Patient decision aid based on multi-criteria decision analysis for disease-modifying drugs for multiple sclerosis: prototype development.

BACKGROUND: Since decision making about treatment with disease-modifying drugs (DMDs) for multiple sclerosis (MS) is preference sensitive, shared decision making between patient and healthcare professional should take place. Patient decision aids could support this shared decision making process by providing information about the disease and the treatment options, to elicit the patient's preference and to support patients and healthcare professionals in discussing these preferences and matching them with a treatment. Therefore, a prototype of a patient decision aid for MS patients in the Netherlands-based on the principles of multi-criteria decision analysis (MCDA) -was developed, following the recommendations of the International Patient Decision Aid Standards. MCDA was chosen as it might reduce cognitive burden of considering treatment options and matching patient preferences with the treatment options. RESULTS: After determining the scope to include DMDs labelled for relapsing-remitting MS and clinically isolated syndrome, users' informational needs were assessed using focus groups (N = 19 patients) and best-worst scaling surveys with patients (N = 185), neurologists and nurses (N = 60) to determine which information about DMDs should be included in the patient decision aid. Next, an online format and computer-based delivery of the patient decision aid was chosen to enable embedding of MCDA. A literature review was conducting to collect evidence on the effectiveness and burden of use of the DMDs. A prototype was developed next, and alpha testing to evaluate its comprehensibility and usability with in total thirteen patients and four healthcare professionals identified several issues regarding content and framing, methods for weighting importance of criteria in the MCDA structure, and the presentation of the conclusions of the patient decision aid ranking the treatment options according to the patient's preferences. Adaptations were made accordingly, but verification of the rankings provided, validation of the patient decision aid, evaluation of the feasibility of implementation and assessing its value for supporting shared decision making should be addressed in further development of the patient decision aid. CONCLUSION: This paper aimed to provide more transparency regarding the developmental process of an MCDA-based patient decision aid for treatment decisions for MS and the challenges faced during this process. Issues identified in the prototype were resolved as much as possible, though some issues remain. Further development is needed to overcome these issues before beta pilot testing with patients and healthcare professionals at the point of clinical decision-making can take place to ultimately enable making conclusions about the value of the MCDA-based patient decision aid for MS patients, healthcare professionals and the quality of care.

Real-World Results of Ocrelizumab Treatment for Primary Progressive Multiple Sclerosis.

BACKGROUND: Recently, ocrelizumab (Ocrevus®) was approved for the treatment of primary progressive multiple sclerosis (PPMS) based on data from the ORATORIO clinical trial. Real-world data about the clinical effectiveness of ocrelizumab has yet to be gathered. OBJECTIVE: The aim of this study was to provide data about the clinical effectiveness of ocrelizumab for patients diagnosed with PPMS in a real-world setting. METHODS: We conducted a retrospective cohort study of all patients with PPMS who started ocrelizumab treatment (n = 21) in St. Antonius Hospital (Utrecht/Nieuwegein, the Netherlands) between April 2018 and December 31, 2018. Primary outcome was pre- versus post-ocrelizumab disability worsening rate (from 96 weeks prior to first ocrelizumab administration up to 24 weeks post first ocrelizumab administration). RESULTS: Disability worsening rate while on treatment significantly differed (lower) from disability worsening rate in pre-treatment period (Z = -2.81, p ≤ .01). Three out of 17 patients showed a clinically relevant improvement in disability status after treatment start. CONCLUSION: Ocrelizumab can stabilize disability progression in patients with PPMS. Some patients even showed a clinically relevant improvement in disability status. Further research should help to identify which patients benefit most from ocrelizumab.

A tumefactive demyelinating lesion in a person with MS after five years of fingolimod.

A 38-year-old man with relapsing remitting multiple sclerosis (RRMS) developed a tumefactive demyelinating lesion (TDL) after being clinically and radiologically stable on fingolimod for the last five years. TDLs in MS tend to occur early on in the disease and are uncommon in longstanding MS. Compared to other immune modifying drugs used in MS, there is a relatively high and still increasing number of reports describing the development of TDL under treatment with fingolimod, suggesting a causal relation.

[Contribution to quality of care or caught in a digital labyrinth? Experience with electronic records of patients receiving long-term mental health care]. / Kwaliteitsverbetering of digitaal doolhof? Praktijkervaring met het elektronisch patiëntendossier bij langdurige behandelingen in de ggz.

