 1 (HTLV-1) in peripheral blood mononuclear cells (PBMCs) has been reported in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The aim of the present study was to investigate the role of HTLV-1 proviral load in PBMCs (expressed as the number of copies per 10(6) PBMCs) in HAM/TSP disease course. One hundred consecutive HAM/TSP patients were recruited and assigned on the basis of the disability score and disease duration to either a rapid (n=38) or a slow (n=62) progression group. Thirty-four asymptomatic HTLV-1 carriers were also included. HTLV-1 proviral load was quantified in all HAM/TSP patients and asymptomatic subjects. The mean HTLV-1 proviral load was 6-fold lower in asymptomatic carriers than in HAM/TSP patients (18,224+/-24,811 vs. 107,905+/-96,651, p<0.0001) and significantly higher in rapid progression patients than in slow progression patients (146,469+/-98,943 vs. 84,270+/-87,912, p=0.0002). HTLV-1 proviral load in HAM/TSP patients was independent of age at the time of study, age at onset, and disease duration, and was not related to ophthalmological-associated disease or Chisholm grade. A high level of pulmonary lymphocytosis correlated with high HTLV-1 proviral load level (p=0.01). Our results suggest that the level of HTLV-1 proviral load in PBMCs parallels the course of HTLV-1 infection, being low in asymptomatic carriers and high and very high, respectively, in slow and rapid progression HAM/TSP patients. The magnitude of the HTLV-1 proviral load in PBMCs can be used as a biological marker of disease progression and could be a useful marker of disease activity in the monitoring of therapeutic trials.