Administration of intravenous immunoglobulins (IVIgs) is established for long-term treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Prevention of secondary axonal loss going along with permanent clinical disability and muscular atrophy is a major aim in CIDP therapy. To assess long-term clinical efficacy of IVIg treatment despite heterogenous disease course and variable complaints reported by the patients, long-term electrophysiological monitoring was performed for systematic evaluation of therapeutic efficacy of IVIg.
A total of 21 patients with CIDP treated with IVIg 1 g/kg bodyweight every 3–6 weeks were examined electrophysiologically every 12 months over a period of 2 years.
Assessment of clinical symptoms, using the Inflammatory Neuropathy Cause and Treatment (INCAT) and Hughes functional grading score (F-score) revealed improvement of motor and sensory symptoms over a period of 2 years. As electrophysiological results remained stable, IVIg treatment seems to be suitable to prevent axonal loss in CIDP.
This study confirms efficacy of IVIg as firstline therapy in CIDP. Doses and frequency of IVIg application should be adapted based on clinical evaluation and analysis of long-term electrophysiological findings.
Tetrabenazine (TBZ) is commonly used in hyperkinetic movement disorders. In this retrospective study, we aimed to assess the TBZ effectiveness and adverse events (AEs) in Huntington disease (HD), vascular chorea, tics, dystonia, tardive oromandibular (OM) dyskinesia and other tardive syndromes (TS).
Qualitative analysis of clinical response was used to estimate TBZ effectiveness. TBZ-associated AE frequency and subsequent discontinuation rate were used to estimate tolerability; the tolerability profile was measured through the TBZ minimal dose and exposure time required to elicit AEs.
Of 108 included patients, 87% had a clinically meaningful improvement sustained over a period of 40 months. TBZ-responder rate ranged from 100% in HD to 62.5% and 77.1% in tic disorders and OM dyskinesia, respectively (p < 0.001). TBZ-associated AE frequency ranged from 40.9% in other TS and 41.7% in vascular chorea and HD, to 60% in OM dyskinesia (p < 0.001). The most common AEs were Parkinsonism (51.8%) and psychiatric disorders (25%). The ‘other AEs’ category (mainly somnolence) presented the shortest minimal exposure time (3 months). AE-eliciting dose differed from 18.8 mg and 25 mg in tics and tardive disorders, to 75 mg in HD (p = 0.003). Patients with AEs were tendentiously older at TBZ initiation (p = 0.022).
TBZ proved an effective and relatively well tolerated treatment in hyperkinetic disorders, with excellent results in HD. AEs were more common in OM dyskinesia, which may be related to higher age at TBZ initiation. TBZ-associated somnolence and Parkinsonism were more frequent during the titration and maintenance periods, respectively.
In the pivotal phase III 2-year ADVANCE study, subcutaneous peginterferon beta-1a 125 mcg every 2 weeks demonstrated significant improvements in clinical outcomes, including disability endpoints, in patients with relapsing–remitting multiple sclerosis (RRMS). Here, we aim to further evaluate disability data from ADVANCE, and explore associations between confirmed disability progression (CDP), functional status, and health-related quality of life (HRQoL).
In total, 1512 patients were randomized to placebo or peginterferon beta-1a 125 mcg every 2 or 4 weeks. After 1 year, patients on placebo were re-randomized to peginterferon beta-1a every 2 or 4 weeks. CDP was defined as >=1.0 point increase from a baseline Expanded Disability Status Scale (EDSS) score >= 1.0, or >=1.5-point increase from baseline 0, confirmed 12 or 24 weeks after onset.
Peginterferon beta-1a every 2 weeks significantly reduced risk of 12- and 24-week CDP at 1 year compared with placebo (12-week CDP: 6.8% versus 10.5%, p = 0.038; 24-week CDP: 4% versus 8.4%, p = 0.0069, peginterferon beta-1a every 2 weeks versus placebo, respectively). Benefits were maintained over 2 years (11.2% and 7.7%, peginterferon beta-1a every 2 weeks in 12- and 24-week CDP, respectively). Approximately 90% of patients with 24-week CDP had simultaneous worsening by >=1 point in at least one functional system score, most commonly pyramidal. Displaying a 24-week CDP was associated with worse scores on the Multiple Sclerosis Functional Composite (MSFC) scale and several HRQoL instruments; the impact of CDP was attenuated by treatment with peginterferon beta-1a every 2 weeks.
Peginterferon beta-1a has the potential to prevent/delay worsening of disability in patients with relapsing–remitting multiple sclerosis. Furthermore, improved benefits in disability status with peginterferon beta-1a were also associated with improved functional status and HRQoL
[ClinicalTrials.gov identifier: NCT00906399].
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, which often causes progressive neurological disability. In addition to motor and sensory dysfunction, cognitive decline and fatigue are frequent manifestations of the disease. Fatigue is probably the most common symptom, with up to 90% of MS individuals reporting fatigue at some point. Cognitive impairment affects about 50% of patients and may be present at all MS stages. The aim of this observational study was to evaluate changes in cognition, fatigue, and disability status in 300 relapsing–remitting MS (RRMS) patients, treated with subcutaneous (sc) interferon (IFN) β-1a over 2 years.
The study was designed as an observational, multicentre, prospective, single-arm, phase IV study carried out in 13 MS centres in the Czech Republic. Cognition status was assessed using the Paced Auditory Serial Addition Task (PASAT), fatigue using the Fatigue Descriptive Scale (FDS), and disability using the Expanded Disability Status Scale (EDSS), at baseline, and after 6, 12 and 24 months. The percentage of patients with changed versus stable cognition, fatigue status and disability was calculated at each time point and the changes in these scores were evaluated.