BACKGROUND: In recent years electronic health records (EHRs) have been introduced on a large scale into mental health care. EHRs have a great number of advantages, one of the main ones being readability. However, very little attention seems to have been paid to the potential disadvantages and risks associated with EHRs. AIM: To point to some of the disadvantages and risks of EHRs, in their present form, particularly in relation to the care of patients with severe mental illness (SMI). METHOD: On the basis of clinical experience and relevant literature, we discuss some of the disadvantages and risks associated with EHRs in their current form. RESULTS: In long-term, multidisciplinary and complex treatments of patients with SMI, EHRs in their current form fail to provide the psychiatrist with an adequate overview of the treatment process. This is largely due to the way they are designed: an ever-increasing quantity of information about complex treatment stored in separate files that can only be accessed individually and that contain free text. In mental health care the introduction of new technology, unlike the introduction of new drugs, seems to occur without structured surveillance of the disadvantages and risks involved. CONCLUSION: EHRs need to be re-designed at the earliest opportunity.

Genotoxic exposure: novel cause of selection for a functional ΔN-p53 isoform.

The p53 gene is frequently mutated in cancers and it is vital for cell cycle control, homeostasis and carcinogenesis. We describe a novel p53 mutational spectrum, different to those generally observed in human and murine tumors. Our study shows a high prevalence of nonsense mutations in the p53 N terminus of 2-acetylaminofluorene (2-AAF)-induced urinary bladder tumors. These nonsense mutations forced downstream translation initiation at codon 41 of Trp53, resulting in the aberrant expression of the p53 isoform ΔN-p53 (or p44). We propose a novel mechanism for the origination and the selection for this isoform. We show that chemical exposure can act as a novel cause of selection for this truncated protein. In addition, our data suggest that the occurrence of ΔN-p53 accounts, at least in mice, for a cancer phenotype. We also show that gene expression profiles of embryonic stem (ES) cells carrying the ΔN-p53 isoform in a p53-null background are divergent from p53 knockout ES cells, and therefore postulate that ΔN-p53 itself has functional transcriptional properties.

Associations between patterns of EEG abnormalities and diagnosis in a large memory clinic cohort.

AIM: To describe associations of abnormalities in the electroencephalogram (EEG) with the most prevalent diagnoses in a memory clinic cohort. METHODS: Associations between visual EEG findings and diagnoses in 1,116 consecutive patients [382 Alzheimer's disease (AD), 274 subjective complaints, 190 mild cognitive impairment (MCI), 118 psychiatric disorder, 61 frontotemporal lobar degeneration, 53 vascular dementia (VaD), 38 dementia with Lewy bodies (DLB)] were determined by prevalence ratio (PR). RESULTS: Diagnoses of subjective complaints [PR = 1.6; 95% confidence interval (CI) = 1.4-1.9] and psychiatric disorder (1.4; 95% CI = 1.1-1.9) were associated with a normal EEG, while subjects with both focal and diffuse EEG disturbances were more likely to have DLB (3.5; 95% CI = 2.1-5.6), VaD (2.3; 95% CI = 1.4-3.6) or AD (1.5; 95% CI = 1.3-1.8). Subjects with only diffuse EEG abnormalities were more likely to have AD (PR = 1.5; 95% CI = 1.3-1.9). The prevalence of MCI was higher among those with only focal EEG abnormalities (PR = 1.3; 95% CI = 1.0-1.7). CONCLUSIONS: A normal EEG argues for subjective complaints or psychiatric diagnosis. An EEG with only focal abnormalities supports MCI. An EEG with only diffuse abnormalities argues for AD. An EEG with both focal and diffuse abnormalities argues for DLB, VaD or AD.

Value of health-related quality of life to predict disability course in multiple sclerosis.

OBJECTIVE: To determine the value of health-related quality of life (HRQoL) to predict change in disability status in patients with multiple sclerosis (MS). METHODS: Over a 5-year period, data were collected on HRQoL (Medical Outcomes Study Short Form-36 Health Survey) and disability status (Expanded Disability Status Scale) from a heterogeneous group of 81 Dutch-speaking patients with MS. RESULTS: Multivariate logistic regression analysis showed that HRQoL in the domains of Physical Functioning and Role-Physical Functioning is a significant predictor of change in disability status. CONCLUSIONS: A patient's subjectively perceived health-related quality of life may not be only a clinically and psychosocially meaningful outcome per se but may also be a predictor of objective outcomes such as change in disability status over a substantial period of time.

Multiple Sclerosis Impact Scale (MSIS-29): relation to established measures of impairment and disability.

