Opinion statement
Treatment of transthyretin familial amyloid polyneuropathy (TTR FAP) must be tailored to disease stage. Patients with early stage disease (i.e., without major impairment in walking ...ability), especially younger patients, should be referred as soon as possible for liver transplantation (LT) in the absence of major comorbid conditions. LT remains the most effective treatment option to date and should be offered to these patients as early as possible. Bridging therapy with an oral TTR stabilizer (tafamidis or diflunisal, according to local access to these treatments) should be started as soon as the diagnosis of TTR FAP is established. Early stage patients who do not wish to or have contraindications to LT should be treated with an oral TTR stabilizer or get access to the newly developed therapeutic options (IONIS TTR-Rx, patisiran, doxycycline/TUDCA). Late stage patients (presenting with significant walking impairment) are usually older and notoriously difficult to treat. They should be offered an oral TTR stabilizer but are not candidates for LT due to a significant rate of perioperative complications and increased risk of progressive neurological and especially cardiac disease despite LT. Access to the different therapies in development should also be considered depending on respective inclusion and exclusion criteria. The abovementioned treatment options were mostly validated in Val30Met mutation patients, but should also be offered to non-Val30Met patients, although mortality rates after LT are higher in these patients. Treatment decisions should be made on an individual basis. Screening for heart, eye, and renal involvement is mandatory for every patient at disease diagnosis and regularly thereafter, even in transplanted patients. Symptomatic treatment should be offered as needed, as well as genetic counseling to at-risk family members. Asymptomatic mutation carriers should benefit from regular screening for early symptoms of disease. Current therapeutic management of TTR FAP will hopefully be changed in the near future with data from the ongoing phase 2/3 studies testing the TTR gene silencing agents. In the longer term, it is likely that combined therapeutic approaches will be necessary to reverse the disease process.
We evaluated the effect of DMTs on Covid‐19 severity in patients with MS, with a pooled‐analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with ...Covid‐19 severity was assessed by multivariate ordinal‐logistic models and pooled by a fixed‐effect meta‐analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti‐CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid‐19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled‐analysis confirms an increased risk of severe Covid‐19 in patients on anti‐CD20 therapies and supports the protective role of interferon.
Longitudinally extensive transverse myelitis (LETM) is classically related to aquaporin (AQP4)-antibodies (Ab) neuromyelitis optica spectrum disorders (NMOSD) or more recently to myelin ...oligodendrocyte glycoprotein (MOG)-Ab associated disease. However, some patients remain negative for any diagnosis, despite a large work-up including AQP4-Ab and MOG-Ab. Data about natural history, disability outcome, and treatment are limited in this group of patients. We aimed to (1) describe clinical, biological, and radiological features of double seronegative LETM patients; (2) assess the clinical course and identify prognostic factors; and (3) assess the risk of recurrence, according to maintenance immunosuppressive therapy.
Retrospective evaluation of patients with a first episode of LETM, tested negative for AQP-Ab and MOG-Ab, from the French nationwide observatory study NOMADMUS.
Fifty-three patients (median age 38 years (range 16-80)) with double seronegative LETM were included. Median nadir EDSS at onset was 6.0 (1-8.5), associated to a median EDSS at last follow-up of 4.0 (0-8). Recurrence was observed in 24.5% of patients in the 18 following months, with a median time to first relapse of 5.7 months. The risk of recurrence was lower in the group of patients treated early with an immunosuppressive drug (2/22, 9%), in comparison with untreated patients (10/31, 32%).
A first episode of a double seronegative LETM is associated to a severe outcome and a high rate of relapse in the following 18 months, suggesting that an early immunosuppressive treatment may be beneficial in that condition.
Complement activation emerged as a key actor of anti-neutrophil cytoplasmic antibodies-associated vasculitis (AAV). Whether serum levels of C3 (sC3) or C3 kidney deposition may help to refine the ...prognosis of AAV remains elusive.
Retrospective multicentric study that included 154 patients with a first flare of AAV and sC3 (n = 143) or C3 kidney staining (n = 95) available at diagnosis. Clinical presentations, kidney pathology, and survival of patients with normal or low sC3 were compared using univariate analyses, Kaplan-Maier curves with log-rank comparison, or multivariate Cox’ model, as appropriate.