The proportion of patients with cognitive improvement was higher compared with those with a stable or decreased PASAT scores at all time points, and the average cognitive performance improved during the follow-up period. Also the proportion of patients with stable or improved fatigue and EDSS scores was higher compared with those in which FDS or EDSS scores declined, this was found at all time points of the analysed sample. However, the direct effect of IFN β-1a on cognition and fatigue cannot be concluded from this study.
The results of this observational study have demonstrated a stable or improved cognitive performance, fatigue status, and disability level in the majority of RRMS patients treated with sc IFN β-1a over a two-year follow-up period, in a real life setting, in the Czech Republic.
The current study aimed to examine the psychometric properties of an attributional style measure that can be administered remotely, to people who have multiple sclerosis (MS).
A total of 495 participants with MS were recruited. Participants completed the Attributional Style Questionnaire-Survey (ASQ-S) and two comparison measures of cognitive variables via postal survey on three occasions, each 12 months apart. Internal reliability, test-retest reliability and congruent validity were considered.
The internal reliability of the ASQ-S was good (α > 0.7). The test-retest correlations were significant, but failed to reach the 0.7 set. The congruent validity of the ASQ-S was established relative to the comparisons.
The psychometric properties of the ASQ-S indicate that it shows promise as a tool for researchers investigating depression in people with MS and is likely sound to use clinically in this population.
The objective of this study was to evaluate monthly intramuscular adrenocorticotropic hormone (ACTH) gel versus intravenous methylprednisolone (IVMP) add-on therapy to interferon β for breakthrough disease in patients with relapsing forms of multiple sclerosis.
This was a prospective, open-label, examiner-blinded, 15-month pilot study evaluating patients with Expanded Disability Status Scale (EDSS) score 3.0–6.5 and at least one clinical relapse or new T2 or gadolinium-enhanced lesion in the previous year. Twenty-three patients were randomized to ACTH (n = 12) or IVMP (n = 11) and completed the study. The primary outcome measure was the cumulative number of relapses. Secondary outcomes included EDSS, Mental Health Inventory (MHI), plasma cytokines, MS Functional Composite (MSFC), Quality-of-Life (MS-QOL) score, bone mineral density (BMD), and new or worsened psychiatric symptoms per month. Brain magnetic resonance imaging was analyzed post hoc. This was a preliminary and small-scale study.
Relapse rates differed significantly [ACTH 0.08, 95% confidence interval (CI) 0.01–0.54 versus IVMP 0.80, 95% CI 0.36–1.75; rate ratio, IVMP versus ACTH: 9.56, 95% CI 1.23–74.6; p = 0.03]. ACTH improved (p = 0.03) MHI (slope 0.95 ± 0.38 points/month; p = 0.02 versus slope –0.38 ± 0.43 points/month; p = 0.39). On-study decreases (all p < 0.05) in eight cytokine levels occurred only in the ACTH group. However, on-study EDSS, MSFC, MS-QOL, BMD, and MRI lesion changes were not significant between groups. Psychiatric symptoms per patient were greater with IVMP than ACTH (0.55, 95% CI 0.12–2.6 versus 0; p < 0.0001). Other common adverse events were insomnia and urinary tract infections (IVMP, seven events each) and fatigue or flu symptoms (ACTH, five events each).
This study provided class II evidence that ACTH produced better examiner-assessed cumulative rates of relapses per patient than IVMP in the adjunctive treatment of breakthrough disease in multiple sclerosis.
The aim of this study was to analyse registry data of seizure outcome and adverse events (AEs) for perampanel as add-on therapy in patients with focal epilepsy since its approval in 2012 for adjunctive treatment of focal epilepsy in patients >=12 years.
A retrospective 2-year chart review of all patients receiving perampanel was carried out.
A total of 122 patients received perampanel [median treatment length: 20.1 (range: 3.4–26.8) months]; 71 (58%) remained on treatment at last follow up. Overall, 33 patients (27%) were seizure-free for >=3 months at last follow up; of these, eight were seizure free for >=3 times the longest interictal interval before perampanel therapy; 18 (15%) had reduced seizure frequency >=50%. A total of 58 (47%) had an AE and 34 (28%) withdrew from treatment because of AEs. AEs included dizziness (33%), fatigue (12%), psychiatric symptoms (8%), cognitive deficits (7%), speech problems (5%), nausea (4%) and gait problems (4%). AEs subsided in 17/18 patients (94%) following a 2 mg dose reduction. A total of 43 (35%) took a concomitant enzyme inducer. Patients not taking enzyme inducers were more likely to be seizure free (p = 0.002); there were no other between-group differences.
Perampanel was well tolerated and improved seizure control in 42% of patients (50– 100% reduction), with higher rates in those not receiving a concomitant enzyme inducer. AEs, particularly dizziness, were common but often disappeared with a slight dose reduction. The results are consistent with those from randomized controlled trials.
Dimethyl fumarate (DMF) was approved by the US Food and Drug Administration (FDA) for treatment of relapsing–remitting multiple sclerosis (RRMS) based on two phase III randomized clinical trials (RCTs). There were not enough non-White patients enrolled in these RCTs to allow for subgroup analysis based on race. Efficacy and tolerability of DMF therapy across various racial groups is unknown.
Retrospective chart review was performed on all patients with RRMS who were started on DMF in two tertiary multiple sclerosis (MS) clinics. Efficacy and tolerability of DMF was compared across three self-identified racial groups: White-American (WA), African-American (AA) and Hispanic-American (HA).
A total of 390 RRMS patients were included in the study: 261 (66.9%) WA, 69 (17.7%) AA and 52 (13.3%) HA. When comparing ‘pre-DMF’ (1 year) and ‘on DMF’ (mean follow up of 14 months) periods, statistically significant reduction in rates of annualized relapses (WA from 0.44 to 0.19, AA from 0.39 to 0.15, and HA from 0.39 to 0.14; no differences between groups), new T2 lesions (WA from 45% to 23%, AA from 39% to 23%, HA from 52% to 26%; no difference between groups), and Gd+ lesions (WA from 25% to 13%, AA from 24% to 7%, HA from 23% to 12%; no difference between groups) were seen. DMF was relatively well tolerated across all groups, with an overall discontinuation rate of 20% (no difference between the three groups).
