The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little ...is known so far about the clinical impact of AQP4-Ab seropositivity.
To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus.
Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%).
Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of ≤ 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades ≤ 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions ≥ 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome.
This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients.
Objective
Neuromyelitis optica (NMO) attacks often are severe, are difficult to treat, and leave residual deficits. Here, we analyzed the frequency, sequence, and efficacy of therapies used for NMO ...attacks.
Methods
A retrospective review was made of patient records to assess demographic/diagnostic data, attack characteristics, therapies, and the short‐term remission status (complete remission CR, partial remission PR, no remission NR). Inclusion criteria were NMO according to Wingerchuk's 2006 criteria or aquaporin‐4 antibody–positive NMO spectrum disorder (NMOSD). Remission status was analyzed with generalized estimating equations (GEEs), a patient‐based statistical approach.
Results
A total of 871 attacks in 185 patients (142 NMO/43 NMOSD, 82% female) were analyzed. The 1,153 treatment courses comprised high‐dose intravenous steroids (HD‐S; n = 810), plasma exchange (PE; n = 192), immunoadsorption (IA; n = 38), other (n = 80), and unknown (n = 33) therapies. The first treatment course led to CR in 19.1%, PR in 64.5%, and NR in 16.4% of attacks. Second, third, fourth, and fifth treatment courses were given in 28.2%, 7.1%, 1.4%, and 0.5% of attacks, respectively. This escalation of attack therapy significantly improved outcome (p < 0.001, Bowker test). Remission rates were higher for isolated optic neuritis versus isolated myelitis (p < 0.001), and for unilateral versus bilateral optic neuritis (p = 0.020). Isolated myelitis responded better to PE/IA than to HD‐S as first treatment course (p = 0.037). Predictors of CR in multivariate GEE analysis were age (odds ratio OR = 0.97, p = 0.011), presence of myelitis (OR = 0.38, p = 0.002), CR from previous attack (OR = 6.85, p < 0.001), and first‐line PE/IA versus HD‐S (OR = 4.38, p = 0.006).
Interpretation
Particularly myelitis and bilateral optic neuritis have poor remission rates. Escalation of attack therapy improves outcome. PE/IA may increase recovery in isolated myelitis. Ann Neurol 2016;79:206–216
To analyse predictors for relapses and number of attacks under different immunotherapies in patients with neuromyelitis optica spectrum disorder (NMOSD).
This is a retrospective cohort study ...conducted in neurology departments at 21 regional and university hospitals in Germany. Eligible participants were patients with aquaporin-4-antibody-positive or aquaporin-4-antibody-negative NMOSD. Main outcome measures were HRs from Cox proportional hazard regression models adjusted for centre effects, important prognostic factors and repeated treatment episodes.
265 treatment episodes with a mean duration of 442 days (total of 321 treatment years) in 144 patients (mean age at first attack: 40.9 years, 82.6% female, 86.1% aquaporin-4-antibody-positive) were analysed. 191 attacks occurred during any of the treatments (annual relapse rate=0.60). The most common treatments were rituximab (n=77, 111 patient-years), azathioprine (n=52, 68 patient-years), interferon-β (n=32, 61 patient-years), mitoxantrone (n=34, 32.1 patient-years) and glatiramer acetate (n=17, 10 patient-years). Azathioprine (HR=0.4, 95% CI 0.3 to 0.7, p=0.001) and rituximab (HR=0.6, 95% CI 0.4 to 1.0, p=0.034) reduced the attack risk compared with interferon-β, whereas mitoxantrone and glatiramer acetate did not. Patients who were aquaporin-4-antibody-positive had a higher risk of attacks (HR=2.5, 95% CI 1.3 to 5.1, p=0.009). Every decade of age was associated with a lower risk for attacks (HR=0.8, 95% CI 0.7 to 1.0, p=0.039). A previous attack under the same treatment tended to be predictive for further attacks (HR=1.5, 95% CI 1.0 to 2.4, p=0.065).