20 patients (14 %) had low sC3. sC3 (as bivariate low/normal or as a continuous variable) was associated with 5-year mortality but not with kidney survival. C3 kidney deposition (C3+) was identified in 23 patients who were characterized by more frequent chronic hypertension and lower eGFR at presentation (p = 0.04). C3+ correlated with IgG, IgM, C1q deposition (p = 0.07, p < 0.0001 and p = 0.003, respectively). Chronicity and activity scores were similar in C3+ and C3- patients. Among C3+ patients, those with C3 deposition ≥2+ had lower eGFR at presentation (p = 0.006) and were more frequently classified as sclerotic using the Berden classification (p = 0.04) and as ‘high risk’ using the Brix score (p = 0.03). However, eGFR improvement following induction regimen was similar between C3+ and C3- patients, and kidney survival at 5 years was similar.
Correlation of sC3 with mortality confirms mechanistic links between complement pathways and AAV, but the lack of clear predictive sC3 cut-off and the similar kidney outcome irrespective of C3 deposition precludes their use as biomarkers of AAV outcomes and response to treatment.
T cells differentiate into functionally distinct effector subsets in response to pathogen encounter. Cells of the innate immune system direct this process; CD1d-restricted invariant natural killer T ...(iNKT) cells, for example, can either promote or inhibit Th₁ and Th₂ responses. Recently, a new subset of CD4⁺ T helper cells, called Th₁₇, was identified that is implicated in mucosal immunity and autoimmune disorders. To investigate the influence of iNKT cells on the differentiation of naïve T cells we used an adoptive transfer model of traceable antigen-specific CD4⁺ T cells. Transferred naïve CD25⁻CD62L⁺ CD4⁺ T cells were primed by antigen immunization of the recipient mice, permitting their expansion and Th₁₇ differentiation. This study establishes that in vivo activation of iNKT cells during T-cell priming impedes the commitment of naïve T cells to the Th₁₇ lineage. In vivo cytokine neutralization experiments revealed a role for IL-4, IL-10, and IFN-γ in the iNKT-cell-mediated regulation of T-cell lineage development. Moreover, by comparing IL-17 production by antigen-experienced T cells from unmanipulated wild-type mice and iNKT-cell-deficient mice, we demonstrate an enhanced Th₁₇ response in mice lacking iNKT cells. This invigorated Th₁₇ response reverts to physiological levels when iNKT cells are introduced into Jα18⁻/⁻ mice by adoptive transfer, indicating that iNKT cells control the Th₁₇ compartment at steady state. We conclude that iNKT cells play an important role in limiting development of the Th₁₇ lineage and suggest that iNKT cells provide a natural barrier against Th₁₇ responses.
Risk factors associated with the severity of coronavirus disease 2019 (COVID-19) in patients with multiple sclerosis (MS) are unknown. Disease-modifying therapies (DMTs) may modify the risk of ...developing a severe COVID-19 infection, beside identified risk factors such as age and comorbidities.
To describe the clinical characteristics and outcomes in patients with MS and COVID-19 and identify factors associated with COVID-19 severity.
The Covisep registry is a multicenter, retrospective, observational cohort study conducted in MS expert centers and general hospitals and with neurologists collaborating with MS expert centers and members of the Société Francophone de la Sclérose en Plaques. The study included patients with MS presenting with a confirmed or highly suspected diagnosis of COVID-19 between March 1, 2020, and May 21, 2020.
COVID-19 diagnosed with a polymerase chain reaction test on a nasopharyngeal swab, thoracic computed tomography, or typical symptoms.
The main outcome was COVID-19 severity assessed on a 7-point ordinal scale (ranging from 1 not hospitalized with no limitations on activities to 7 death) with a cutoff at 3 (hospitalized and not requiring supplemental oxygen). We collected demographics, neurological history, Expanded Disability Severity Scale score (EDSS; ranging from 0 to 10, with cutoffs at 3 and 6), comorbidities, COVID-19 characteristics, and outcomes. Univariate and multivariate logistic regression models were used to estimate the association of collected variables with COVID-19 outcomes.
