Background

Retinal thinning is a biomarker of neuroaxonal degeneration in multiple sclerosis (MS) and is associated with disability progression. Recently, the term PIRA, or progression independent of relapse, has emerged purporting to quantify the proportion of disability worsening due to non-inflammatory neurodegenerative processes.

Objectives

The objective of this study was to determine the association of retinal thinning with PIRA in comparison to traditional physical disability worsening and relapse.

Methods

In a 4-year prospective observational study including 171 relapsing MS (RMS) patients, retinal thinning was determined by annual spectral-domain optical coherence tomography measuring macular-ganglion-cell-and-inner-plexiform-layer(mGCIPL). Physical disability was assessed by expanded disability status scale (EDSS), cognitive disability by the symbol digit modalities test (SDMT). PIRA was defined as either an EDSS or SDMT worsening during the observation period confirmed after 24 weeks with no relapse in the 30 days before or after the disability worsening. Multivariate linear regression models adjusted for sex, age, disease duration and disease-modifying treatment regarding retinal thinning were calculated.

Results

Each PIRA event was associated with a mean additional loss of GCIPL (1.8µm) and pRNFL (1.9µm), similar to the impact of EDSS and SDMT worsening. Overall relapse and relapse without subsequent EDSS worsening did not influence retinal thinning, while a relapse with EDSS worsening was associated with an additional loss of GCIPL (1.3µm) and pRNFL (1.4µm).

Conclusions

PIRA is associated with retinal thinning, likely reflecting non-inflammatory neurodegenerative processes. It might be a clinical measure to identify MS patients with ongoing MS-associated neurodegeneration.

Background

Peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell plus inner plexiform layer (mGCIPL) thinning are markers of neuroaxonal degeneration in relapsing multiple sclerosis (RMS). pRNFL and mGCIPL thinning is more pronounced in patients with physical or cognitive disability progression, while it is reduced by disease-modifying treatment (DMT).

Objectives

The objective of this study was to investigate the potential of retinal layer thinning for prediction of treatment response in RMS.

Methods

In this 4-year prospective observational study on 113 RMS patients, pRNFL and GCIPL were measured at DMT initiation and after 12 (M12) and 24 months (M24) of follow-up by spectral-domain optical coherence tomography (OCT). Inclusion criteria included adherence to DMT for at least 2 years. Patients suffering optic neuritis between baseline and M24 were excluded. Treatment response was defined as absence of 6 month confirmed EDSS progression and Symbol Digit Modalities Test (SDMT) worsening during the observation period. Best possible cut-off values of retinal thinning for predicting treatment response were determined by receiver-operating characteristics (ROC) analyses. Odds ratios (OR) for treatment response were calculated by multivariate logistic regression models correcting for age, sex, disease duration and EDSS/SDMT at baseline.

Results

Thinning of mGCIPL <0.5mm at M24 displayed superior prediction of treatment response (odds ratio [OR] 4.5; 95% confidence interval [CI]: 1.8 – 7.6; p<0.001; specificity 91%, sensitivity 81%) followed by mGCIPL <0.3mm at M12 (OR 3.9; 95% CI: 1.4 – 6.9; p<0.001; specificity 85%, sensitivity 78%) and pRNFL <2mm at M24 (OR 3.7; 95% CI: 1.1 – 6.5; p=0.023; specificity 84%, sensitivity 69%), while pRNFL at M12 was not significantly predictive.

Conclusions

mGCIPL – and to a lesser degree pRNFL – thinning predict physical and cognitive disability progression upon DMT initiation. Pending validation, retinal layer thinning may be a useful and easily accessible biomarker of treatment response in RMS.

Background

There is a growing need to identify the course of aggressive multiple sclerosis (agMS) at an early stage so that affected patients can be treated with suitable disease modifying drugs (DMD). Investigations of treatment patterns in agMS and non-agMS patients are of interest, particularly in the context of the multitude of agMS definitions.

Objectives

We aimed to determine characteristics of DMDs at baseline for comparative analyses of agMS patients and non-agMS patients.

Methods

We included patients from the German Multiple Sclerosis registry who started DMD use between 2010 and 2020 and were assessable on whether they are agMS patients according to a commonly used criterium of reaching EDSS ≥6.0, or by a criterium for highly active MS, i.e. ≥2 relapses during 12 months, or gd+ lesions on MRI. Both were assessed within the first 5 years of disease duration.

