Effects Of Disease-modifying Drugs Research Articles

Effect of disease-modifying drugs for spinal muscular atrophy on the ventilation support of type 1 children

Objective: To summarize the effects of disease-modifying drugs for spinal muscular atrophy (SMA) on the ventilation support of type 1 children after acute respiratory failure. Methods: A case-control study was conducted, including the data of clinical characteristics, medication and ventilation supports of 38 SMA patients of type 1 with pneumonia and acute respiratory failure hospitalized in Children's Hospital Affiliated to Capital Institute of Pediatrics from January 2020 to July 2023. Children were divided into the treatment group and the untreated group based on whether they started and persisted in using Nusinersen or Risdiplam or not before hospitalization. The differences of ventilation support between the 2 groups were analyzed. The children of the treatment group were divided into the improved group and the unimproved group based on whether they could be avoid of prolonged dependence on continuous mechanical ventilation in the next six months after discharge. The differences in clinical characteristics between the two groups were analyzed. T-test and χ2 test were used for comparison. Results: Among the enrolled children, 19 were male and 19 were female. The age was 1.3 (0.6, 2.0) years at the time of hospitalization due to pneumonia. There were 26 cases in the treatment group and 12 cases in the untreated group. The treatment group had a higher proportion of patients without prolonged dependence on continuous mechanical ventilation in the next six months after discharge (69% (18/26) vs. 2/12, χ2=9.10, P<0.05). Eighteen children were improved among the treated group, while 8 children were not. The improved group had a larger age of first onset of acute respiratory failure (1.6 (0.4, 3.4) vs. 0.5 (0.3, 0.7) years, Z=2.07, P<0.05), a longer duration of medication taken before hospitalization (3.6 (2.4, 8.7) vs. 1.2 (1.2, 2.4) months, t=2.74, P<0.05), and a smaller proportion with underlying diseases (1/18 vs. 6/8, χ2=13.58, P<0.05). Conclusions: SMA disease-modifying drugs are useful for type 1 children to avoid of prolonged dependence on continuous mechanical ventilation after acute respiratory failure. The patients who take medication longer, or have acute respiratory failure for the first-time at an older age, or without underlying diseases are more likely to avoid of.

Rehabilitation Strategies for Patients With Spinal Muscular Atrophy in the Era of Disease-Modifying Therapy.

The impact of disease-modifying therapy ranges from cure to no impact with a wide range of intermediates. In cases where the intermediate group reaches a plateau after the acquisition of some muscle strength, it is necessary to set a functional level appropriate for increased motor power and establish a long-term exercise plan to maintain it. As the disease status stabilizes and the life span increases, early nonsurgical interventions are required, such as using a standing frame to prevent joint contracture, applying a spinal brace at the early stage of scoliosis, and maintaining sitting postures that exaggerate lumbar lordosis. In cases where scoliosis and hip displacement occur and progress even after conservative managements are implemented, early referral to surgery should be considered. Oromotor activity and swallowing function are influenced not only by the effects of disease-modifying drugs, but also by post-birth experience and training. Therefore, although the feeding tube cannot be removed, it is necessary to make efforts to simulate the infant feeding development while maintaining partial oral feeding. Since the application period of non-invasive ventilators has increased, it has become more important to prevent long-term complications such as facial abrasion, skin allergy, orthodontic deformities, and maxillary flattening caused by the interface. Dual ventilator mode or interface can also be utilized.