Efficacy of DMF in our clinic population did not differ across three major ethnic groups, WA, AA and HA, and was comparable with results observed in the pivotal studies. These ‘real-life’ data suggest that race is not a factor that needs to be taken into account when initiating DMF.
Novel oral anticoagulants (NOACs) have shown to be both safe and effective for ischemic stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). We conducted a network meta-analysis (NMA) using published data from secondary prevention subgroups of different phase III randomized clinical trials (RCTs) comparing individual NOACs with warfarin.
Eligible studies were identified by searching MEDLINE and SCOPUS and the Cochrane Central Register of Controlled Trials databases. First, we conducted a pairwise meta-analysis for each pairwise comparison, and then we performed NMA to combine direct and indirect evidence for any given pair of treatments. The comparative effects of all NOACs against warfarin were ranked with the surface under the cumulative ranking (SUCRA) curve for each outcome.
We identified four RCTs (including 15,240 patients) comparing individual NOACs (apixaban, dabigatran, rivaroxaban) with warfarin. Using indirect evidence, dabigatran was related to a significantly lower risk of hemorrhagic stroke compared with rivaroxaban [risk ratio (RR) 0.28; 95% confidence interval (CI) 0.11–0.75], while rivaroxaban was associated with a significantly lower risk of major gastrointestinal bleeding compared with dabigatran (RR 0.14; 95% CI 0.03–0.74). We also performed clustered ranking plot for the primary efficacy and safety endpoints to identify the treatment with the probably best benefit-to-risk ratio profile.
The three NOACs showed differences in terms of safety and efficacy for secondary stroke prevention in NVAF. Our findings can serve only as hypothesis generation and require independent confirmation in head-to-head RCTs, owing to the sparse available evidence and increased uncertainty in both indirect effect estimates and ranking of treatments.
The objective of this study was to analyze published literature on autoimmune epilepsy and assess predictors of seizure outcome.
From PubMed and EMBASE databases, two reviewers independently identified publications reporting clinical presentations, management and outcomes of patients with autoimmune epilepsy. A meta-analysis of 46 selected studies was performed. Demographic/clinical variables (sex, age, clinical presentation, epilepsy focus, magnetic resonance imaging [MRI] characteristics, time to diagnosis and initiation of immunomodulatory therapy, and type of immunomodulatory therapy) were compared between two outcome groups (responders and nonresponders). Clinical response was defined as >50% reduction in seizure frequency. Unstandardized effect sizes were collected for the studies for responder and nonresponder groups. Sample size was used as the weight in the meta-analysis. The random effects model was used to account for heterogeneity in the studies.
The 46 reports included 186 and 96 patients in responder and nonresponder groups respectively. Mean age of the responders and nonresponders was 43 and 31 years (p < 0.01). Responders were more likely to have cell-surface antibodies (68% versus 39%, p < 0.05), particularly voltage-gated potassium channel complex antibodies (p < 0.01). Mean duration from symptom onset to diagnosis, and symptom onset to initiation of immunomodulation was significantly lower among the responders (75 versus 431 days, p < 0.05, and 80 versus 554, p < 0.01, respectively). There was no outcome difference based on gender, MRI characteristics, seizure type, type of acute immunomodulatory therapy, or use of chronic immunomodulation.
Among published cases to date, older age, presence of cell-surface antibodies, early diagnosis and immunomodulatory treatment are associated with better seizure outcomes among patients with autoimmune epilepsy.
Approximately one in two patients with multiple sclerosis (MS) suffer from comorbid depression. The primary objective of this study was to evaluate the safety and tolerability of fingolimod and antidepressant combination in relapsing–remitting MS patients with mild-to-moderate depression. Efficacy outcome variables were quality of life (QoL), fatigue, disability and depression.
Patients received open-label fingolimod 0.5 mg over 2 weeks, followed by fingolimod plus citalopram (40 mg), fluoxetine (40 mg) or venlafaxine (150 mg) over 16 weeks. The antidepressant was selected at the physician’s discretion.
In total, 54 patients were recruited at 25 centres across Germany. No new safety signals (including cardiac) emerged compared with previous clinical studies. Adverse events (mostly mild-to-moderate) were reported in 43 patients. A total of three patients had serious adverse events and 10 discontinued the study. QoL (mean [95% confidence interval]) improved by 2.2 (–3.3, –1.2; Patient Reported Indices for MS questionnaire), fatigue by 8.2 (–13.1, –3.3; modified Fatigue Impact Scale) and depression by 6.3 (–8.4, –4.2; Hamilton Depression Scale) points. However, the results must be interpreted cautiously owing to limited patient numbers.
Combination of fingolimod with antidepressant medication showed no unexpected safety signals. Patient-reported outcomes (QoL, disability, fatigue and depression) remained stable or improved.
The cumulative safety and efficacy measures of percutaneous transluminal angioplasty and stenting (PTAS) for secondary stroke prevention in patients with symptomatic intracranial arterial stenosis (sICAS) have not previously been evaluated using a meta-analytical approach.
We conducted a systematic review and random effects meta-analysis of all available randomized controlled trials (RCTs) evaluating the safety and efficacy of PTAS (in comparison with medical therapy) for sICAS.