Age, antibody status and possibly previous attacks predict further attacks in patients treated for NMOSD. Azathioprine and rituximab are superior to interferon-β.
Non-arteritic branch/central retinal artery occlusions (BRAO/CRAO) and amaurosis fugax (AF) are predominantly caused by embolism. Additionally, transported embolic material could cause ischemic ...stroke. The aim of the study was to investigate the prevalence, pattern and underlying cause of concurrent acute brain infarctions in unselected patients with RAO and AF.
A total of 213 consecutive patients with BRAO (20.7%), CRAO (47.4%), or AF (31.9%) were retrospectively studied from 2008 to 2013. Magnetic resonance imaging (MRI) was used to detect acute brain infarctions and a cardiovascular workup was performed to detect underlying etiologies according to the Trial of Org 10172 in Acute Stroke Management (TOAST).
MRI was obtained after 23.78 (±32.26) hours from the time of symptom onset. Acute brain infarctions were detected in 49 patients (23%); 44 of them (89.8%) did not experience any additional neurological symptoms. Older age (p < 0.001/p < 0.001), hypertension (p = 0.01/p = 0.03), atrial fibrillation (p = 0.006/p = 0.03) and type of RAO (p = 0.02/p = 0.016) were associated with total/silent stroke, respectively. In multivariate analysis, only age and type of occlusion remained positive predictors for silent stroke. Etiology of BRAO/CRAO and AF remained undetermined in 124 patients (58.2%). This rate was lower in patients with acute stroke (40.8 vs. 63.4%).
Silent brain infarction is a frequent finding in unselected patients with BRAO/CRAO and AF. Etiology remains undetermined in approximately every second case. Because silent brain infarctions bear a high risk of future stroke, patients with BRAO/CRAO and AF should undergo prompt neuroimaging and cardiovascular checkup, preferably on a stroke unit.
Oligoclonal bands (OCB) are the most widely used CSF test to support the diagnosis of MS and to predict conversion of clinically isolated syndrome (CIS) to multiple sclerosis (MS). Since OCB tests ...are based on non-quantitative and difficult to standardise techniques, measurement of immunoglobulin kappa free light chains (KFLC) may represent an easier to use quantitative test.
KFLC were measured in CSF and serum of 211 patients using ELISA. These include patients without any inflammatory central nervous system reaction (NIND, n = 77), MS (n = 20), viral CNS infections (V-CNS-I, n = 10), neuroborreliosis (NB, n = 17) and other bacterial CNS infections (B-CNS-I, n = 10). Furthermore a cohort of 77 patients with CIS, including 39 patients that remained CIS over follow-up of two years (CIS-CIS) and 38 patients that developed MS over the same follow-up time (CIS-MS).
CSF-serum ratio of KFLC (Q KFLC) was elevated in all patients with MS, 86.8% of patients with CIS-MS and 61.5% of patients with CIS-CIS. It was significantly elevated in CIS with presence of OCB (p<0.001). Q KFLC significantly correlated with other CSF variables such as CSF leukocyte count (p<0.001, R = 0.46), CSF CXCL13 levels (p<0.001, R = 0.64) and also intrathecal IgG synthesis (p<0.001, R = 0.74) as determined by nephelometry and quotient diagram. OCB were detected in 66.7% of CIS-CIS and in 92.1% of CIS-MS.
Although the measurement of CSF KFLC is a rapid and quantitative easy to standardize tool, it is almost equal but not superior to OCB with regard to diagnostic sensitivity and specificity in patients with early MS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There is increasing recognition of the importance of B lymphocytes in the immunopathogenesis of multiple sclerosis (MS), encouraging the evaluation of B cell-associated biomarkers in the ...cerebrospinal fluid (CSF). We aimed to evaluate the relevance of the B cell chemoattractant CXCL13 as a prognostic marker in patients with clinically isolated syndrome (CIS) regarding conversion to MS, and to compare it to Barkhof criteria in magnetic resonance imaging (MRI), oligoclonal bands (OCB) and the polyspecific intrathecal B cell response against measles, rubella and varicella zoster virus (MRZR).