Alternative Endpoints and Models for AD Prevention Trials

AbstractBackgroundThere are several challenges for AD prevention trials. First, the subtle cognitive change in asymptomatic disease stages requires large sample sizes, e.g. 400‐500/arm for two phase 3 confirmatory trials, or 800‐900/arm for a single phase 3 confirmatory trial, using the traditional MMRM. Second, large, international trials may necessitate the use of different tracers for imaging biomarker assessment due to global availability issues, however, statistical models that harmonize tracer differences within clinical trials are still lacking. Third, primary prevention trials using time to event endpoint demands even larger sample sizes, e.g., 1650/arm for TRAILBLAZER‐ALZ 3 with time‐to‐first‐conversion from CDR global 0 to &gt;0 as the outcome. The percentage slowing relative to placebo decline (e.g., lecanemab led to 27% slowing at 18 months) is a popular concept to describe treatment effect. Instead of estimating the absolute difference using MMRM, we proposed to model this percentage treatment effect directly using the percentage or proportional MMRM (pMMRM). pMMRM can harmonize assessments from different tracers by converting the absolute difference into a shared proportional treatment effect across tracers. When using time‐to‐conversion as the primary outcome, instead of using a single event, Cox proportional hazards models for recurrent events can capture the treatment effect after the first event, where a recurrent event is defined as any increment over the previous visit in CDR global.MethodWe first demonstrated that disease modifying treatment effects are essentially proportional retreatment effects. Then, we evaluated the power advantage of pMMRM over MMRM and Cox recurrent events model over single event model through simulations. Finally, we demonstrated how to harmonize data from different tracers using pMMRM.ResultFigure 1 demonstrates that disease modifying treatment effects are like proportional treatment effects, leading to diverged disease progression trajectories and increased absolute differences. Figure 2 shows the power comparison between MMRM and pMMRM. pMMRM led to a power increase up to 30% over MMRM.ConclusionAlternative models such as pMMRM or Cox recurrent event models can yield greater power and pMMRM can harmonize assessment from different tracers, which may help enable global prevention trials in AD with disease modifying drug effects.

The Renal Protective Effect of Sickle Cell Disease-Modifying Drugs

Background Patients affected by sickle cell disease (SCD) often present with renal impairment due to the deleterious effects of polymerized red blood cells at the level of the nephron. The resulting glomerular damage leads to proteinuria as well as increased tubular secretion of creatinine, which in turn allows for the use of the urine protein:creatinine ratio (PCR) to monitor disease progression in SCD patients. Aim We aimed to evaluate the renal protective effect of various disease-modifying therapies via changes in urine PCR. Method This was a retrospective cohort study of patients with SCD (all genotyped, ≥16 years old) at UT Comprehensive Sickle Cell Center during the study period of 2019-2023. Demographics, clinical, and laboratory findings were collected and analyzed. Both the albumin:creatinine ratio (ACR) and PCR are comparable measures of kidney function. We measured PCR at our center due to test availability, and it also allowed the measurement of non-albumin urinary proteins that maybe important for prognosis. PCR was measured once or twice annually. Descriptive statistics are presented in percentages, medians, and interquartile ranges. Changes in urine PCR were calculated based on the difference in initial and recent urine PCR. A positive change means that there was improvement in the most recent urine PCR (i.e., measuring less than the initial urine PCR) or vice versa. An unpaired Student's t test was used to determine the level of significance in differences between initial and recent urine PCR for various disease-modifying drugs, with p &amp;lt;0.05 considered to be statistically significant. Data was analyzed using GraphPad Prism version 9.0.2. Results There was a total of 90 study participants eligible for analysis during the study period. Forty-three (47.8%) were male and 47 (52.2%) were female; the median age was 30 (IQR 24-35.3) years. The most common genotype was HbSS (81.1%), followed by HbSC (10%), and HbSB null (8.9%). Patient with sickle cell trait were excluded from this study. The majority of the patients (81.1%) received at least one treatment, and 24 (26.7%) were on combination therapy. Among the various SCD-modifying therapies, hydroxyurea was the most common therapy (64.4%) used, followed by voxelotor (13.3%), crizanlizumab (12.2%), and L-glutamine (11.1%). A detailed analysis is given in Table 1. The median initial urine PCR was 140 (IQR 90.0-242.5) mg/g. The median recent urine PCR of the study cohort was 135 mg/g (IQR 88.5-287.5), and the median change was 0 (IQR -45.0 to 43.5) mg/g. In stratifying by different disease-modifying drugs, the median change in urine PCR for hydroxyurea was -106.3 mg/g, L-glutamine 5.5 mg/g, voxelotor 19 mg/g, and crizanlizumab -22 mg/g. There was a statistically significant difference in the change in urine PCR for voxelotor and L-glutamine, compared with hydroxyurea (p=0.0361 and 0.0423, respectively) (Figure 1). Conclusion This is one of the first retrospective analyses to evaluate the renal protective effect of disease-modifying drugs at our comprehensive sickle cell center. The SCD-modifying therapies voxelotor and pharmaceutical-brand L-glutamine had the highest renal protective abilities and were associated with significant changes in urine PCR, compared with hydroxyurea. Larger studies are needed to corroborate these findings.