Three RCTs (678 total patients) were included in the quantitative analysis. PTAS was associated with a higher risk of recurrent ischemic stroke in the territory of qualifying artery both within 30 days [risk ratio (RR) = 2.21, 95% confidence interval (CI) 1.10–4.43] and 1 year (RR = 1.92, 95% CI 1.10–3.36). PTAS was also related to a higher risk of any ischemic stroke within 30 days from the index event (RR = 2.08, 95% CI 1.17–3.71). The risk for intracranial hemorrhage was found to be higher in PTAS patients both within 30 days (RR = 10.60, 95% CI 1.98–56.62) and 1 year (RR = 8.15, 95% CI 1.50–44.34). The composite outcome of any stroke or death within 1 year (RR = 2.29, 95% CI 1.13–4.66) and 2 years (RR = 1.52, 95% CI 1.04–2.21) was higher in PTAS than in medical therapy. PTAS was associated with a higher risk of any stroke or death within 2 years in the sICAS subgroup located in posterior circulation (RR = 2.37, 95% CI 1.27–4.42).
PTAS is associated with adverse early and long-term outcomes and should not be recommended in patients with sICAS. Further research to identify subgroups of patients who could also serve as candidates for future interventional trials along with efforts to reduce procedure-related complications are needed.
Neuromyelitis optica spectrum disorder (NMOSD) is a neuroinflammatory disorder of the central nervous system, distinct from multiple sclerosis by affecting predominantly the optic nerve and the spinal cord, and mediated by antibodies directed against aquaporin 4 (AQP4-ab) as a possible pathomechanistic hallmark of NMOSD. Therapeutic options include immunosuppression with steroids or B-cell-depleting agents as baseline therapies, as well as plasma exchange (PLEX) and/or immunoadsorption (IA) during relapses. Until now, data concerning the efficacy of IA alone are scarce.
Visual evoked potentials (VEPs), visual acuity and changes of symptoms at relapse leading to admission in NMOSD patients (n = 10) treated with IA in a single-centre setting were evaluated retrospectively.
All patients profited from the procedure and showed an amelioration of admission symptoms. Three patients improved in visual acuity, another three patients remained stable, whereas five patients showed an improvement in VEPs.
In this small cohort, IA constitutes a valid therapeutic option for patients with NMOSD as an equivalent to PLEX. Analysis in larger cohorts is warranted.
In the USA, stable intravenous tissue plasminogen activator (IV tPA) patients have traditionally been cared for in an intensive care unit (ICU). We examined the safety of using an acuity-adaptable stroke unit (SU) to manage IV tPA patients.
We conducted an observational study of consecutive patients admitted to our acuity-adaptable SU over the first 3 years of operation. Safety was assessed by symptomatic intracerebral hemorrhage (sICH) rates, systemic hemorrhage (SH) rates, tPA-related deaths, and transfers from SU to ICU; cost savings and length of stay (LOS) were determined.
We admitted 333 IV tPA patients, of which 302 were admitted directly to the SU. A total of 31 (10%) patients had concurrent systemic hemodynamic or pulmonary compromise warranting direct ICU admission. There were no differences in admission National Institutes of Health Stroke Scale scores between SU and ICU patients (9.0 versus 9.5, respectively). Overall sICH rate was 3.3% (n = 10) and SH rate was 2.9 (n = 9), with no difference between SU and ICU patients. No tPA-related deaths occurred, and no SU patients required transfer to the ICU. Estimated hospital cost savings were US$362,400 for ‘avoided’ ICU days, and hospital LOS decreased significantly (p = 0.001) from 9.8 ± 15.6 days (median 5) in year 1, to 5.2 ± 4.8 days (median 3) by year 3.
IV tPA patients may be safely cared for in a SU when nurses undergo extensive education to ensure clinical competence. Use of the ICU solely for monitoring may constitute significant overuse of system resources at an expense that is not associated with additional safety benefit.
With recent developments in drug therapy for multiple sclerosis (MS), new treatment options have become available presenting patients with complex treatment decisions.
The objective of this study was to elicit patients’ preferences for different attributes of MS drug therapy.
A representative sample of patients with MS across Canada (n=189) participated in a best–worst scaling study to quantify preferences for different attributes of MS drug therapy, including delaying progression, improving symptoms, preventing relapse, minor side effects, rare but serious adverse events (SAEs), and route of administration. Conditional logit models were fitted to estimate the relative importance of each attribute in influencing patients’ preferences.
A latent-class analysis revealed heterogeneity of preferences across respondents, with preferences differing across five classes. The most important attributes of drug therapy were the avoidance of SAEs for three classes and the improvement of symptoms for two other classes. Only a smaller group of patients demonstrated a specific preference for avoiding SAEs, and route of administration.
This study shows that preferences for drug therapy among patients with MS are different, some of which can be explained by experiences with their disease and treatment. These findings can help to inform the focus of interactions that healthcare practitioners have with patients with MS, as well as further drug development.
Disease-modifying therapies (DMTs) are applied to delay or prevent disease progression in multiple sclerosis (MS). While this has mostly been proven for physical symptoms, available studies regarding long-term effects of DMTs on cognitive functions are rare and sometimes inconsistent due to methodological shortcomings. Particularly in the case of fingolimod, comprehensive data on cognitive functions are not yet available. Therefore, we set out to reliably assess cognitive functions in patients with relapsing–remitting MS (RRMS) treated with DMTs over 1 year.
Cognitive functions were assessed with eight tests at three timepoints: baseline, 6-month follow up and 12-month follow up. First, we investigated whether the stability of cognitive functions (i.e. not falling below the 5% cut-off in more than one test) over 1 year in RRMS patients (n = 41) corresponds to the stability in healthy individuals (n = 40) of a previous study. Second, we compared the percentage of declined and improved patients in the different tests. Third, we compared patients treated with fingolimod (n = 22) with patients treated with natalizumab (n = 11) with regard to cognitive stability. Fourth, based on the patient data, the Reliable Change Index was applied to compute cut-offs for reliable cognitive change.
