Background:
Patients with multiple sclerosis (MS) and clinically isolated syndrome (CIS) may show alterations of retinal layer architecture as measured by optical coherence tomography. Little is ...known about changes in the retinal vascular network during MS.
Objective:
To characterize retinal vessel structures in patients with MS and CIS and to test for associations with MS disease activity.
Method:
In all, 42 patients with MS or CIS and 50 healthy controls underwent retinal optical coherence tomography angiography (OCT-A) with analysis of the superficial and deep vascular plexuses and the choriocapillaries. We tested OCT-A parameters for associations with retinal layer volumes, history of optic neuritis (ON), and the retrospective disease activity.
Results:
Inner retinal layer volumes correlated positively with the density of both the superficial and deep vascular plexuses. Eyes of MS/CIS patients with a history of ON revealed reduced vessel densities of the superficial and deep vascular plexuses as compared to healthy controls. Higher choriocapillary vessel densities were associated with ongoing inflammatory disease activity during 24 months prior to OCT-A examination in MS and CIS patients.
Conclusion:
Optic neuritis is associated with rarefaction of the superficial and deep retinal vessels. Alterations of the choriocapillaries might be linked to disease activity in MS.
To determine the prevalence of antibodies to Epstein-Barr virus (EBV) in a large cohort of patients with early multiple sclerosis (MS).
Serum samples were collected from 901 patients with a ...clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS) participating in the German National MS cohort, a prospective cohort of patients with early MS with stringent inclusion criteria. Epstein-Barr nuclear antigen (EBNA)-1 and viral capsid antigen (VCA) antibodies were measured in diluted sera by chemiluminescence immunoassays (CLIAs). Sera of EBNA-1 and VCA antibody-negative patients were retested undiluted by an EBV IgG immunoblot. For comparison, we retrospectively analysed the EBV seroprevalence across different age cohorts, ranging from 0 to >80 years, in a large hospital population (N=16 163) from Berlin/Northern Germany.
EBNA-1 antibodies were detected by CLIA in 839 of 901 patients with CIS/RRMS. Of the 62 patients without EBNA-1 antibodies, 45 had antibodies to VCA as detected by CLIA. In all of the remaining 17 patients, antibodies to EBV were detected by immunoblot. Altogether, 901 of 901 (100%) patients with CIS/RRMS were EBV-seropositive. EBV seropositivity increased with age in the hospital population but did not reach 100% in any of the investigated age cohorts.
The complete EBV seropositivity in this large cohort of patients with early MS strengthens the evidence for a role of EBV in MS. It also suggests that a negative EBV serology in patients with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS.
Background and aim
Optic neuritis (ON) is a frequent manifestation of multiple sclerosis (MS), traditionally diagnosed clinically and by visually evoked potentials (VEP). However, ON can also be ...assessed by MRI. Here we compare the diagnostic performance of 3D-double inversion recovery-MRI (3D-DIR) and VEPs in patients with definite MS or clinically isolated syndrome (CIS).
Methods
39 patients and 17 healthy controls were studied. Whole-brain-3D-DIR images (3T) were independently assessed for DIR-hyperintense optic nerve lesions (DHLs) by two neuroradiologists, and results related to quantitative VEP-parameters.
Results
Interrater concordance for DHLs was high (
κ
= 0.82). No DHLs were observed in controls. In patients, abnormal VEPs, i.e. prolonged latencies, diminished amplitudes or abnormal latency or amplitude differences (re contralateral nerve) of the P100-component, were observed in 22, and DHLs in 32 of 78 optic nerves, the latter including 11 nerves with normal VEPs, 10 without clinical signs or history of ON, and 6 with both normal VEPs and no clinical evidence for ON. Using either abnormal VEPs and/or presence of DHLs and/or clinical evidence for ON as a compound reference criterion of optic nerve affection, sensitivity was significantly higher for 3D-DIR than for VEPs (91%, 95%-CI 77–98% vs. 63%, 95%-CI 45–79%, respectively,
p
= 0.006).
Conclusion
DHLs are highly specific for optic nerve pathology. In the context of MS, 3D-DIR-MRI is a suitable tool to reveal acute or chronic optic nerve lesions and more sensitive than VEPs. The significance of optic nerve involvement in the diagnostic classification of CIS vs. definite MS requires further study.
Background:
Damage of different brain structures has been related to fatigue. Alternatively, functional alterations of central nervous system (CNS) cells by the inflammatory milieu within the CNS may ...be responsible for the development of fatigue.
Aim:
To investigate the effect of structural brain damage and inflammatory cerebrospinal fluid (CSF) changes on fatigue in multiple sclerosis (MS).