Genetically-informed prediction of short-term Parkinson’s disease progression

Parkinson’s disease (PD) treatments modify disease symptoms but have not been shown to slow progression, characterized by gradual and varied motor and non-motor changes overtime. Variation in PD progression hampers clinical research, resulting in long and expensive clinical trials prone to failure. Development of models for short-term PD progression prediction could be useful for shortening the time required to detect disease-modifying drug effects in clinical studies. PD progressors were defined by an increase in MDS-UPDRS scores at 12-, 24-, and 36-months post-baseline. Using only baseline features, PD progression was separately predicted across all timepoints and MDS-UPDRS subparts in independent, optimized, XGBoost models. These predictions plus baseline features were combined into a meta-predictor for 12-month MDS UPDRS Total progression. Data from the Parkinson’s Progression Markers Initiative (PPMI) were used for training with independent testing on the Parkinson’s Disease Biomarkers Program (PDBP) cohort. 12-month PD total progression was predicted with an F-measure 0.77, ROC AUC of 0.77, and PR AUC of 0.76 when tested on a hold-out PPMI set. When tested on PDBP we achieve a F-measure 0.75, ROC AUC of 0.74, and PR AUC of 0.73. Exclusion of genetic predictors led to the greatest loss in predictive accuracy; ROC AUC of 0.66, PR AUC of 0.66–0.68 for both PPMI and PDBP testing. Short-term PD progression can be predicted with a combination of survey-based, neuroimaging, physician examination, and genetic predictors. Dissection of the interplay between genetic risk, motor symptoms, non-motor symptoms, and longer-term expected rates of progression enable generalizable predictions.

Headache in Multiple Sclerosis - Pharmacological Aspects.

For decades, the headache was not considered a typical symptom of multiple sclerosis (MS) and was construed as a "red flag" for important differential diagnoses such as cerebral vasculitis. Meanwhile, several studies have demonstrated an increased prevalence of headaches in MS compared to the general population. This is due to the heterogeneity of headache genesis with frequent occurrence of both primary and secondary headaches in MS. On the one hand, MS and migraine are often comorbid. On the other hand, secondary headaches frequently occur, especially in the course of MS relapses. These are often migraine-like headaches caused by inflammation, which can improve as a result of MS-specific therapy. Headaches are particularly common in the early stages of chronic inflammatory CNS disease, where inflammatory activity is the greatest. In addition, headaches can also occur as a side effect of disease-modifying drugs (DMDs). Headache can occur with most DMDs and is most frequently described with interferon-beta therapy. The aim of this work is to present the prevalence of headaches and describe the heterogeneity of possible causes of headaches in MS. In addition, important therapeutic aspects in the treatment of MS patients, in general, will be presented as well as different approaches to the treatment of headaches in MS depending on the etiological classification.

Hydromethylthionine enhancement of central cholinergic signalling is blocked by rivastigmine and memantine.