A total of 347 patients (mean SD age, 44.6 12.8 years, 249 women; mean SD disease duration, 13.5 10.0 years) were analyzed. Seventy-three patients (21.0%) had a COVID-19 severity score of 3 or more, and 12 patients (3.5%) died of COVID-19. The median EDSS was 2.0 (range, 0-9.5), and 284 patients (81.8%) were receiving DMT. There was a higher proportion of patients with a COVID-19 severity score of 3 or more among patients with no DMT relative to patients receiving DMTs (46.0% vs 15.5%; P < .001). Multivariate logistic regression models determined that age (odds ratio per 10 years: 1.9 95% CI, 1.4-2.5), EDSS (OR for EDSS ≥6, 6.3 95% CI. 2.8-14.4), and obesity (OR, 3.0 95% CI, 1.0-8.7) were independent risk factors for a COVID-19 severity score of 3 or more (indicating hospitalization or higher severity). The EDSS was associated with the highest variability of COVID-19 severe outcome (R2, 0.2), followed by age (R2, 0.06) and obesity (R2, 0.01).
In this registry-based cohort study of patients with MS, age, EDSS, and obesity were independent risk factors for severe COVID-19; there was no association found between DMTs exposure and COVID-19 severity. The identification of these risk factors should provide the rationale for an individual strategy regarding clinical management of patients with MS during the COVID-19 pandemic.
Late-onset multiple sclerosis (LOMS) frequently features a primary progressive (PP) course, strongly predicting severe disability. In this population-based cohort, we estimated the prognostic role of ...age at multiple sclerosis (MS) onset, independent of PP course, on disability progression.
The association of age at disease onset (adult, <50 years AOMS, vs. late, ≥50 years LOMS) and time to Expanded Disability Status Scale (EDSS) score 4 and 6 was estimated by Cox regression modelling.
Among 3,597 patients, 245 had LOMS. Relapsing-remitting (RR) disease was less frequent with LOMS than AOMS (51.8 vs. 90.8%, p < 0.0001). PP course, LOMS and male gender predicted short time to EDSS 4 and 6. Worse outcome with LOMS (time to EDSS 4 and 6, HR 2.0 95% CI 1.7-2.4 and 2.3 1.9-2.9) was independent of PP course or male gender. LOMS had greater impact on RR than PP disease (time to EDSS 4 and 6, HR 3.1 2.3-4.0 and 4.0 2.9-5.6). Only LOMS predicted time from EDSS 4 to 6 (p < 0.0001).
Late onset MS was strongly associated with poor prognosis, independent of initial disease course, in predicting the disability progression along time.
To report the clinical, biological, and imaging features and clinical course of a French cohort of patients with glial fibrillary acidic protein (GFAP) autoantibodies.
We retrospectively included all ...patients who tested positive for GFAP antibodies in the CSF by immunohistochemistry and confirmed by cell-based assay using cells expressing human GFAPα since 2017 from 2 French referral centers.
We identified 46 patients with GFAP antibodies. Median age at onset was 43 years, and 65% were men. Infectious prodromal symptoms were found in 82%. Other autoimmune diseases were found in 22% of patients, and coexisting neural autoantibodies in 11%. Tumors were present in 24%, and T-cell dysfunction in 23%. The most frequent presentation was subacute meningoencephalitis (85%), with cerebellar dysfunction in 57% of cases. Other clinical presentations included myelitis (30%) and visual (35%) and peripheral nervous system involvement (24%). MRI showed perivascular radial enhancement in 32%, periventricular T2 hyperintensity in 41%, brainstem involvement in 31%, leptomeningeal enhancement in 26%, and reversible splenial lesions in 4 cases. A total of 33 of 40 patients had a monophasic course, associated with a good outcome at last follow-up (Rankin Score ≤2: 89%), despite a severe clinical presentation. Adult and pediatric features are similar. Thirty-two patients were treated with immunotherapy. A total of 11/22 patients showed negative conversion of GFAP antibodies.