Results

7249 patients fulfilled the inclusion criteria. Of these, 860 were identified as agMS. In agMS patients, Interferons (INFs) were the most frequently used DMDs with 34.8% followed by Glatiramer acetate (GLAT, 24.0%), Dimethyl fumarate (DMF, 15.8%), Teriflunomide (TRF, 7.6%), Natalizumab (NTZ, 5.4%), Fingolimod (FTY, 3.9%), Ocrelizumab (OCR, 3.2%), Steroids (STE, 1.8%), and others (3.5%). Regarding patients with non-agMS, INFs were also most frequent with 30.5% followed by GLAT (18.1%), DMF (13.2%), FTY (8.1%), NTZ (7.7%), TRF (7.5%), OCR (5.9%), STE (2.3%), and others (6.7%).

Within 5 years of disease duration, switches to another DMD were observed for 51% of agMS patients whereas only 17% of non-agMS switched to a second DMD. The average time spent on the first DMD was 1.3 (±1.1) years for agMS patients and 3.4 (±3.6) years for non-agMS patients (p<0.001; Mann-Whitney test). With regard to DMD use, significant differences between agMS and non-agMS patients were detected (p<0.001; χ²-test): INFs (p=0.009), GLAT (p<0.001) and DMF (p=0.03) were used significantly more often by agMS patients while FTY (p<0.001), NTZ (p=0.02) and OCR (p=0.002) were used more often by non-agMS patients.

Conclusions

Our analysis showed that in line with the (national) guidelines, the new immunomodulatory treatments are accessible to all MS patients. The patients classified as agMS spent less time on the first DMD than non-agMS patients did. To investigate causal factors in the connection between DMD preference and resulting disease progression, Marginal Structural Models are required, adjusting for relevant time-varying confounders such as patient demography, clinical visit details, MRI, and relapse parameters.

Background

There is a lack of evidence guiding treatment decisions regarding discontinuation of disease-modifying therapy (DMT) in multiple sclerosis (MS)

Objectives

To generate and validate a composite (clinical and MRI-based) score able to identify individual patients with relapsing MS (RMS) with a high risk of experiencing disease reactivation after discontinuation of DMT.

Methods

The study was conducted using a generation and a validation dataset drawn from two separate prospectively collected observational databases. We included RMS patients who received interferon-beta or glatirameracetate for ≥12 months, then discontinued DMT for ≥6 months and had ≥2 years of follow-up available. In the generation sample (n=168), regression analysis was performed to identify clinical or MRI variables independently predicting disease reactivation after DMT discontinuation. A predictive score was calculated using the variables included in the multivariable model. This score was then applied to the validation sample (n=98).

Results

The variables included in the final model as independent predictors of disease reactivation were age at discontinuation (p<0.001), MRI activity at discontinuation (p<0.001), and duration of clinical stability (p<0.001). The resulting score (Vienna Innsbruck DMT discontinuation score based on age, activity on MRI and duration in stable course; VIAADISC) was able to identify patients at high (83-84%), moderate (35-38%) and low risk (7%) of disease reactivation within 5 years after DMT discontinuation both in the generation and in the validation cohorts.

Conclusions

The composite VIAADISC score may be a valuable tool informing patients and neurologists in the face of deciding if and when to discontinue injectable DMTs.

Background

“Spinal pain”, girdle-like dysesthesia, and painful spasms were noted already in earliest disease descriptions in the 18^th century. Nowadays it has become clear that pain is a frequent and one of the most disabling symptoms in these patients. Due to the rarity of NMOSD most previous studies of pain and depression were relatively small or included a mixed population AQP4-IgG-seropositive and seronegative patients, while recent clinical trials clearly indicate that pathogenetic mechanisms are different in these forms.

Objectives

To evaluate prevalence, clinical characteristics and predictive factors of pain, depression and their impact on the quality of life (QoL) in a large European seropositive neuromyelitis optica spectrum disease (NMOSD) cohort.

Methods

We included 166 patients with aquaporin-4-seropositive NMOSD from 13 tertiary referral centers of Neuromyelitis Optica Study Group (NEMOS). Clinical data, including expanded disability status scale and localization of spinal lesions on MRI, were retrieved from the NEMOS database or local electronic patient records. Data on pain, depression and quality of life were captured by self-reporting questionnaires.

Results

125 (75.3%) patients suffered from chronic NMOSD-associated pain. Of these, 65.9% had neuropathic pain, 68.8% reported spasticity-associated pain and 26.4% painful tonic spasms. Number of previous myelitis attacks (OR 1.27, p=0.018) and involved upper thoracic segments (OR 1.31, p=0.018) were the only predictive factors for chronic pain. Interestingly, the latter was specifically associated with spasticity-associated (OR 1.36, p=0.002), but not with a neuropathic pain. 39.8% suffered from depression (moderate to severe in 51.5%). Pain severity (OR 1.81, p<0.001) and especially neuropathic character (OR 3.44, P<0.001) were strongly associated with depression. 70.6% of patients with moderate or severe depression and 42.5% of those with neuropathic pain had no specific medications. 64.2% of those under symptomatic treatment still reported moderate to severe pain. Retrospectively, 39.5% of pain-sufferers reported improvement of pain after start of immunotherapy: 37.3% under rituximab, 40.0% under azathioprine, 33.3% under mycophenolate mofetil and 66.7% under tocilizumab. However, there was no difference in terms of pain prevalence or intensity in patients with different immunotherapies. Pain intensity, walking impairment and depression could explain 56% of the physical QoL variability, while depression was the only factor, explaining 46% of the mental QoL variability.

Conclusions

Myelitis episodes involving upper thoracic segments are main drivers of pain in NMOSD. Although pain intensity was lower than in previous studies, pain and depression remain undertreated and strongly affect QoL. Interventional studies on targeted treatment strategies for pain are urgently needed in NMOSD.

Background

Multiple sclerosis (MS) related disability and sexual dysfunction (SD) are known to lower a patient’s health related quality of life (HRQoL) detrimentally. However, taking a sexual history in routine care is commonly evaded. Furthermore, there is not much knowledge on SD being either an independent symptom or merely a byproduct of other symptoms such as depression or anxiety.

Objectives

To investigate the prevalence of SD in patients with MS and unveil possible associations with disease parameters, depression, anxiety and HRQoL.

Methods

We present results from a cross-sectional study of 93 patients with MS. SD was determined based on the Multiple Sclerosis Intimacy and Sexuality Questionnaire-19 (MSISQ-19) and correlated with physical disability (Expanded disability status scale, EDSS), depression and anxiety (Hospital Anxiety and Depression Scale, HADS), and HRQoL (Multiple Sclerosis Quality of Life-54 questionnaire, MSQoL-54).We present results from a cross-sectional study of 93 patients with MS. SD was determined based on the Multiple Sclerosis Intimacy and Sexuality Questionnaire-19 (MSISQ-19) and correlated with physical disability (Expanded disability status scale, EDSS), depression and anxiety (Hospital Anxiety and Depression Scale, HADS), and HRQoL (Multiple Sclerosis Quality of Life-54 questionnaire, MSQoL-54).

Results

The mean (standard deviation) age in our cohort was 39 (11.4) years and sex distribution was 3:2 (f:m). At the time of enrollment, two thirds of patients had relapsing MS. The median (IQR) EDSS was 2.0 (0-4.5) with one third of patients being rated as 4.0 or higher. SD was reported by 43 (46%) patients on the MSISQ-19. Out of all included patients, 32 (34%) suffered from anxiety and 15 (16%) from depression. In comparison of patients with and without SD, we found that patients affected by SD were significantly more likely to be depressed (28% vs. 6%, p=0.005) and had a higher median [IQR] EDSS (1 [1-3] vs. 4 [1.5-6], p<0.001). HRQoL was significantly poorer in patients with MS suffering from SD (median [IQR] MSQoL-54 scores: physical subscale 52 [41-68] vs. 81 [69-89], p<0.001; mental subscale 50 [38-82] vs. 86 [70-89], p<0.001). Furthermore, SD occurred more frequently in the progressive phase of the disease. We found no associations between sexual functioning and age, sex or MS disease duration. In a multivariate linear regression model, we found the risk for SD to be 18.1-fold higher (95%CI 3.3-31.4, p<0.001) in patients with EDSS≥4, while neither depression nor anxiety were independent predictors of SD.

Conclusions

SD is common among people with MS and should be addressed in clinical routine. The risk for SD is growing substantially with increasing EDSS while being independent of depression and anxiety. SD is clearly associated with poorer HRQoL. Nonetheless, guidelines for a structured approach, patient needs and treatment strategies should be investigated further.