Approximately 75% of RRMS patients treated with DMTs remained stable over the course of 1 year. The Paced Auditory Serial Addition Test (PASAT) and the Spatial Recall Test (SPART), produced improvements in 12.5% and 30.6%, respectively, probably due to practice effects. Patients treated with fingolimod did not differ from patients treated with natalizumab with regard to cognitive stability.
Cognitive functions remain relatively stable under DMT treatment over 1 year, irrespective of the type of medication. Furthermore, the tests PASAT and SPART should be interpreted cautiously in studies examining performance changes over time. The provided RCI norms may help clinicians to determine whether a difference in two measurements observed in a RRMS patient is reliable.
There are limited pharmacological treatments for patients with neurological Wilson’s disease (WD) and a history of copper-chelating treatment failure.
We retrospectively evaluated the clinical records of 38 patients with WD who were treated with sodium dimercaptopropanesulfonate (DMPS) and zinc (group 1) or zinc alone (group 2). All patients had a history of neurological deterioration during their previous treatment with D-penicillamine (DPA).
Twenty-one patients were treated with intravenous DMPS for 4 weeks, followed by zinc gluconate for 6 months, and the treatment protocol was repeated twice. Relative to the baseline, repeated DMPS therapy and zinc maintenance therapy decreased neurological scores continuously (p < 0.01). Sixteen patients (76.2%) demonstrated neurological improvements after 1 year of therapy and four patients (19.0%) exhibited neurological deterioration at the follow-up session. In addition, 17 patients were treated with zinc monotherapy for 12 months. Two patients (11.8%) demonstrated neurological improvements and five patients (29.4%) exhibited neurological deterioration. Compared with the patients in group 2, a greater improvement ratio (p < 0.01) and lower deterioration ratio (p < 0.01) were observed in the patients in group 1 after 1 year of therapy.
Our findings indicate that the safety and efficacy of combined treatment of DMPS and zinc is superior to those of zinc monotherapy in patients with neurological WD with a history of DPA treatment failure.
Improved clinical effectiveness and therefore positive modification of multiple sclerosis (MS) with basic therapy can be achieved by long-term regular intake of drugs as prescribed but investigations have shown that a high percentage of patients do not take their medications as prescribed.
We assessed the satisfaction and adherence of patients with MS with their current disease-modifying treatment under clinical practice conditions. We compared different facets of satisfaction as well as their internal relationship and identified predictors in an exploratory manner.
Therapy satisfaction in patients with relapsing–remitting multiple sclerosis (THEPA-MS) was a noninterventional, prospective cross-sectional study performed throughout Germany in 2013 and 2014, and included patients with clinically isolated syndrome or relapsing–remitting MS. We applied a standardized approach to document satisfaction and adherence by patient-reported outcomes (Treatment Satisfaction Questionnaire for Medication) as well as by physician ratings.
Of 3312 patients with a mean age of 43.7 years, 73.3% were women and the mean level of disability according to the Expanded Disability Status Scale was 2.29; 13.3% did not receive any medication at the time of documentation, 21.3% received interferon β1a intramuscularly, 20.7% had interferon β1a subcutaneously, 17.0% had interferon β1b subcutaneously and 23.7% had glatiramer acetate. Adherence rates varied between 60% (lifetime) and 96.5% (current medication). Differences between current medications were found for side effects and convenience scores but not for effectiveness, satisfaction and adherence. Higher global satisfaction and effectiveness were associated with fewer relapses, longer duration of medication, lower disability score and the absence of several side effects.
In a connected model of patient satisfaction, effectiveness, side effects, convenience and adherence, patients’ individual needs and concerns have to be addressed. Most differences were found with respect to side effects and convenience of treatment. Therefore, an improvement in these two domains seems to be the most promising proximate approach to elevate adherence levels.
Efficacy of interferon beta in multiple sclerosis (MS) can be dampened in patients who develop neutralizing antidrug antibodies (NAbs). Peginterferon beta1a is an interferon conjugated with a polyethylene glycol (PEG) moiety. Pegylation increases a drug’s half life and exposure, and may also reduce immunogenicity.
The objective of this study was to characterize the incidence and impact of immunogenicity to peginterferon beta1a over 2 years in patients with MS.
Patients with relapsing–remitting MS (N = 1512) were randomized to subcutaneous peginterferon beta1a 125 μg every 2 or 4 weeks, or placebo, for 1 year; patients in the placebo group were rerandomized to active treatment in year 2. The incidence and titers of binding antibodies (BAbs) and NAbs to interferon and antibodies to PEG (anti-PEG) were assessed in analytically validated assays. The clinical impact of immunogenicity on relapse and magnetic resonance imaging endpoints was evaluated.
Over 2 years, 6%, less than 1%, and 7% of patients developed anti-interferon BAbs, NAbs, and anti-PEG antibodies, respectively. There was no discernible clinically meaningful effect of antibody status on the pharmacodynamic, efficacy, or safety parameters evaluated, although these analyses were limited by the low incidence of treatment-emergent antibodies.
The treatment effect of peginterferon beta1a in patients with relapsing–remitting MS is not expected to be attenuated by immunogenicity.
The goal of this study was to analyze safety and assess the efficacy of standard plasma exchange (PE) compared with immunoadsorption (IA) alone, or an alternating combination of both in deteriorating myasthenia gravis (MG).
A total of 72 patients with MG who had received PE procedures for treatment of severe deterioration were retrospectively analyzed. They received either five cycles of PE (1–1.5 plasma volumes), or five cycles of IA in line with plasma separation, or a sequential alternating procedure of one cycle of PE followed by two cycles of IA, which was repeated once or more if needed.
A total of 19 patients received PE, 24 patients IA, and 29 the alternating combination therapy. All groups were equally distributed by sex and mean MG score before treatment. The number of treatment cycles and days on therapy did not differ between the groups. Mean MG scores at discharge were 3.0 (PE), 1.8 (IA) and 1.6 (combination) (p = 0.028 for combination versus PE). Inpatient time was 30.7 days (PE), 22.3 days (IA) and 20.0 days in combination therapy (p < 0.05 for combination versus PE). Side effects such as allergic reactions or hypocoagulability were significantly more frequent in the PE group (37% in PE versus 4% in IA and 3.6% in the alternating combination, p < 0.05).