OBJECTIVE: To validate the newly developed Multiple Sclerosis Impact Scale (MSIS-29) in a large, well characterized, independent group of MS patients by investigating the relation between the MSIS-29 and the Guy's Neurological Disability Scale (GNDS), the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC). METHODS: Two hundred MS patients were recruited at our outpatient department. At the same visit GNDS, EDSS, MSFC and MSIS-29 were assessed. Data obtained from GNDS, EDSS and MSFC assessment were compared to both physical and psychological impact scores of the MSIS-29. In addition the contribution of GNDS subcategories, EDSS functional systems and MSFC components to the physical and psychological impact scores of the MSIS-29 was studied. RESULTS: Median scores were 37.5 for the physical and 22.2 for the psychological impact score of the MSIS-29, 13.0 for GNDS and 4.0 for EDSS. Mean MSFC was 0.07. The physical impact score showed good correlations with both GNDS (0.79) and EDSS (0.68) and a moderate correlation with the MSFC (-0.53). The psychological impact score showed weak correlations with EDSS (0.22) and MSFC (-0.30) and a moderately strong correlation with the GNDS (0.58). In 50 (25%) patients, scores on physical and psychological impact scales diverted, i.e., a relative high score on one scale combined with a relative low score on the other scale. This was related to the clinical disease course. CONCLUSION: Our study supports the use of the MSIS-29 as a measure for the assessment of physical impact of MS on normal daily life. In addition, our data provides a deeper understanding of the factors that determine both physical and psychological disease impact. Discrepancies between the latter two aspects deserve further attention.

The patient's perception of a (reliable) change in the Multiple Sclerosis Functional Composite.

OBJECTIVE: To prospectively characterize the relation between two-year changes in functional impairment as measured by the Multiple Sclerosis Functional Composite (MSFC) and changes in patient perceived disability as measured by the Guy's Neurological Disability Scale (GNDS). METHODS: One hundred and eighty-eight patients with multiple sclerosis (MS) were recruited at our outpatient clinic. Impairment and disability were assessed using the MSFC and GNDS at baseline and follow-up. Longitudinal correlations were studied between changes in MSFC and GNDS and their corresponding components. We also studied changes in GNDS in relation to what can be classified as a reliable change in MSFC; for example, 20% change in each MSFC component or a change of 0.5 in total MSFC score. In addition, we studied the change in total number of GNDS subcategories with a score of 3 or higher in relation to the predefined MSFC changes, these subcategories being indicative of the requirement for help by another person. RESULTS: Despite good cross-sectional correlations between MSFC and GNDS, no significant correlation was found between longitudinal changes in MSFC and GNDS. Analysing the change in GNDS in relation to the predefined MSFC changes shows that GNDS changes are nicely rank ordered when more stringent definitions of reliable change were applied. In addition, analysing the number of GNDS subcategories scored 3 or higher indicate that there is a profile of worsening on the MSFC being associated with increase in the amount of help required from others. CONCLUSION: Our longitudinal data suggest that a reliable change is associated with a likewise change in patient perceived disability, the smallest reliable change being identified by at least 20% change in each MSFC component.

Decreased levels of the brain specific 24S-hydroxycholesterol and cholesterol precursors in serum of multiple sclerosis patients.

The serum concentration of 24S-hydroxycholesterol reflecting brain cholesterol turnover may be a possible marker for neurodegeneration and demyelination in multiple sclerosis. Serum was analyzed for cholesterol precursors and oxysterols in multiple sclerosis patients of different clinical subtypes (n=20 each subtype) and in 37 healthy controls. Serum 24S-hydroxycholesterol levels were lower in primary progressive and in older relapsing remitting multiple sclerosis patients. Furthermore, serum levels of lathosterol were decreased in all clinical subtypes. The results are important given recent interest in statin treatment in multiple sclerosis, which will further decrease the cholesterol precursor and oxysterol levels. The decreased levels of brain specific and peripheral sterols indicate a role for cholesterol homeostasis in relation to the pathology of multiple sclerosis, at least in the primary progressive clinical subtype.

Immunomodulatory effects of orally administered cannabinoids in multiple sclerosis.

Cannabinoids can modulate the function of immune cells. We here present the first human in vivo study measuring immune function in 16 MS patients treated with oral cannabinoids. A modest increase of TNF-alpha in LPS-stimulated whole blood was found during cannabis plant-extract treatment (p=0.037), with no change in other cytokines. In the subgroup of patients with high adverse event scores, we found an increase in plasma IL-12p40 (p=0.002). The results suggest pro-inflammatory disease-modifying potential of cannabinoids in MS.

One year changes in disability in multiple sclerosis: neurological examination compared with patient self report.

OBJECTIVE: To characterise prospectively the relation between one year changes in neurologist rating of neurological exam abnormalities as measured by the Expanded Disability Status Scale (EDSS) and changes in patient perceived disability as measured by the Guy's Neurological Disability Scale (GNDS) in patients with multiple sclerosis. METHODS: Two hundred and fifty patients with MS were recruited at an outpatient clinic. Disability at baseline and one year follow-up was assessed using the EDSS and GNDS. Correlations between change in EDSS, GNDS-sum score, Functional Systems and GNDS subcategories were studied as well as the significance of changes in EDSS associated with changes in perceived disability. RESULTS: The correlation between one year changes in EDSS versus GNDS was substantially lower (0.19) than cross-sectional correlations between EDSS and GNDS either at baseline (0.62) or at follow-up (0.77). Notably, changes in functional system scores that are based on neurological examination are poorly or not at all correlated with changes in disability as perceived by the patient. Analysing the impact of a significant worsening in EDSS-score, a commonly applied outcome criterion in clinical trials, we found that this was associated with significant worsening, insignificant change, and significant improvement in the patients' perceived disability in 45%, 39% and 15% of patients, respectively. CONCLUSION: Patients' perception of change in disability differs not only quantitatively but also qualitatively from that of an examining physician. This seems to be due both to the fact that there are true differences in change as perceived by the patient and that measured by the physician and to the fact that changes in many dimensions of disability that are relevant to the patient have no measurable impact on the EDSS.

The INTERMED: a screening instrument to identify multiple sclerosis patients in need of multidisciplinary treatment.

OBJECTIVE: To analyse the value of the INTERMED, a screening instrument to assess case complexity, compared with the Expanded Disability Status Scale (EDSS) and the Guy's Neurological Disability Scale (GNDS) to identify multiple sclerosis (MS) patients in need of multidisciplinary treatment. METHODS: One hundred MS patients underwent INTERMED, EDSS, and GNDS examinations. Patient care needs were assessed by a multidisciplinary team and a goal oriented treatment plan was defined. Correlations between INTERMED, individual INTERMED domains, EDSS, GNDS sum score, and total number of proposed disciplines involved in the treatment plan were studied. RESULTS: Mean (SD) age was 40.6 (10.1) years. Median scores were 14.0 for the INTERMED, 4.0 for the EDSS, and 13.5 for the GNDS sum score. Moderate correlations were found between the INTERMED sum score and EDSS (r=0.59) and GNDS sum score (r=0.60). The number of disciplines as proposed by the multidisciplinary team showed the highest statistically significant correlation with the INTERMED sum score (r=0.41) compared with EDSS (r=0.32) and GNDS sum score (r=0.34). No significant or only weak correlations were found between the psychological domain of the INTERMED and EDSS or GNDS. CONCLUSION: The findings in this study show that there is an additional value of the INTERMED compared with the EDSS and GNDS in identifying MS patients in need of multidisciplinary treatment. The INTERMED domains show the area of the patient's vulnerability and care needs: especially the INTERMED's psychological and social domains may guide the clinician to deal with specific problems that complicate healthcare delivery.

Cerebral volume changes in multiple sclerosis patients treated with high-dose intravenous methylprednisolone.

OBJECTIVE: Multiple sderosis (MS) patients develop varying degrees of cerebral atrophy, which may already begin at disease onset The purpose of this study is to examine the effect of steroid treatment on cerebral volume in MS patients. METHODS: Thirty-five MS patients participating in a clinical trial of oral interferon beta, which induded monthly MRI, were included in this study. They suffered from an acute relapse and were treated with intravenous methylprednisolone (IV-MP); 13 of the patients were treated with oral prednisolone tapering after IV-MP. The last MRI scan before and the first (and second for oral tapering patients) scan after IV-MP treatment were used for measuring parenchymal fraction (PF) and ventricular fraction (VF). Changes in PF and VF were analysed using Student's t test. RESULTS: For the total population no significant changes in PF or VF were found. However, the subgroup of patients receiving oral tapering after IV-MP showed changes, compatible with atrophy in both PF and VF, that were significant immediately after IV-MP treatment and still persisted (though not statistically significant anymore) after a mean interval of 30 days. The magnitude of these changes was about the same as the annual change in cerebral volume as reported in natural history studies. CONCLUSION: Our data indicate that short courses of intravenous steroids (restricted to three or five days) have no major impact, whereas prolonged treatment with oral tapering does significantly affect brain volume. These findings are important for longitudinal studies and clinical trials in which brain volume is used as an outcome measure.