CXCL13 was determined in a prospective study over 2 years including 46 patients that remained CIS over follow-up (CIS-CIS), 45 patients that developed MS (CIS-RRMS), and 30 controls using ELISA. CSF CXCL13 was significantly elevated in CIS-RRMS as compared to CIS-CIS and controls (p<0.001). It was significantly elevated in CIS with OCB (p<0.001), positive MRZR (p=0.04), and gadolinium enhancement in MRI (p=0.02) and showed a significant correlation with CSF leukocyte count (p<0.001) and QIgG (p<0.001). CXCL13 showed the best positive predictive value (PPV) of all parameters investigated (70%, 95%-CI: 53-84%), which could be further increased by combination with Barkhof criteria in MRI (80%).
Our data indicate the relevance of CXCL13 in CIS to predict conversion to MS. It furthermore shows CXCL13 to be an important mediator in the inflammatory cascade associated with the polyspecific intrathecal B cell response that manifests itself in OCB and MRZR.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In a retrospective study of a consecutive autopsy series of 2060 elderly subjects (mean age 78.5 ± 6.8 SD years), sporadic cerebral amyloid angiopathy (CAA) of various degrees was detected in 73.2% ...and in 98.5% of autopsy-confirmed cases of typical (plaque and tangle) Alzheimer disease (AD). Spontaneous (non-traumatic) intracerebral hemorrhages (ICH) (excluding microbleeds) were seen in 5.6% of the total cohort and in 7.2% of definite AD cases; CAA was found in 49% of brains without and in 48.7% with ICH which was not significantly different. The latter groups showed a significantly higher frequency of severe degrees of CAA than those without ICH (80.4 vs 30.9%, p < 0.001). Patients with CAA were older than those without CAA, showing a higher frequency of clinical dementia and pathologically confirmed AD, but signs of hypertension (history and/or autopsy) were seen in 41 and 33.6% of these cases, respectively, compared to 70–75% in patients with non-CAA related ICHs. CAA-related ICH much more frequently involved cerebral lobes or hemispheres, while non-CAA related lesions were more often located in basal ganglia and brainstem. The data of a lower prevalence of CAA in cases without than with ICH, but a similar prevalence of ICH with and without CAA do not support the concept that CAA represents the most evident risk factor for ICH in the aged. While severe degrees of CAA were indeed associated with ICH, the general prevalence of large ICH in this autopsy cohort was much higher in cases without CAA, probably due to other risk factors including hypertension, which was documented in around 40% of cases with CAA-related ICH. APOE ε3/4 and ε4/4 were significantly more frequent in AD (n = 163) than in age-matched controls (n = 47) and were associated with more severe degrees of CAA, but no general genotyping in ICHs with and without CAA was performed. Hence, the role of APOE in the pathogenesis of ICH with and without CAA needs further elucidation.
Optical Coherence Tomography (OCT) is a noninvasive imaging method, which provides an in vivo image of the retina. It allows for quantitative measurements of retinal and macular thickness, including ...single-layer analysis. Because the retinal nerve fibre layer comprises the first axons of the visual pathway and is unmyelinated, it can be considered a unique anatomical model, which may provide insight into the pathophysiological processes of diseases with a neurodegenerative character. In fact, past OCT studies have emphasized the role of the visual pathway as an ideal structure for exploring neurodegeneration and have demonstrated the potential of the method as an instrument for longitudinally monitoring structural changes in neurological disorders such as multiple sclerosis. Progress in signal processing and advancements to the OCT technique enables the illustration of structural changes in the retinal layers in a quick, reproducible, and objective manner with a spatial resolution comparable to those of histological slices.Findings from computer-based magnetic resonance imaging analyses and neuropathological studies support the hypothesis of a degenerative component of certain psychiatric disorders such as schizophrenia. Studies in schizophrenia incorporating OCT are currently rare and have yielded further heterogeneous results. This article elucidates the method of OCT and the retina's role as a "window to the brain". Furthermore, in delineating the degenerative components of schizophrenia, we discuss the possible applications of OCT in the schizophrenia population.