Semiselective IA in combination with PE, and to a lesser extent IA alone, was associated with a shorter hospital stay and more pronounced reduction of the MG score than PE.
Cerebrospinal fluid analysis may provide insight into the interplay between chronic inflammation and response to treatment.
To demonstrate the impact of one intrathecal triamcinolone injection on the redox potential and on ascorbyl radical appearance in the cerebrospinal fluid of chronic progressive multiple sclerosis patients.
A total of 16 patients received 40 mg triamcinolone. Electron-spin resonance spectroscopy measured the oxidation range after copper ion [Cu (II)] addition and ascorbyl-radical bioavailability.
There was an increase of Cu (II) ion absorption, which reflects an augmented content of reduced proteins. Ascorbyl radicals were present in contrast to healthy controls according to the literature.
Intrathecal steroid application alters the redox potential in cerebrospinal fluid. Our findings support the beneficial role of steroids on oxidative stress generally demonstrated by ascorbyl radical appearance. Reactive oxygen species decline is necessary for an upregulated production of reduced proteins.
Multiple sclerosis (MS), an inflammatory disease affecting the central nervous system, is considered to exhibit an important neurodegenerative component as well. Laquinimod is an orally administered quinoline-3-carboxamide under development for the treatment of MS. In vitro and animal studies have revealed various mechanisms by which laquinimod may exert its effects on the immune and nervous systems. These include effects on the innate immune system that promote the differentiation of anti-inflammatory/regulatory T cells, the activation of microglia cells, an increase in the expression of brain-derived neurotrophic factor, as well as the prevention of inflammation-induced excitotoxicity. Two phase III studies revealed the clinical benefits of laquinimod in patients with relapsing–remitting MS and exhibited a benign safety profile for this drug. Ongoing clinical trials will help to define the optimal dose and indication for laquinimod in MS. This article reviews current experimental and clinical evidence on the role of laquinimod in patients with this disabling disease.
To date, the most frequently used Parkinson’s disease (PD) biomarkers are the brain imaging measures of dopaminergic dysfunction using positron emission tomography and single photon emission computed tomography. However, major advances have occurred in the development of magnetic resonance imaging (MRI) biomarkers for PD in the past decade. Although conventional structural imaging remains normal in PD, advanced techniques have shown changes in the substantia nigra and the cortex. The most well-developed MRI markers in PD include diffusion imaging and iron load using T2/T2* relaxometry techniques. Other quantitative biomarkers such as susceptibility-weighted imaging for iron load, magnetization transfer and ultra-high-field MRI have shown great potential. More sophisticated techniques such as tractography and resting state functional connectivity give access to anatomical and functional connectivity changes in the brain, respectively. Brain perfusion can be assessed using non-contrast-agent techniques such as arterial spin labelling and spectroscopy gives access to metabolites concentrations. However, to date these techniques are not yet fully validated and standardized quantitative metrics for PD are still lacking. This review presents an overview of new structural, perfusion, metabolic and anatomo-functional connectivity biomarkers, their use in PD and their potential applications to improve the clinical diagnosis of Parkinsonian syndromes and the quality of clinical trials.
Laquinimod is a novel immunomodulatory agent, in development as a potential disease-modifying treatment for multiple sclerosis (MS). Structurally related to linomide, its pharmacological predecessor, laquinimod combines anti-inflammatory and possibly clinically relevant neuroprotective effects with the convenience of oral administration. In this review we aim to highlight the immunomodulatory and neuroprotective effects of laquinimod, and to describe its effects in animal models of MS. Furthermore, we focus on current results of clinical studies in MS. Randomized, controlled clinical trials in relapsing MS demonstrate a dose–response effect on disease activity, measured by reduced clinical relapse rate, reduced number of brain MRI active lesions, as well as on sustained disability and brain atrophy. Laquinimod has a favourable tolerability and safety profile. A new phase III study, recently completed, will soon provide further details on the therapeutic potential of this drug. Laquinimod is a promising emerging treatment for relapsing–remitting MS that may provide a new therapeutic option in the near future.
Objective: Efficacy and tolerability profiles of Treximet [sumatriptan/naproxen sodium combination tablet (SNC)] have been established in clinical trials but have to date been virtually unstudied in pragmatic research. The primary objective of this study was to compare the overall satisfaction of SNC to its monotherapy components, S/N [one 100 mg Imitrex tablet (S) and two Aleve (naproxen sodium) 220 mg tablets, total dose 440 mg (N)] administered concomitantly using the Patient Perception of Migraine Questionnaire –Revised (PPMQ-R).
Methods: Adults with migraine (n = 50) without ‘medication overuse headache’ were treated for up to 18 migraine attacks per 3-month study period with study medication; SNC during one study period and S/N during the other study period. For all endpoints, differences between treatments were compared with paired t tests.
Results: The percentage of patients reporting satisfied/very satisfied for Overall Satisfaction of SNC versus S/N (primary endpoint) was 85% versus 72% respectively (p = 0.054). For Overall Effectiveness, the results were 82% for SNC versus 73% for S/N (p = 0.159); and for Overall Side Effects the results were 86% for SNC versus 69% for S/N (p = 0.005). Mean PPMQ-R scores reflect greater satisfaction with SNC than S/N for Total score and for each of four subscales. The difference between SNC and S/N was significant for the Ease of Use subscale (p = 0.004) and met the criterion of being clinically meaningful for both the Total score and Ease of Use. SNC did not differ from S/N with respect to pain-free response 2 h post dose, pain relief 2 h post dose, sustained 24 h pain-free response, or sustained 24 h pain relief.
