To assess whether the presence of concomitant diseases at multiple sclerosis (MS) diagnosis is associated with the choice and the treatment persistence in an Italian MS cohort.
We included newly diagnosed patients (2010–2016) followed in 20 MS centers and collected demographic and clinical data. We evaluated baseline factors related to the presence of comorbidities and the association between comorbidities and the clinical course of MS and the time to the first treatment switch.
The study cohort included 2,076 patients. Data on comorbidities were available for 1,877/2,076 patients (90.4%). A total of 449/1,877 (23.9%) patients had at least 1 comorbidity at MS diagnosis. Age at diagnosis (odds ratio 1.05, 95% confidence interval [CI] 1.04–1.06; p < 0.001) was the only baseline factor independently related to the presence of comorbidities. Comorbidities were not significantly associated with the choice of the first disease-modifying treatment, but were significantly associated with higher risk to switch from the first treatment due to intolerance (hazard ratio 1.42, CI 1.07–1.87; p = 0.014). Association of comorbidities with risk of switching for intolerance was significantly heterogeneous among treatments (interferon β, glatiramer acetate, natalizumab, or fingolimod; interaction test, p = 0.04).
Comorbidities at diagnosis should be taken into account at the first treatment choice because they are associated with lower persistence on treatment.
To examine the effects of disease activity, disability, and disease-modifying therapies (DMTs) on serum neurofilament light (NFL) and the correlation between NFL concentrations in serum and CSF in multiple sclerosis (MS).
NFL concentrations were measured in paired serum and CSF samples (n = 521) from 373 participants: 286 had MS, 45 had other neurologic conditions, and 42 were healthy controls (HCs). In 138 patients with MS, the serum and CSF samples were obtained before and after DMT treatment with a median interval of 12 months. The CSF NFL concentration was measured with the UmanDiagnostics NF-light enzyme-linked immunosorbent assay. The serum NFL concentration was measured with an in-house ultrasensitive single-molecule array assay.
In MS, the correlation between serum and CSF NFL was r = 0.62 (p < 0.001). Serum concentrations were significantly higher in patients with relapsing-remitting MS (16.9 ng/L) and in patients with progressive MS (23 ng/L) than in HCs (10.5 ng/L, p < 0.001 and p < 0.001, respectively). Treatment with DMT reduced median serum NFL levels from 18.6 (interquartile range [IQR] 12.6–32.7) ng/L to 15.7 (IQR 9.6–22.7) ng/L (p < 0.001). Patients with relapse or with radiologic activity had significantly higher serum NFL levels than those in remission (p < 0.001) or those without new lesions on MRI (p < 0.001).
Serum and CSF NFL levels were highly correlated, indicating that blood sampling can replace CSF taps for this particular marker. Disease activity and DMT had similar effects on serum and CSF NFL concentrations. Repeated NFL determinations in peripheral blood for detecting axonal damage may represent new possibilities in MS monitoring.
To study the effect of pregnancy on the frequency of neuromyelitis optica spectrum disorder (NMOSD) relapse and evaluate rates of pregnancy-related complications in an international multicenter setting.
We administered a standardized survey to 217 women with NMOSD from 7 medical centers and reviewed their medical records. We compared the annualized relapse rate (ARR) during a baseline period 2 years prior to a participant's first pregnancy to that during pregnancy and to the 9 months postpartum. We also assessed pregnancy-related complications.
There were 46 informative pregnancies following symptom onset in 31 women with NMOSD. Compared to baseline (0.17), ARR was increased both during pregnancy (0.44; p = 0.035) and during the postpartum period (0.69; p = 0.009). The highest ARR occurred during the first 3 months postpartum (ARR 1.33). A total of 8 of 76 (10.5%) with onset of NMOSD prior to age 40 experienced their initial symptom during the 3 months postpartum, 2.9 times higher than expected.
The postpartum period is a particularly high-risk time for initial presentation of NMOSD. In contrast to published observations in multiple sclerosis, in neuromyelitis optica, relapse rate during pregnancy was also increased, although to a lesser extent than after delivery.
To demonstrate single abobotulinumtoxinA injection efficacy in lower limb vs placebo for adults with chronic hemiparesis and assess long-term safety and efficacy of repeated injections.
In a multicenter, double-blind, randomized, placebo-controlled, single-cycle study followed by a 1-year open-label, multiple-cycle extension, adults ≥6 months after stroke/brain injury received one lower limb injection (abobotulinumtoxinA 1,000 U, abobotulinumtoxinA 1,500 U, placebo) followed by ≤4 open-label cycles (1,000, 1,500 U) at ≥12-week intervals. Efficacy measures included Modified Ashworth Scale (MAS) in gastrocnemius–soleus complex (GSC; double-blind primary endpoint), physician global assessment (PGA), and comfortable barefoot walking speed. Safety was the open-label primary endpoint.
After a single injection, mean (95% confidence interval) MAS GSC changes from baseline at week 4 (double-blind, n = 381) were as follows: –0.5 (–0.7 to –0.4) (placebo, n = 128), –0.6 (–0.8 to –0.5) (abobotulinumtoxinA 1,000 U, n = 125; p = 0.28 vs placebo), and –0.8 (–0.9 to –0.7) (abobotulinumtoxinA 1,500 U, n = 128; p = 0.009 vs placebo). Mean week 4 PGA scores were as follows: 0.7 (0.5, 0.9) (placebo), 0.9 (0.7, 1.1) (1,000 U; p = 0.067 vs placebo), and 0.9 (0.7, 1.1) (1,500 U; p = 0.067); walking speed was not significantly improved vs placebo. At cycle 4, week 4 (open-label), mean MAS GSC change reached –1.0. Incremental improvements in PGA and walking speed occurred across open-label cycles; by cycle 4, week 4, mean PGA was 1.9, and walking speed increased +25.3% (17.5, 33.2), with 16% of participants walking >0.8 m/s (associated with community mobility; 0% at baseline). Tolerability was good and consistent with the known abobotulinumtoxinA safety profile.
In chronic hemiparesis, single abobotulinumtoxinA (Dysport Ipsen) administration reduced muscle tone. Repeated administration over a year was well-tolerated and improved walking speed and likelihood of achieving community ambulation.
NCT01249404, NCT01251367.
The double-blind phase of this study provides Class I evidence that for adults with chronic spastic hemiparesis, a single abobotulinumtoxinA injection reduces lower extremity muscle tone.
To compare weight change over time in patients with Parkinson disease (PD), those with atypical parkinsonism, and matched controls; to identify baseline factors that influence weight loss in parkinsonism; and to examine whether it predicts poor outcome.
We analyzed data from the Parkinsonism Incidence in North-East Scotland (PINE) study, an incident, population-based prospective cohort of parkinsonian patients and age- and sex-matched controls with annual follow-up. Mixed-model analysis described weight change in patients with PD, those with atypical parkinsonism, and controls. Baseline determinants of sustained clinically significant weight loss (>5% loss from baseline) and associations between early sustained weight loss and death, dementia, and dependency in parkinsonism were studied with Cox regression.
A total of 515 participants (240 controls, 187 with PD, 88 with atypical parkinsonism) were followed up for a median of 5 years. At diagnosis, atypical parkinsonian patients had lower body weights than patients with PD, who were lighter than controls. Patients with PD lost weight more rapidly than controls, and weight loss was most rapid in atypical parkinsonism. After multivariable adjustment for potential confounders, only age was independently associated with sustained clinically significant weight loss (hazard ratio [HR] for 10-year age increase 1.83, 95% confidence interval [CI] 1.44–2.32). Weight loss occurring within 1 year of diagnosis was independently associated with increased risk of dependency (HR 2.11, 95% CI 1.00–4.42), dementia (HR 3.23, 95% CI 1.40–7.44), and death (HR 2.23, 95% CI 1.46–3.41).
Weight loss occurs in early parkinsonism and is greater in atypical parkinsonism than in PD. Early weight loss in parkinsonism has prognostic significance, and targeted dietary interventions to prevent it may improve long-term outcomes.
To clarify the temporal relationship between systemic inflammation and neurodegeneration, we examined whether a higher level of circulating inflammatory markers during midlife was associated with smaller brain volumes in late life using a large biracial prospective cohort study.
Plasma levels of systemic inflammatory markers (fibrinogen, albumin, white blood cell count, von Willebrand factor, and Factor VIII) were assessed at baseline in 1,633 participants (mean age 53 [5] years, 60% female, 27% African American) enrolled in the Atherosclerosis Risk in Communities Study. Using all 5 inflammatory markers, an inflammation composite score was created for each participant. We assessed episodic memory and regional brain volumes, using 3T MRI, 24 years later.
Each SD increase in midlife inflammation composite score was associated with 1,788 mm3 greater ventricular (p = 0.013), 110 mm3 smaller hippocampal (p = 0.013), 519 mm3 smaller occipital (p = 0.009), and 532 mm3 smaller Alzheimer disease signature region (p = 0.008) volumes, and reduced episodic memory (p = 0.046) 24 years later. Compared to participants with no elevated (4th quartile) midlife inflammatory markers, participants with elevations in 3 or more markers had, on average, 5% smaller hippocampal and Alzheimer disease signature region volumes. The association between midlife inflammation and late-life brain volume was modified by age and race, whereby younger participants and white participants with higher levels of systemic inflammation during midlife were more likely to show reduced brain volumes subsequently.
Our prospective findings provide evidence for what may be an early contributory role of systemic inflammation in neurodegeneration and cognitive aging.
To determine whether baseline clinical and MRI features predict rate of clinical decline in patients with progressive apraxia of speech (AOS).
Thirty-four patients with progressive AOS, with AOS either in isolation or in the presence of agrammatic aphasia, were followed up longitudinally for up to 4 visits, with clinical testing and MRI at each visit. Linear mixed-effects regression models including all visits (n = 94) were used to assess baseline clinical and MRI variables that predict rate of worsening of aphasia, motor speech, parkinsonism, and behavior. Clinical predictors included baseline severity and AOS type. MRI predictors included baseline frontal, premotor, motor, and striatal gray matter volumes.
More severe parkinsonism at baseline was associated with faster rate of decline in parkinsonism. Patients with predominant sound distortions (AOS type 1) showed faster rates of decline in aphasia and motor speech, while patients with segmented speech (AOS type 2) showed faster rates of decline in parkinsonism. On MRI, we observed trends for fastest rates of decline in aphasia in patients with relatively small left, but preserved right, Broca area and precentral cortex. Bilateral reductions in lateral premotor cortex were associated with faster rates of decline of behavior. No associations were observed between volumes and decline in motor speech or parkinsonism.
Rate of decline of each of the 4 clinical features assessed was associated with different baseline clinical and regional MRI predictors. Our findings could help improve prognostic estimates for these patients.
To quantify the risk of intracranial bleeds (ICBs) associated with new use of prophylactic low-dose aspirin using a population-based primary care database in the United Kingdom.
A cohort of new users of low-dose aspirin (75–300 mg; n = 199,079) aged 40–84 years and a 1:1 matched cohort of nonusers of low-dose aspirin at baseline were followed (maximum 14 years, median 5.4 years) to identify incident cases of ICB, with validation by manual review of patient records or linkage to hospitalization data. Using 10,000 frequency-matched controls, adjusted rate ratios (RRs) with 95% confidence intervals (CIs) were calculated for current low-dose aspirin use (0–7 days before the index date [ICB date for cases, random date for controls]); reference group was never used.
There were 1,611 cases of ICB (n = 743 for intracerebral hemorrhage [ICH], n = 483 for subdural hematoma [SDH], and n = 385 for subarachnoid hemorrhage [SAH]). RRs (95% CI) were 0.98 (0.84–1.13) for all ICB, 0.98 (0.80–1.20) for ICH, 1.23 (0.95–1.59) for SDH, and 0.77 (0.58–1.01) for SAH. No duration of use or dose–response association was apparent. RRs (95% CI) for ≥1 year of low-dose aspirin use were 0.90 (0.72–1.13) for ICH, 1.20 (0.91–1.57) for SDH, and 0.69 (0.50–0.94) for SAH.
Low-dose aspirin is not associated with an increased risk of any type of ICB and is associated with a significantly decreased risk of SAH when used for ≥1 year.
To systematically review the evidence and make recommendations with regard to diagnostic utility of cervical and ocular vestibular evoked myogenic potentials (cVEMP and oVEMP, respectively). Four questions were asked: Does cVEMP accurately identify superior canal dehiscence syndrome (SCDS)? Does oVEMP accurately identify SCDS? For suspected vestibular symptoms, does cVEMP/oVEMP accurately identify vestibular dysfunction related to the saccule/utricle? For vestibular symptoms, does cVEMP/oVEMP accurately and substantively aid diagnosis of any specific vestibular disorder besides SCDS?
The guideline panel identified and classified relevant published studies (January 1980–December 2016) according to the 2004 American Academy of Neurology process.
Level C positive: Clinicians may use cVEMP stimulus threshold values to distinguish SCDS from controls (2 Class III studies) (sensitivity 86%–91%, specificity 90%–96%). Corrected cVEMP amplitude may be used to distinguish SCDS from controls (2 Class III studies) (sensitivity 100%, specificity 93%). Clinicians may use oVEMP amplitude to distinguish SCDS from normal controls (3 Class III studies) (sensitivity 77%–100%, specificity 98%–100%). oVEMP threshold may be used to aid in distinguishing SCDS from controls (3 Class III studies) (sensitivity 70%–100%, specificity 77%–100%). Level U: Evidence is insufficient to determine whether cVEMP and oVEMP can accurately identify vestibular function specifically related to the saccule/utricle, or whether cVEMP or oVEMP is useful in diagnosing vestibular neuritis or Ménière disease. Level C negative: It has not been demonstrated that cVEMP substantively aids in diagnosing benign paroxysmal positional vertigo, or that cVEMP or oVEMP aids in diagnosing/managing vestibular migraine.