Chitinase 3-like 1 (CHI3L1) has been proposed as a biomarker associated with the conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes, based on the ...finding of increased cerebrospinal fluid CHI3L1 levels in clinically isolated syndrome patients who later converted to multiple sclerosis compared to those who remained as clinically isolated syndrome. Here, we aimed to validate CHI3L1 as a prognostic biomarker in a large cohort of patients with clinically isolated syndrome. This is a longitudinal cohort study of clinically isolated syndrome patients with clinical, magnetic resonance imaging, and cerebrospinal fluid data prospectively acquired. A total of 813 cerebrospinal fluid samples from patients with clinically isolated syndrome were recruited from 15 European multiple sclerosis centres. Cerebrospinal fluid CHI3L1 levels were measured by enzyme-linked immunosorbent assay. Multivariable Cox regression models were used to investigate the association between cerebrospinal fluid CHI3L1 levels and time to conversion to multiple sclerosis and time to reach Expanded Disability Status Scale 3.0. CHI3L1 levels were higher in patients who converted to clinically definite multiple sclerosis compared to patients who continued as clinically isolated syndrome (P = 8.1 × 10(-11)). In the Cox regression analysis, CHI3L1 levels were a risk factor for conversion to multiple sclerosis (hazard ratio = 1.7; P = 1.1 × 10(-5) using Poser criteria; hazard ratio = 1.6; P = 3.7 × 10(-6) for McDonald criteria) independent of other covariates such as brain magnetic resonance imaging abnormalities and presence of cerebrospinal fluid oligoclonal bands, and were the only significant independent risk factor associated with the development of disability (hazard ratio = 3.8; P = 2.5 × 10(-8)). High CHI3L1 levels were associated with shorter time to multiple sclerosis (P = 3.2 × 10(-9) using Poser criteria; P = 5.6 × 10(-11) for McDonald criteria) and more rapid development of disability (P = 1.8 × 10(-10)). These findings validate cerebrospinal fluid CHI3L1 as a biomarker associated with the conversion to multiple sclerosis and development of disability and reinforce the prognostic role of CHI3L1 in patients with clinically isolated syndrome. We propose that determining cerebrospinal fluid chitinase 3-like 1 levels at the time of a clinically isolated syndrome event will help identify those patients with worse disease prognosis.
Background:
Gender and age at onset are important epidemiological factors influencing prevalence, clinical presentation, and treatment response in autoimmune diseases.
Objective:
To evaluate the ...impact of female sex and fertile age on aquaporin-4-antibody (AQP4-ab) status, attack localization, and response to attack treatment in patients with neuromyelitis optica (NMO) and its spectrum disorders (neuromyelitis optica spectrum disorder (NMOSD)).
Methods:
Female-to-male ratios, diagnosis at last visit (NMO vs NMOSD), attack localization, attack treatment, and outcome were compared according to sex and age at disease or attack onset.
Results:
A total of 186 NMO/SD patients (82% female) were included. In AQP4-ab-positive patients, female predominance was most pronounced during fertile age (female-to-male ratio 23:1). Female patients were more likely to be positive for AQP4-abs (92% vs 55%; p < 0.001). Interval between onset and diagnosis of NMO/SD was longer in women than in men (mean 54 vs 27 months; p = 0.023). In women, attacks occurring ⩽40 years of age were more likely to show complete remission (p = 0.003) and better response to high-dose intravenous steroids (p = 0.005) compared to woman at >40 years.
Conclusion:
Our data suggest an influence of sex and age on susceptibility to AQP4-ab-positive NMO/SD. Genetic and hormonal factors might contribute to pathophysiology of NMO/SD.
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