Safety, tolerability, and efficacy of orally administered cannabinoids in MS.

The authors conducted a randomized, double-blind, placebo-controlled, twofold crossover study in 16 patients with MS who presented with severe spasticity to investigate safety, tolerability, and efficacy of oral Delta(9)-Tetrahydrocannabinol (THC) and Cannabis sativa plant extract. Both drugs were safe, but adverse events were more common with plant-extract treatment. Compared with placebo, neither THC nor plant-extract treatment reduced spasticity. Both THC and plant-extract treatment worsened the participant's global impression.

Differential treatment effect on measures of neurologic exam, functional impairment and patient self-report in multiple sclerosis.

OBJECTIVE: To determine the relative sensitivity of the Expanded Disability Status Scale (EDSS), the newly developed MS Functional Composite (MSFC) and the Guy's Neurological Disability Scale (GNDS) to changes in the neurological condition of Multiple Sclerosis (MS) patients induced by treatment with intravenous methylprednisolone (IV-MP). METHODS: Sixty MS patients were treated with IV-MP. On the first day of treatment patients were trained for the three domains of the MSFC; on the second day baseline data were obtained for all measurements. Follow-up data were obtained 6-8 weeks after IV-MP treatment RESULTS: Significant changes were found for both EDSS and GNDS. Remarkably, the improvements on the GNDS were mainly due to changes in the subcategories cognition, speech, fatigue and 'others'. No significant change was found for the MSFC Forty-seven patient reported a subjective improvement in their condition. Twenty-one patients showed a significant improvement in the EDSS, 28 patients showed a significant improvement in the GNDS and a very small number of significant changes were found on the MSFC (actual number depending on the definition of the reference population). CONCLUSION: The observations in this study show that the relative sensitivity to change in acute or subacute deterioration in MS patients, is low for the MSFC and high for the GNDS. It is obvious from this study that such a treatment can have a differential effect on measurements of functional impairment, rating of neurologic examination and patient self-report.

Comparisons of patient self-report, neurologic examination, and functional impairment in MS.

OBJECTIVE: To compare the recently developed Guy's Neurologic Disability Scale (GNDS), based on patient self-report, with both neurologist rating of neurologic examination abnormalities using the Expanded Disability Status Scale (EDSS) and observations of functional impairment on the Multiple Sclerosis Functional Composite (MSFC) in the assessment of disease impact in MS. METHODS: Two hundred ninety MS patients were recruited at an outpatient clinic. Impairment and disability were assessed using GNDS, EDSS, and MSFC. Correlations between GNDS, EDSS, MSFC, and their corresponding components were studied for the total population, MS phenotypes, and three disability strata. RESULTS: Mean scores were 4.6 (SD, 2.0) for EDSS, 0.0 (SD, 0.8) for MSFC, and 14.6 (SD, 7.9) for GNDS. Good correlations were found between GNDS and EDSS (r = 0.73), between GNDS and MSFC (r = -0.68), and between different subcategories of the GNDS and EDSS, MSFC, and their corresponding components. Remarkably good correlations were found between lower limb function and all three scales. Poor correlations were also found, especially between different measurements focusing on cognitive function. CONCLUSION: The good correlations between GNDS and both EDSS and MSFC were mainly due to the importance of spinal-cord-related neurologic functions in all three scoring systems. A marked discrepancy was found for the assessment of cognition between objective measurements and subjective complaints. Because patients' self-reporting correlates well with results of physical examination, GNDS can offer a valuable way to measure disease impact in MS. However, GNDS is not an adequate screen of cognitive dysfunction.

The novel MMS-inducible gene Mif1/KIAA0025 is a target of the unfolded protein response pathway.

In a search for genes induced by DNA-damaging agents, we identified two genes that are activated by methyl methanesulfonate (MMS). Expression of both genes is regulated after endoplasmic reticulum (ER) stress via the unfolded protein response (UPR) pathway. The first gene of those identified is the molecular chaperone BiP/GRP78. The second gene, Mif1, is identical to the anonymous cDNA KIAA0025. Treatment with the glycosylation inhibitor tunicamycin both enhances the synthesis of Mif1 mRNA and protein. The Mif1 5' flanking region contains a functional ER stress-responsive element which is sufficient for induction by tunicamycin. MMS, on the other hand, activates Mif1 via an UPR-independent pathway. The gene encodes a 52 kDa protein with homology to the human DNA repair protein HHR23A and contains an ubiquitin-like domain. Overexpressed Mif1 protein is localized in the ER.