Conclusion: Although the primary endpoint only just failed, the results of this pragmatic outcomes study demonstrate SNC to have benefits over its concomitantly administered components in the acute treatment of migraine.
Objective: The objective of this study was to analyse our initial experience using an interdisciplinary angio suite approach to neurosurgical treatment of complex neurovascular lesions and expound technical feasibility and possible applications.
Subjects: Six out of 451 patients with cranial or spinal neurovascular lesions were surgically treated in the angio suite (biplane angiographic system) during a 28-month observation period. Clinical baseline data, radiological and intraoperative findings as well as clinical and radiological outcome were assessed.
Results: A ventral spinal perimedullary arteriovenous malformation, a ventral spinal perimedullary fistula, two diffuse frontal dural arteriovenous fistulas, a multifocal temporal arteriovenous malformation and a partially embolized fronto-temporo-basal dural arteriovenous fistula were successfully treated with angiographically confirmed complete occlusion and unimpaired neurological condition of the patients at the 12-month follow up.
Conclusion: This study demonstrates the feasibility of this approach and points out possible indications, namely ventrally located spinal lesions and diffuse, deep seated cranial lesions.
In the European Union, the high-concentration capsaicin patch is licensed for the management of neuropathic pain conditions in nondiabetic patients, including postherpetic neuralgia (PHN) and HIV-associated distal sensory polyneuropathy (HIV-DSP). However, in the USA, the Food and Drug Administration approved its use only in PHN patients. Capsaicin is a transient receptor potential vanilloid-1 agonist, which increases the intracellular calcium ion concentration. This triggers calcium-dependent protease enzymes causing cytoskeletal breakdown and leads to the loss of cellular integrity and ‘defunctionalization’ of nociceptor fibres. Efficacy and therapeutic effect has been shown in several clinical studies of PHN and HIV-DSP. The high-concentration capsaicin patch and its practical application are different from low-concentration creams; one application can help for up to 3 months. The process of setting up of a service to use the capsaicin 8% patch is also discussed.
Anxiety disturbances are recognized as common psychiatric comorbidities in Parkinson’s disease (PD) and contribute to significant impairments in areas of cognitive, functional, motor and social performance. Anxiety in PD results in reduced quality of life, higher levels of care dependency and increased caregiver burden. Surprisingly, there is a paucity of treatment data. In one randomized, controlled study, bromazepam was found to be effective for anxiety in PD. However, usage of benzodiazepines in the PD population is limited by potential risk of confusion and falls. There are no controlled studies of selective serotonin reuptake inhibitors (SSRIs) for anxiety in PD. However, results from uncontrolled studies suggest that SSRIs are effective for anxiety in PD, although in these studies anxiety outcomes were secondary. This review underscores that, given the high prevalence of anxiety disturbances in PD, there is a significant paucity of treatment data for this population. Additional studies are warranted. In the meantime, clinicians should rely on empiric assessments of known risks and putative benefits to guide treatment decisions. Cognitive and behavioral therapies (with or without pharmacotherapy) have demonstrated efficacy and warrant consideration. When feasible, a targeted and individualized multimodal approach utilizing psychotherapeutic interventions along with pharmacologic therapies should be considered.
Dementia is a common neuropsychological disorder with an increasing incidence. The most prevalent type of dementia is Alzheimer’s disease. The underlying pathophysiological features of the cognitive decline are neurodegenerative processes, a cerebrovascular dysfunction and immunological alterations. The therapeutic approaches are still limited, although intensive research is being conducted with the aim of finding neuroprotective strategies. The widely accepted cholinesterase inhibitors and glutamate antagonists did not meet expectations of preventing disease progression, and research is therefore currently focusing on novel targets. Nonsteroidal anti-inflammatory drugs, secretase inhibitors and statins are promising drug candidates for the prevention and management of different forms of dementia. The kynurenine pathway has been associated with various neurodegenerative disorders and cerebrovascular diseases. This pathway is also closely related to neuroinflammatory processes and it has been implicated in the pathomechanisms of certain kinds of dementia. Targeting the kynurenine system may be of therapeutic value in the future.
Parkinson’s disease is a slowly progressive neurodegenerative disorder typically characterized by the loss of dopaminergic neurons within the substantia nigra pars compacta, and the intraneuronal deposition of insoluble protein aggregates chiefly comprised of α-synuclein. Patients experience debilitating symptoms including bradykinesia, rigidity and postural instability. No curative treatment currently exists and therapeutic strategies are restricted to symptomatic treatment only. Over the past decade a class of molecular chaperones called the heat shock proteins has emerged as a potentially promising therapeutic target. Heat shock proteins aid in the folding and refolding of proteins, and target denatured proteins to degradation systems. By targeting heat shock proteins through various means including overexpression and pharmacological enhancement, researchers have shown that α-synuclein aggregation and its associated cytotoxicity can be therapeutically modulated in an array of cell and animal models. This review highlights the relevant progress in this field and discusses the relevance of heat shock proteins as therapeutic modulators of α-synuclein toxicity to the rapidly evolving understanding of Parkinson’s disease pathogenesis.
Cytoskeletal dysfunction has been proposed during the last decade as one of the main mechanisms involved in the aetiology of several neurodegenerative diseases. Microtubules are basic elements of the cytoskeleton and the dysregulation of microtubule stability has been demonstrated to be causative for axonal transport impairment, synaptic contact degeneration, impaired neuronal function leading finally to neuronal loss. Several pathways are implicated in the microtubule assembly/disassembly process. Emerging evidence is focusing on Notch as a microtubule dynamics regulator. We demonstrated that activation of Notch signalling results in increased microtubule stability and changes in axonal morphology and branching. By contrast, Notch inhibition leads to an increase in cytoskeleton plasticity with intense neurite remodelling. Until now, several microtubule-binding compounds have been tested and the results have provided proof of concept that microtubule-binding agents or compounds with the ability to stabilize microtubules may have therapeutic potential for the treatment of Alzheimer’s disease and other neurodegenerative diseases. In this review, based on its key role in cytoskeletal dynamics modulation, we propose Notch as a new potential target for microtubule stabilization.