Methods:
We determined the association of different clinical, CSF and magnetic resonance imaging (MRI) parameters with prevalence and severity of fatigue, as measured by the Fatigue Scale for Motor and Cognitive Functions in 68 early MS patients (discovery cohort). We validated our findings in two MS cohorts: the MRI validation cohort (N = 233) for the clinical and MRI parameters, and the CSF validation cohort (N = 81) for the clinical and CSF parameters.
Results:
Fatigue was associated with clinical disability. Fatigue did not correlate with any CSF parameter but correlated negatively with total and cortical grey matter volume. However, when controlling for Expanded Disability Status Scale (EDSS) in a multivariate model, these associations lost significance.
Conclusion:
Disability and disease duration best explain fatigue severity but none of the tested MRI or CSF parameter was reliably associated with fatigue.
Biomarkers to estimate long-term outcomes in patients with multiple sclerosis (MS) and to assign patients to individual treatment regimens are urgently needed.
To assess whether retinal layer volumes ...are correlated with immune cell subsets and immunoglobulin indices in the cerebrospinal fluid and whether retinal layer volumes alone or in combination with intrathecal variables are associated with worsening of disease in patients with relapsing-remitting MS.
This observational cohort study included 312 patients with relapsing-remitting MS in 2 independent cohorts (72 patients with short disease duration cohort 1 and 240 patients with longer disease duration cohort 2) treated at a single German university hospital from April 15, 2013, through November 11, 2015.
The common ganglion cell and inner plexiform layer (GCIPL) and inner nuclear layer (INL) volumes were tested for association with the immunoglobulin indices and the frequencies of immune cells in the cerebrospinal fluid (including B cells, T cells, and natural killer cells) (cohort 1). Volumes of GCIPL alone (cohorts 1 and 2) or GCIPL corrected for intrathecal B-cell frequencies (cohort 1) were tested for their association with worsening disability.
A total of 312 patients (212 women 67.9% and 100 men 32.1%; median age, 34.0 years interquartile range (IQR), 28.0-42.0 years) were available for analysis. In cohort 1 (50 women 69.4% and 22 men 30.6%; median age, 31.0 years IQR, 26.3-38.3 years), with short disease durations (median, 1.0 months IQR, 1.0-2.0 months), low GCIPL volumes were associated with increased intrathecal B-cell frequencies (median, 1.96% IQR, 1.45%-4.20%) and intrathecal IgG synthesis (median cerebrospinal fluid/serum IgG index, 0.78 IQR, 0.53-1.07). The INL volumes correlated with the frequencies of intrathecal CD56bright natural killer cells (r = 0.28; P = .007). Individuals with low GCIPL volumes (<1.99 mm3) had a 6.4-fold risk for worsening disability during follow-up compared with patients with higher GCIPL values (95% CI, 1.7-24.2; P = .007). This finding was reproduced in cohort 2 (162 women 67.5% and 78 men 32.5%; median age, 34.0 years IQR, 29.0-42.0 years) consisting of patients with longer disease durations (median, 36.0 months IQR, 21.0-60.0 months) (hazard ratio, 2.4; 95% CI, 1.2-4.8; P = .02). In both cohorts, INL volumes correlated with the prospective increase in T2 lesion load and the number of gadolinium-enhancing lesions.
Retinal layers reflect different aspects of disease activity during MS. Loss of GCIPL is associated with intrathecal B-cell immunity and constitutes an independent risk factor for worsening disability, whereas high INL volumes are associated with activity on magnetic resonance imaging in the brain parenchyma. Thus, retinal optical coherence tomography might be a means to support stratification of patients with MS for different therapeutic regimens.
Background and purpose
New or enlarging T2‐hyperintense white matter lesions (WML) are associated with clinical disease progression in multiple sclerosis (MS). The prognostic value of WML shrinking ...is unclear. Assuming that waning of acute inflammation and repair processes would be the main drivers of WML shrinking, we aimed to assess the prognostic value of WML shrinking in early MS.
Methods
We retrospectively analyzed a cohort of 144 early MS patients with three brain MRI scans at baseline and after 1 and 3 years available. All patients were therapy naïve at baseline and 70.5% of them treated with disease modifying drugs at year 1. We determined the volume of WML shrinking between MRI scans, total WML volumes, number of gadolinium‐enhancing and new WML, white matter (WM) and gray matter volumes at each MRI scan. Clinical disability was measured by Expanded Disability Status Scale. We performed the correlation analyses of WML shrinking with other MRI parameters and clinical outcome.
Results
White matter lesions shrinking was highly variable between patients and correlated with the initial number of gadolinium‐enhancing WML and with WM volume decrease. WML shrinking was not associated with clinical outcome.
Conclusion
We found no indication of a prognostic value of WML shrinking in early MS patients. WML shrinking seems to be related to waning of acute inflammation.
White matter lesion (WML) shrinking is highly variable between multiple sclerosis patients and correlates with markers of acute inflammation and with white matter volume decrease. WML shrinking is not associated with clinical outcome.
Background:
Despite agreement about spinal cord atrophy in progressive forms of multiple sclerosis (MS), data on clinically isolated syndrome (CIS) and relapsing–remitting MS (RRMS) are conflicting.
...Objective:
To determine the onset of spinal cord atrophy in the disease course of MS.
Methods:
Structural brain magnetic resonance imaging (MRI) was acquired from 267 patients with CIS (85) or RRMS (182) and 64 healthy controls (HCs). The upper cervical cord cross-sectional area (UCCA) was determined at the level of C2/C3 by a segmentation tool and adjusted for focal MS lesions. The coefficient of variation (CV) was calculated from all measurements between C2/C3 and 13 mm above as a measure of structural variability.
Results:
Compared to HCs (76.1±6.9 mm2), UCCA was significantly reduced in CIS patients (73.5±5.8 mm2, p=0.018) and RRMS patients (72.4±7.0 mm2, p<0.001). Structural variability was higher in patients than in HCs, particularly but not exclusively in case of focal lesions (mean CV HCs/patients without/with lesions: 2.13%/2.55%/3.32%, all p-values<0.007). UCCA and CV correlated with Expanded Disability Status Scale (EDSS) scores (r =−0.131/0.192, p=0.044/<0.001) and disease duration (r=−0.134/0.300, p=0.039/< 0.001). CV additionally correlated with hand and arm function (r=0.180, p=0.014).
Conclusion:
In MS, cervical cord atrophy already occurs in CIS. In early stages, structural variability may be a more meaningful marker of spinal cord pathology than atrophy.
•To date ocrelizumab is the only PPMS therapy with efficacy in a phase 3 trial.•We provide real-world short-term safety data of ocrelizumab for PPMS treatment.•CUP offered ocrelizumab to 489 German ...patients with PPMS before European approval.•More heterogeneous population (e.g., age, advanced PPMS) than in clinical trials.•Ocrelizumab was generally well-tolerated.
In January 2018, the European Union (EU) approved ocrelizumab in relapsing multiple sclerosis (RMS) and as the first disease-modifying therapy (DMT) for patients with primary progressive multiple sclerosis (PPMS) with efficacy proven in a phase 3 randomised controlled trial. Eleven months prior to the European regulatory approval, a compassionate use programme (CUP) made ocrelizumab available to 489 patients with PPMS in Germany, thereby for the first time providing a therapeutic option to patients with PPMS who could not participate in ocrelizumab studies. Here, we report real-world patient characteristics and short-term safety data of patients with PPMS treated with ocrelizumab in this CUP.
This CUP was initiated in February 2017 – shortly before US Food and Drug administration approval in March 2017 – and ended in January 2018, following ocrelizumab approval in the EU. Adult patients (age ≥18 years) with PPMS who had a positive benefit/risk ratio according to the treating physician were eligible for inclusion at German treatment centres. The main exclusion criteria were current/recent treatment with other immune therapies and unresolved/chronic/active infections. Patients received methylprednisolone and an antihistamine before treatment with intravenous ocrelizumab in 6-month cycles. The first ocrelizumab dose was a 300 mg infusion followed by a second 300 mg infusion 2 weeks later; subsequent doses were delivered as a single 600 mg infusion. Adverse events were reported immediately.
Of 580 requests received from 104 centres, 525 patients met the eligibility criteria. Thirty-five patients did not participate due to withdrawal by the treating physician, and one due to death prior to treatment. A total of 489 patients received at least one 600 mg dose of ocrelizumab (administered as two 300 mg infusions) and 51 received a second dose. Due to termination of the CUP upon marketing authorisation, the maximum follow-up period was 12 months. Median patient age was 52 years (range: 24–73), and 49% were female. Previous immunomodulatory or immunosuppressive therapies had been received by 41% of patients, with the most commonly used being glucocorticoids, mitoxantrone, interferon-β and glatiramer acetate. Patients with a previous malignancy, serious disease or infection (42 patients, 9%) had recovered from this prior to the CUP. Nine serious adverse events and 70 non-serious adverse events were reported in 40 patients. Adverse event categories were generally consistent with the known safety profile of ocrelizumab; one patient had carry-over progressive multifocal leukoencephalopathy (PML) due to previous natalizumab treatment.
This CUP provides first real-world observations of ocrelizumab for the treatment of PPMS in a large patient cohort in Germany, supporting that ocrelizumab is generally well-tolerated in clinical practice. Physicians should be vigilant for early symptoms of PML, as to date, 9 PML cases that were all confounded have been reported in patients treated with ocrelizumab worldwide, with 8 carry-over cases from a prior DMT.
PDF