The prevention of tau protein aggregations is a therapeutic goal for the treatment of Alzheimer's disease (AD), and hydromethylthionine (HMT) (also known as leucomethylthioninium-mesylate [LMTM]), is a potent inhibitor of tau aggregation in vitro and in vivo. In two Phase 3clinical trials in AD, HMT had greater pharmacological activity on clinical endpoints in patients not receiving approved symptomatic treatments for AD (acetylcholinesterase (AChE) inhibitors and/or memantine) despite different mechanisms of action. To investigate this drug interaction in an animal model, we used tau-transgenic L1 and wild-type NMRI mice treated with rivastigmine or memantine prior to adding HMT, and measured changes in hippocampal acetylcholine (ACh) by microdialysis. HMT given alone doubled hippocampal ACh levels in both mouse lines and increased stimulated ACh release induced by exploration of the open field or by infusion of scopolamine. Rivastigmine increased ACh release in both mouse lines, whereas memantine was more active in tau-transgenic L1mice. Importantly, our study revealed a negative interaction between HMT and symptomatic AD drugs: the HMT effect was completely eliminated in mice that had been pre-treated with either rivastigmine or memantine. Rivastigmine was found to inhibit AChE, whereas HMT and memantine had no effects on AChE or on choline acetyltransferase (ChAT). The interactions observed in this study demonstrate that HMT enhances cholinergic activity in mouse brain by a mechanism of action unrelated to AChE inhibition. Our findings establish that the drug interaction that was first observed clinically has a neuropharmacological basis and is not restricted to animals with tau aggregation pathology. Given the importance of the cholinergic system for memory function, the potential for commonly used AD drugs to interfere with the treatment effects of disease-modifying drugs needs to be taken into account in the design of clinical trials.

The QOSMOS Study: Pharmacist-Led Multicentered Observational Study on Quality of Life in Multiple Sclerosis.

Health-related quality of life is frequently included in patient-reported outcomes aimed at evaluating the effectiveness of disease-modifying drugs for multiple sclerosis, but recent data about Italian patients are missing. A multicenter observational and cross-sectional study was performed by students of hospital pharmacy to update existing data on quality of life and to correlate it with the pharmacological and medical history of patients. Quality of life (QoL) was assessed using the MS-QoL54 questionnaire, and the pharmacist collected patients’ characteristics, medical and pharmacological history, and Expanded Disability Status Scale (EDSS). Three hundred and forty-nine patients with multiple sclerosis were recruited from 16 centers between May 2018 and June 2019 (median age = 44.1 years; 68.9% women). The composite indexes of physical and mental well-being showed direct correlation with each other (R = 0.826; p < 0.001), and EDSS disability was an independent negative predictor of both indexes (R2 = 35.08% p < 0.001 and R2 = 15.74% p < 0.001, respectively). A trend of association between Physical Health Composite Score and different classes of oral disease-modifying drugs (DMDs) was observed. Our study found a decrease in QoL correlated with teriflunomide, which deserves further investigation. This experience demonstrates that joint action between scientific society and students association can be successful in conducting a no-profit multicenter observational study in a real-world setting.

FTY720 Exacerbates Blood-Brain Barrier Dysfunction Induced by IgG Derived from Patients with NMO and MOG Disease.

Neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) antibody-related disease (MOG disease) are inflammatory demyelinating diseases of the central nervous system (CNS). The disruption of the blood-brain barrier (BBB) is considered a key step in the pathogenesis of NMO and MOG disease. Although a previous report indicated that circulating immunoglobulin G (IgG) from NMO patients disrupts the BBB, the effect of IgG from patients with MOG disease has not been elucidated. In addition, it has been reported that some disease-modifying drugs for multiple sclerosis are harmful to NMO by an unknown mechanism. This study aimed to examine the effects of IgG from patients with NMO or MOG disease on BBB integrity. We also examined the effects of disease-modifying drugs (fingolimod [FTY720] and dimethyl fumarate [DMF]) on IgG-treated brain capillary endothelial cells. We used in vitro BBB models constructed with rat brain capillary endothelial cells (RBECs) to examine the effects on BBB function. The integrity of the RBECs was assessed by measuring transendothelial resistance (TEER) and cell viability. NMO or MOG-IgG treatment decreased TEER and cell viability in the endothelial monolayer model. Although FTY720 and DMF did not affect barrier function or cell viability under normal conditions, disease IgG-induced barrier dysfunctions were worsened by the presence of FTY720. These data indicate that circulating IgG in patients with NMO or MOG disease worsens BBB function. Furthermore, in patients with NMO or MOG disease treated with FTY720, changes in the integrity of the BBB were found to exacerbate the disease.

Family Planning for People with Multiple Sclerosis in Saudi Arabia: an Expert Consensus.

More than half of all patients with multiple sclerosis (MS) in the Kingdom of Saudi Arabia (KSA) are women of childbearing age. Raising a family is an important life goal for women in our region of the world. However, fears and misconceptions about the clinical course of relapsing-remitting MS (RRMS) and the effects of disease-modifying drugs (DMDs) on the foetus have led many women to reduce their expectations of raising a family, sometimes even to the point of avoiding pregnancy altogether. The increase in the number of DMDs available to manage RRMS and recent studies on their effects in pregnancy have broadened management options for these women. Interferon beta now has an indication in Europe for use during pregnancy (according to clinical need) and can be used during breastfeeding. Glatiramer acetate is a further possible option for women with lower levels of RRMS disease activity who are, or about to become, pregnant; natalizumab may be used up to 30 weeks in patients with higher levels of disease activity. Where possible, physicians need to support and encourage women to pursue their dream of a fulfilling family life, supported where necessary by active interventions for RRMS that are increasingly evidence based.

Longitudinal treatment responsiveness on plasma neurofilament light chain and glial fibrillary acidic protein levels in neuromyelitis optica spectrum disorder.

Background:Neurofilament light chain (NfL) and glial fibrilliary acidic protein (GFAP) have been suggested to be biomarkers of the pathophysiological process of neuromyelitis optica spectrum disorders (NMOSD), but the relationship between the plasma levels of these molecules with disease activity and treatment is incompletely understood.Objective:To investigate the treatment effects of disease-modifying drugs on plasma neurofilament light chain (pNfL) and plasma glial fibrillary acidic protein (pGFAP) and explore the predictive value of pNfL and pGFAP in the activity of NMOSD.Methods:pNfL and pGFAP levels were measured using single-molecule arrays in 72 patients with NMOSD and 38 healthy controls (HCs). Patients with NMOSD received tocilizumab (n = 29), rituximab (n = 23), oral prednisone (n = 16), and oral azathioprine or mycophenolate mofetil (n = 4).Results:NMOSD patients had significantly higher pNfL and pGFAP levels than HCs (pNfL, 18.3 (11.2–39.3) versus 11.5 (7.0–23.3) pg/mL; p = 0.001; pGFAP, 149.7 (88.6–406.5) versus 68.7 (59.4–80.8) pg/mL; p < 0.001). Multivariable regression analyses indicated that baseline pNfL concentration was associated with age (p = 0.017), Expanded Disability Status Scale (EDSS) score (p = 0.002), and recent relapses (p < 0.001). Baseline pGFAP concentration was also associated with EDSS (p < 0.001) and recent relapses (p < 0.001). Compared with prednisone, tocilizumab and rituximab significantly reduced pNfL [tocilizumab, exp(β), 0.65; 95% confidence interval (CI), 0.56–0.75; p < 0.001; rituximab, exp(β), 0.79; 95% CI = 0.68–0.93; p = 0.005] and pGFAP levels [tocilizumab, exp(β), 0.64; 95% CI, 0.51–0.80; p < 0.001; rituximab, exp(β), 0.77; 95% CI, 0.61–0.98; p = 0.041] at the end of the study. The pNfL levels in the tocilizumab and rituximab groups were reduced to those of HCs [tocilizumab, 8.5 (7.06–17.90) pg/mL; p = 0.426; rituximab, 14.0 (9.94–21.80) pg/mL; p = 0.216]. However, the pGFAP levels did not decrease to those of HCs in NMOSD patients at the end of study [tocilizumab, 88.9 (63.4–131.8) pg/mL; p = 0.012; rituximab, 141.7 (90.8–192.7) pg/mL; p < 0.001].Conclusion:pNfL and pGFAP may serve as biomarkers for NMOSD disease activity and treatment effects.

Disease-modifying drugs can reduce disability progression in relapsing multiple sclerosis.

An ever-expanding number of disease-modifying drugs for multiple sclerosis have become available in recent years, after demonstrating efficacy in clinical trials. In the real-world setting, however, disease-modifying drugs are prescribed in patient populations that differ from those included in pivotal studies, where extreme age patients are usually excluded or under-represented. In this multicentre, observational, retrospective Italian cohort study, we evaluated treatment exposure in three cohorts of patients with relapsing-remitting multiple sclerosis defined by age at onset: paediatric-onset (≤18 years), adult-onset (18-49 years) and late-onset multiple sclerosis (≥50 years). We included patients with a relapsing-remitting phenotype, ≥5 years follow-up, ≥3 Expanded Disability Status Scale (EDSS) evaluations and a first neurological evaluation within 3 years from the first demyelinating event. Multivariate Cox regression models (adjusted hazard ratio with 95% confidence intervals) were used to assess the risk of reaching a first 12-month confirmed disability worsening and the risk of reaching a sustained EDSS of 4.0. The effect of disease-modifying drugs was assessed as quartiles of time exposure. We found that disease-modifying drugs reduced the risk of 12-month confirmed disability worsening, with a progressive risk reduction in different quartiles of exposure in paediatric-onset and adult-onset patients [adjusted hazard ratios in non-exposed versus exposed >62% of the follow-up time: 8.0 (3.5-17.9) for paediatric-onset and 6.3 (4.9-8.0) for adult-onset, P < 0.0001] showing a trend in late-onset patients [adjusted hazard ratio = 1.9 (0.9-4.1), P = 0.07]. These results were confirmed for a sustained EDSS score of 4.0. We also found that relapses were a risk factor for 12-month confirmed disability worsening in all three cohorts, and female sex exerted a protective role in the late-onset cohort. This study provides evidence that sustained exposure to disease-modifying drugs decreases the risk of disability accumulation, seemingly in a dose-dependent manner. It confirms that the effectiveness of disease-modifying drugs is lower in late-onset patients, although still detectable.

The apparently milder course of multiple sclerosis: changes in the diagnostic criteria, therapy and natural history.

In the past decade, changes have occurred in the spectrum of multiple sclerosis courses. The natural history of multiple sclerosis appears milder from the first sign of demyelinating disease to the progressive course, probably as a result of an interplay between several factors including changes in the diagnostic criteria, changes in the epidemiology of multiple sclerosis, impact of early and appropriate disease-modifying treatment and improvement of the general state of health in the population. It has been suggested to regard incidental findings of demyelinating lesions in MRI in individuals without any history of clinical symptoms consistent with neurological dysfunction, so-called radiological isolated syndrome, as the initial course of multiple sclerosis. New diagnostic criteria have enabled the multiple sclerosis diagnosis in many patients at the first clinical demyelinating event, clinically isolated syndrome. The remaining patients with clinically isolated syndrome have a more benign prognosis, and for relapsing-remitting multiple sclerosis, the prognosis has become more favourable. Reduced disease activity in patients with relapsing-remitting multiple sclerosis can partly be ascribed to more efficacious new disease-modifying therapies but decrease in disease activity has also be seen in placebo-treated patients in clinical trials. This may be explained by several factors: change in the diagnostic criteria, more explicit inclusion criteria, exclusion of high-risk patients e.g. patients with co-morbidities, and more rigorous definitions of relapses and disease worsening. However, these factors also make the disease course in patients treated with disease-modifying therapies seem more favourable. In addition, change in the therapeutic target to stable disease (no evidence of disease activity = no relapses, no disease worsening and no MRI activity) could by itself change the course in relapsing-remitting multiple sclerosis. The effectiveness of disease-modifying drugs has reduced the transition from relapsing-remitting to secondary progressive multiple sclerosis. The concept of progressive multiple sclerosis has also evolved from two very distinct categories (primary progressive and secondary progressive multiple sclerosis) to a unified category of progressive multiple sclerosis, which can then be split into the categories of active or inactive. Also, an increasing tendency to treat progressive multiple sclerosis with disease-modifying therapies may have contributed to change the course in progressive multiple sclerosis. In conclusion, during the past decade the entire course of multiple sclerosis from the first sign of a demyelinating disorder through the progressive course appears to be milder due to a complex interplay of several factors.

Automated quantification of EEG spikes and spike clusters as a new read out in Theiler's virus mouse model of encephalitis-induced epilepsy

Intracerebral infection of C57BL/6 mice with Theiler's murine encephalomyelitis virus (TMEV) replicates many features of viral encephalitis-induced epilepsy in humans, including neuroinflammation, early (insult-associated) and late (spontaneous) seizures, neurodegeneration in the hippocampus, and cognitive and behavioral alterations. Thus, this model may be ideally suited to study mechanisms involved in encephalitis-induced epilepsy as potential targets for epilepsy prevention. However, spontaneous recurrent seizures (SRS) occur too infrequently to be useful as a biomarker of epilepsy, e.g., for drug studies. This prompted us to evaluate whether epileptiform spikes or spike clusters in the cortical electroencephalogram (EEG) may be a useful surrogate of epilepsy in this model. For this purpose, we developed an algorithm that allows efficient and large-scale EEG analysis of early and late seizures, spikes, and spike clusters in the EEG. While 77% of the infected mice exhibited early seizures, late seizures were only observed in 33% of the animals. The clinical characteristics of early and late seizures did not differ except that late generalized convulsive (stage 5) seizures were significantly longer than early stage 5 seizures. Furthermore, the frequency of SRS was much lower than the frequency of early seizures. Continuous (24/7) video-EEG monitoring over several months following infection indicated that the latent period to onset of SRS was 61 (range 16–91) days. Spike and spike clusters were significantly more frequent in infected mice with late seizures than in infected mice without seizures or in mock-infected sham controls. Based on the results of this study, increases in EEG spikes and spike clusters in groups of infected mice may be used as a new readout for studies on antiepileptogenic or disease-modifying drug effects in this model, because the significant increase in average spike counts in mice with late seizures obviously indicates a proepileptogenic alteration.

Désirée van der Heijde: a focus on outcomes in rheumatic diseases

When researching the progress of rheumatoid arthritis and related conditions, many rheumatologists will have used the Sharp/van der Heijde scoring system for measuring radiographically observed damage. The first half of that eponym denotes John Sharp, the American rheumatologist who devised and published the scale in 1985 with a view to measuring the effectiveness of disease-modifying drugs. Sharp died in 2008, but Désirée van der Heijde, the Dutch rheumatologist who modified Sharp's original system, is alive and well and Professor of Rheumatology at Leiden University Medical Centre (LUMC) in the Netherlands. The studies that prompted her modification of the Sharp score marked the onset of a career in research on outcomes that has earned her an international reputation in rheumatology.

What are the effects of disease-modifying drugs in people with a first clinical attack suggestive of multiple sclerosis?

What are the effects of disease-modifying drugs in people with a first clinical attack suggestive of multiple sclerosis?

O101 Evoked potentials in multiple sclerosis – Still a useful tool?

In the early diagnosis of multiple sclerosis (MS) the evoked potentials (EP) have been in the recent decades displaced by magnetic resonance imaging, which is reflected in their marginal position in the current McDonald’s diagnostic criteria. However, the parameters of EP were demonstrated to correspond well with clinical symptoms of MS and the degree of disability. Thus they have been used as measures of the disease progression, in monitoring of the MS natural course as well as effectiveness of disease-modifying drugs. There is also some evidence of the prognostic value of EP, performed at the early stage of the disease, with regard to subsequent relapses and a long-term disability accumulation. The advanced techniques of stimulation and collective analysis of multimodal EP further increase their sensitivity and specificity in revealing the dysfunction of the central nervous system pathways. Overall, EP have remained useful electrophysiological biomarkers of the degree and dynamics of neurological deficit in the course of MS. The integration of EP with neuroimaging and clinical issues may also provide a better insight into pathological processes underlying the disease.

The effects of different familial Alzheimer\u2019s disease mutations on APP processing in vivo

BackgroundDisturbed amyloid precursor protein (APP) processing is considered to be central to the pathogenesis of Alzheimer’s disease (AD). The autosomal dominant form of the disease, familial AD (FAD), may serve as a model for the sporadic form of AD. In FAD the diagnosis of AD is reliable and presymptomatic individuals carrying FAD mutations can give valuable insights into the earliest stages of the disease where therapeutic interventions are thought to be the most effective.MethodsIn the current cross-sectional study, products of APP processing (e.g., sAPPα, sAPPβ, Aβ38, Aβ40 and Aβ42) were measured in the cerebrospinal fluid (CSF) of individuals carrying one of three FAD mutations, APPswe (p.KM670/671NL), APParc (p.E693G) and PSEN1 (p.H163Y), as well as in non-mutation carriers from the same families.ResultsWe observed pathological APP processing in presymptomatic carriers of FAD mutations, with different profiles of APP and Aβ isoforms in the three mutation carrier groups, APPswe (p.KM670/671NL), APParc (p.E693G) and PSEN1 (p.H163Y), except for the well-established decrease in CSF Aβ42 that was found with all mutations.ConclusionsThese findings add to the current evidence that AD pathophysiology differs between disease-causing mutations and can be monitored in the presymptomatic disease stage by CSF analyses. This may also be important from a therapeutic standpoint, by opening a window to monitor effects of disease-modifying drugs on AD pathophysiology.

Observational Study of Switching from Natalizumab to Immunomodulatory Drugs

Objective: To determine the effect of disease-modifying drugs (DMDs) on disease activity rebound in patients discontinuing natalizumab (NTZ). Methods: Twenty-one patients with relapsing-remitting multiple sclerosis (RRMS) treated with NTZ for ≥1 year and who switched to DMDs (glatiramer acetate [GA] or interferon) were followed up for 12 months in clinical practice. Clinical outcomes after NTZ cessation were assessed every 3 months for 1 year and MRI was performed at 12 months. Results: Twelve months after switching from NTZ to DMDs, there were no significant differences in the annualized relapse rate (ARR) compared to the days that NTZ was used (0.3 vs. 0.1; p = 0.083); and the ARR never reached similar values to those prior to NTZ use (1.61; p < 0.001). The percentage of relapse-free patients after switching from NTZ was 71.4%. These patients did not have lower disease activity before NTZ compared with those with clinical relapses (1.3 vs. 1.7; p = 0.302), but they had lower Expanded Disability Status Scale scores (3.4 vs. 5.7; p = 0.001). DMDs had beneficial effects on MRI parameters, as 10 of 16 patients (62.5%) presented no evidence of radiological activity 12 months after NTZ discontinuation. Conclusions: Patients with RRMS and moderate disability who discontinued NTZ for safety reasons may benefit from the DMDs GA and interferon with no known risk for progressive multifocal leukoencephalopathy.

An effect of disease-modifying drugs on the development of children born to mothers with multiple sclerosis

To evaluate an effect of mother's treatment with disease-modifying drugs (DMD) on the mental and physical development of the child in the first year of life. Thirty pregnancies resulted in birth of live babies in patients with multiple sclerosis (MS) were studied. The diagnosis of MS was made to the mother before conception of the child. Seven mothers did not receive DMD at the moment of conception (controls), 13 mother were treated with interferon-beta (IFN) and 10 with glatiramer acetate. A structure interview, examination of the child with the assessment of common anthropometric indices, the WHO scale for achievement of six milestones, medical history and statistical analysis were used. The data on the negative effect of MS on the growth and development of the fetus and the positive impact of treatment of the mother with DMD in the early stages of pregnancy on anthropometric indices and development of the child in the first year of life were confirmed. It has been concluded that DMD positively influence the disease course of the female patient and potentially improve the prognosis for her future offspring.