GFAP autoimmunity is mainly associated with acute/subacute meningoencephalomyelitis with prodromal symptoms, for which tumors and T-cell dysfunction are frequent triggers. The majority of patients followed a monophasic course with a good outcome.
Objective
To describe characteristics and outcomes of a multicenter cohort of patients diagnosed as having primary angiitis of the central nervous system (PACNS).
Methods
In 2010, we initiated a ...cohort study of adults diagnosed as having PACNS ≤15 years ago and with followup of >6 months (unless they died earlier of biopsy‐proven PACNS). Its first analysis was planned at 2 years. Multidisciplinary investigators verified that appropriate investigations were done and excluded patients with possible alternative diagnoses. We analyzed patient demographics and symptoms, laboratory, radiographic, and histologic findings, and treatments. Studied outcomes included treatment response(s), relapse, death, and disability.
Results
We included 52 patients (30 males; median age at diagnosis 43.5 years range 18–79 years) in whom PACNS was diagnosed between 1996 and 2012. Nineteen (61%) of 31 patients who had undergone brain biopsy had histologic vasculitis (biopsy‐proven PACNS), while the other 12 patients had normal or noncontributive biopsy samples. An additional 21 patients had signs suggestive of PACNS on conventional cerebral angiography. All but 1 patient received corticosteroids, and 44 patients received cyclophosphamide (CYC). After a median followup of 35 months (range 2–148 months) postdiagnosis (1 patient with biopsy‐proven PACNS died 2 months after diagnosis), 32 patients responded to treatment with improved modified Rankin scale scores, 4 patients (8%) did not respond, 14 patients (27%) had relapse of their disease at least once, and 3 patients (6%) died (1 patient after a relapse). Relapse was more common in patients with than in those without meningeal gadolinium enhancements on magnetic resonance imaging (MRI) (8 of 10 80% versus 6 of 32 19%; P = 0.001) and more common in patients with than in those without seizures at diagnosis (8 of 17 47% versus 6 of 35 17%; P = 0.04).
Conclusion
In this cohort of patients with PACNS, most patients received corticosteroids and CYC, and mortality was low. Patients with seizures at diagnosis or meningeal enhancements on MRI may be prone to relapse and require a different treatment strategy.
The clinical features of autoimmune encephalitis associated with antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR-Abs) remain poorly defined.
To describe 7 ...patients with encephalitis and AMPAR-Abs and to provide a review of the literature on this disease entity.
The setting was the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (Lyon, France), and participants were 7 consecutive patients diagnosed as having encephalitis and AMPAR-Abs between January 1, 2010, and December 1, 2014. Patients' clinical data were analyzed, with a median follow-up period of 12 months (range, 2-31 months). Relevant articles were identified in the MEDLINE database using the keywords autoimmune encephalitis and AMPA receptor antibodies until February 15, 2015.
Modes of onset, full clinical presentations, and cancer prevalence.
The patients included 4 women and 3 men (median age, 56 years). Four main modes of encephalitis onset were observed, including confusion (3 patients), epileptic (1 patient), amnestic (1 patient), and a severe form of fulminant encephalitis (2 patients). In contrast with previous reports, we observed only 1 patient with seizures. Two patients had cancer (1 lung carcinoma and the other thymic carcinoma). Analysis of the literature identified 35 published cases of encephalitis and AMPAR-Abs, including 18 with clinical data. The same modes of encephalitis onset were observed, including confusion (12 patients), epileptic (1 patient), amnestic (3 patients), and fulminant encephalitis (2 patients). Eleven patients were initially seen with a neoplasm (lung, breast, thymoma, or ovary).
The clinical spectrum of AMPAR encephalitis is variable. Cancer was found in 13 of 27 patients (48%) with known cancer status. Most patients are seen with symptoms suggestive of autoimmune limbic encephalitis, although they can be paucisymptomatic or may manifest severe panencephalitis that evolves to a minimally conscious state and diffuse cortical atrophy. Patients suspected of having autoimmune encephalitis should undergo screening for serum and cerebrospinal fluid AMPAR-Abs.
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