Headache is a common clinical feature in patients in the emergency room and in general neurology clinics. For physicians not experienced in headache disorders it might be difficult sometimes to decide in which patients neuroimaging is necessary to diagnose an underlying brain pathology and in which patients cerebral imaging is unnecessary. Most patients presenting to the primary-care physician with a nonacute headache and no further neurological signs or symptoms will not be suffering from an underlying serious condition. This review focuses on the main primary headache diseases, including migraine, tension-type headache and cluster headache, as well as frequent secondary headache entities with common clinical presentation and appropriate diagnostic and therapeutic algorithms to help guide the decision on the utilization of neuroimaging in the diagnostic workup.
While essential tremor (ET) has traditionally been categorized as a pure motor disease, cross-sectional and longitudinal studies of cognition in ET have demonstrated that these patients may have cognitive dysfunction. Recent epidemiological studies demonstrate an association between ET (particularly with onset after age 65) and increased risk for cognitive impairment and dementia. Although existing studies have generally conceptualized cognitive changes in ET as consistent with a ‘frontosubcortical’ or ‘corticocerebellar’ profile, results from these same studies suggest that cognitive impairment in ET may in fact be heterogeneous. Furthermore, the underlying mechanisms remain uncertain. Cognitive changes could be a byproduct of the cerebellar dysfunction of ET itself; alternately, they may be a feature of concomitant neurodegenerative diseases that have been associated in several studies with ET, including Alzheimer’s disease, Parkinson’s disease or progressive supranuclear palsy. While the study of cognitive dysfunction in ET has received research attention in recent years, the results of these studies have not been translated into the clinical domain and clinical practice. This review first summarizes the current literature on the potential relationships between ET and cognitive change. We then suggest areas of further clinical evaluation and treatment; these suggestions are directed at physicians caring for ET patients who may demonstrate or complain of cognitive impairment. As we discuss, clinicians should ideally screen ET patients for possible signs or symptoms of cognitive impairment in addition to assessing for psychiatric comorbidity and quality of life. These recommendations are in contrast to most current clinical practice, which does not routinely include such assessment among ET patients. To our knowledge, there have been no pharmacotherapeutic trials to date of any agent for cognitive change associated with ET. We believe that studies for this indication are now called for. Future efforts in this direction will also need to take into account the pathobiology of cognitive changes in ET, which itself is an area that is ripe for future investigations.
Pharmacological targeting of ion channels has long been recognized as an attractive strategy for the treatment of various diseases. Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system with a prominent neurodegenerative component. A multitude of different cell types are involved in the complex pathophysiology of this disorder, including cells of the immune system (e.g. T and B lymphocytes and microglia), the neurovascular unit (e.g. endothelial cells and astrocytes) and the central nervous system (e.g. astrocytes and neurons). The pleiotropic expression and function of ion channels gives rise to the attractive opportunity of targeting different players and pathophysiological aspects of MS by the modulation of ion channel function in a cell-type and context-specific manner. We discuss the emerging knowledge about ion channels in the context of autoimmune neuroinflammation. While some pharmacological targets are at the edge of clinical translation, others have only recently been discovered and are still under investigation. Special focus is given to those candidates that could be attractive novel targets for future therapeutic approaches in neuroimmune autoinflammation.
Disease activity in multiple sclerosis (MS) is strongly linked to the formation of new lesions, which involves a complex sequence of inflammatory, degenerative, and reparative processes. Conventional magnetic resonance imaging (MRI) techniques, such as T2-weighted and gadolinium-enhanced T1-weighted sequences, are highly sensitive in demonstrating the spatial and temporal dissemination of demyelinating plaques in the brain and spinal cord. Hence, these techniques can provide quantitative assessment of disease activity in patients with MS, and they are commonly used in monitoring treatment efficacy in clinical trials and in individual cases. However, the correlation between conventional MRI measures of disease activity and the clinical manifestations of the disease, particularly irreversible disability, is weak. This has been explained by a process of exhaustion of both structural and functional redundancies that increasingly prevents repair and recovery, and by the fact that these imaging techniques do not suffice to explain the entire spectrum of the disease process and lesion development. Nonconventional MRI techniques, such as magnetization transfer imaging, diffusion-weighted imaging, and proton magnetic resonance spectroscopy, which can selectively measure the more destructive aspects of MS pathology and monitor the reparative mechanisms of this disease, are increasingly being used for serial analysis of new lesion formation and provide a better approximation of the pathological substrate of MS plaques. These nonconventional MRI-based measures better assess the serial changes in newly forming lesions and improve our understanding of the relationship between the damaging and reparative mechanisms that occur in MS.
The world of metabolic myopathies has been dramatically modified by the advent of enzyme replacement therapy (ERT), the first causative treatment for glycogenosis type II (GSDII) or Pompe disease, which has given new impetus to research into that disease and also other pathologies. This article reviews new advances in the treatment of GSDII, the consensus about ERT, and its limitations. In addition, the most recent knowledge regarding the pathophysiology, phenotype, and genotype of the disease is discussed. Pharmacological, immunotherapy, nutritional, and physical/rehabilitative treatments for late-onset Pompe disease and other metabolic myopathies are covered, including treatments for defects in glycogen metabolism, such as glycogenosis type V (McArdle disease), and glycogenosis type III (debrancher enzyme deficiency), and defects in lipid metabolism, such as carnitine palmitoyltransferase II deficiency and electron transferring flavoprotein dehydrogenase deficiency, or riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency.