A systematic review of the comorbidity between PTSD and alcohol misuse

Purpose

This systematic review aimed to assess (1) the level of comorbidity of post-traumatic stress disorder (PTSD) and alcohol misuse reported in research studies since 2007 and (2) any associations found between specific PTSD symptom clusters and alcohol misuse.

Methods

A literature search was carried out to capture any papers published from 2007 to the end of July 2012. Six hundred and twenty abstracts were identified and reviewed, and 42 papers were included in the final review after applying inclusion and exclusion criteria.

Results

The prevalence of comorbid alcohol misuse in those with PTSD ranged from 9.8 to 61.3 %. The prevalence of comorbid PTSD in those with alcohol misuse ranged from 2.0 to 63.0 %, and the majority of prevalence rates were over 10.0 %. Almost all of the odds ratios representing the strength of association between the conditions across a variety of populations were significant, and those ranged from 1.1 to 4.87. Of the different PTSD symptom clusters, this review found most evidence for associations between alcohol misuse and both avoidance/numbing symptoms and hyperarousal symptoms.

Conclusions

Given that comorbidity appears to be common, the evidence from this systematic review supports the use of routine screening for comorbidity in populations who are known to have PTSD or alcohol misuse.     

The relationship between post traumatic stress disorder and post traumatic growth: gender differences in PTG and PTSD subgroups

Purpose

This study investigated the post traumatic stress disorder (PTSD) and post traumatic growth (PTG) in 2,300 earthquake survivors 1 year after the 2008 Wenchuan earthquake. This study aimed to investigate the relationship between PTSD and PTG and also tested for the gender differences in PTSD and PTG subgroups.

Methods

A stratification random sampling strategy and questionnaires were used to collect the data. The PTSD was assessed using the PTSD Check list-Civilian and the PTG was assessed using the Post traumatic growth inventory. 2,300 individuals were involved in the initial survey with 2,080 completing the final questionnaire, a response rate of 90.4 %. One-way ANOVA analyses were performed to investigate the gender differences in the PTSD and PTG subgroups.

Results

One year following the earthquake, 40.1 and 51.1 % of survivors reported PTSD and PTG, respectively. A bivariate correlation analysis indicated that there was a positive association between PTG and PTSD. The PTG and PTSD variance analysis conducted on female and male subgroups suggested that women were more affected than men.

Conclusions

Given the relatively high PTG prevalence, it was concluded that researchers need to pay more attention to the positive outcomes of an earthquake rather than just focusing on the negative effects. The surveys and analyses indicated that psychological intervention and care for the earthquake disaster survivors should focus more on females and older people, who tend to be more adversely affected.     

Continuity in features of anxiety and attention deficit/hyperactivity disorder in young preschool children

Anxiety disorders and attention deficit/hyperactivity disorder (ADHD) develop before school age, but little is known about early developmental pathways. Here we test two hypotheses: first, that early signs of anxiety and ADHD at 18 months predict symptoms of anxiety and ADHD at age 3½ years; second, that emotional dysregulation at 18 months predicts the outcome of co-occurring anxiety and ADHD at age 3½ years. The study was part of the prospective Norwegian Mother and Child Cohort Study (MoBa) at the Norwegian Institute of Public Health. The 628 participants were clinically assessed at 3½ years. Questionnaire data collected at 18 months were categorized into early behavioural scales of anxiety, ADHD, and emotional dysregulation. We investigated continuity in features of anxiety and ADHD from 18 months to 3½ years of age through logistic regression analyses. Anxiety symptoms at 3½ years were predicted by early signs of anxiety (Odds ratio (OR) = 1.41, CI = 1.15–1.73) and emotional dysregulation (OR = 1.33, CI = 1.15–1.54). ADHD symptoms at 3½ years were predicted by early signs of ADHD (OR = 1.51, CI = 1.30–1.76) and emotional dysregulation (OR = 1.31, CI = 1.13–1.51). Co-occurring anxiety and ADHD symptoms at 3½ years were predicted by early signs of anxiety (OR = 1.43, CI = 1.13–1.84), ADHD (OR = 1.30, CI = 1.11–1.54), and emotional dysregulation (OR = 1.34, CI = 1.13–1.58). We conclude that there were modest continuities in features of anxiety and ADHD through early preschool years, while emotional dysregulation at age 18 months was associated with symptoms of anxiety, ADHD, and co-occurring anxiety and ADHD at age 3½ years.     

Sexual maturation among youth with ADHD and the impact of stimulant medication

Objective

Evaluate the differences in achieving puberty between ADHD and non-ADHD participants and the effects of medication on that process among ADHD participants.

Procedure

A subset of participants with ADHD from the Multimodal Treatment study of ADHD (n = 342) were compared with respect to Tanner staging to participants from a comparison group without ADHD (n = 159) at the 36-month follow-up assessment. Further comparisons were made for Tanner stages and Auxology of the participants in the ADHD group who were always (n = 61), never (n = 56), newly (n = 74) and inconsistently (n = 116) treated with stimulants.

Results

No statistically significant differences in Tanner stages of sexual development were found between the ADHD and non-ADHD groups at the age of assessment (between 10 and 14 years of age) or among the ADHD medication subgroups, although a trend was observed for stimulant-associated delayed pubertal initiation using auxological analysis.

Conclusion

Children with or without ADHD did not differ in Tanner stages at the 3-year follow-up assessment, and exposure to stimulant medication does not appear to affect sexual development within this age range.     

Racial/Ethnic Match and Treatment Outcomes for Women with PTSD and Substance Use Disorders Receiving Community-Based Treatment

This study examined the relationship between racial/ethnic match and treatment outcomes for 224 women who participated in a clinical trial of group treatments for posttraumatic stress disorder (PTSD) and substance use disorders. Generalized estimating equations were used to examine the effect of client–therapist racial/ethnic match on outcomes. Results revealed racial/ethnic match was not significantly associated with session attendance. There was a significant three-way interaction between client race/ethnicity, baseline level of PTSD symptoms, and racial/ethnic match on PTSD outcomes. White clients, with severe PTSD symptoms at baseline, who attended treatment groups where they were matched with their therapist, had greater reductions in PTSD symptoms at follow-up than their counterparts who were racially/ethnically mismatched with their group therapist. Racial/ethnic match did not confer additional benefits for Black clients in terms of PTSD outcomes. Racial/ethnic match interacted with baseline substance use to differentially influence substance use outcomes at follow-up for all women. Clinical implications are discussed.     

The Prevalence and Psychosocial Correlates of Suicide Attempts Among Inpatient Adolescent Offspring of Croatian PTSD Male War Veterans

Despite evidence that children of male war veterans with combat-related posttraumatic stress disorder (PTSD) are at particularly high risk for behavior problems, very little is currently known about suicidal behaviors in this population of youth. This study aimed to examine the prevalence and psychosocial correlates of suicide attempts among psychiatrically hospitalized adolescent offspring of Croatian male PTSD veterans. Participants were psychiatric inpatients, ages 12–18 years. Self-report questionnaires assessed demographics, suicide attempts, psychopathology, parenting style, and family functioning. The prevalence of suicide attempts was 61.5 % (65.2 % for girls and 58.0 % for boys). Internalizing symptoms, family dysfunction, lower levels of maternal and paternal care, and paternal overcontrol were significantly associated with suicide attempts. Our findings suggest that suicide attempts are common among inpatient adolescent offspring of male PTSD veterans and that interventions targeting both adolescent psychopathology and family relationships are needed for adolescents who have attempted suicide.     

Altered peripheral BDNF mRNA expression and BDNF protein concentrations in blood of children and adolescents with autism spectrum disorder

Findings from molecular genetic studies and analyses of postmortem and peripheral tissue led to the hypothesis that neurotrophins—as crucial moderators of neuroplasticity—impact on the pathophysiology of autism spectrum disorder (ASD). The study projects aimed to complement former results on the role of brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family with fundamental impact on brain development and function. The purpose of this work was to investigate peripheral BDNF mRNA expression and BDNF protein concentrations in ASD as potential surrogates for the effects observed in the central nervous system. In a BDNF protein quantification study, serum concentrations were analyzed using Enzyme-Linked Immunosorbent Assays in 24 male patients with ASD, all with an IQ > 70 (age 13.9 ± 3.0 years) and 20 age- and gender-matched healthy control subjects (age 14.4 ± 2.1 years; p = 0.522). In a further independent project, a BDNF mRNA expression analysis, mRNA levels from total blood were assessed by quantitative real-time polymerase chain reaction in a sample of 16 male ASD patients (age 10.8 ± 2.2), 15 age- and gender-matched healthy controls (age 12.1 ± 2.2) and 15 patients with attention deficit hyperactivity disorder as a clinical control group (age 11.8 ± 2.2; p = 0.207). In the protein quantification project, significantly decreased BDNF serum concentrations were found in ASD cases compared to healthy control children (t = ?2.123, df = 42, p < 0.05). Analysis of covariance (ANCOVA) revealed this result in accordance with significant reductions in BDNF mRNA expression in ASD, observed in the mRNA expression study (F = 3.65; df = 2.43; p < 0.05); neither age nor IQ confounded the result, as indicated by ANCOVA (F = 3.961; df = 2.41; p < 0.05, η ²  = 0.162). Our study projects supported the notion that neurotrophins are involved in the pathophysiology of ASD. Further studies may eventually contribute to the identification of distinct peripheral mRNA expression and protein concentration patterns possibly supporting diagnostic and therapeutic processes.     

Who Benefits from Diabetes Self-Management Interventions? The Influence of Depression in the Latinos en Control Trial

Background

Depressive symptoms are common among adults with diabetes. Depression and social support may influence diabetes self-management.

Purpose

This study aimed to examine change in depressive symptoms and the role of depression and support on clinical and dietary outcomes among Latinos with type 2 diabetes participating in a diabetes self-management intervention.

Methods

Participants (N?=?252) were randomized to the intervention or usual care. Mixed effects models were used to examine interaction effects between intervention status and depressive symptoms (Centers for Epidemiologic Studies Depression (CES-D) score) and support for diabetes self-management behaviors at baseline. Outcomes were measured at baseline and 4 and 12 months and included dietary quality, physical activity, depressive symptoms, and hemoglobin A1c levels.

Results

Intervention participants had lower CES-D scores at follow-up than control participants. An interaction effect between intervention status and CES-D scores predicted diet quality.

Conclusion

Latinos with depressive symptoms may derive the greatest benefits from diabetes self-management interventions. Additional research on support during diabetes self-management interventions is warranted.     

Gamma Knife radiosurgery for arteriovenous malformations in pediatric patients

Objective

The authors present the results of Gamma Knife stereotactic radiosurgery performed in a series of children with arteriovenous malformations (AVMs).

Methods

Between June 2005 and January 2014, 75 patients 18 years old or younger received Gamma Knife radiosurgery for AVMs. Of these, 58 patients were eligible for further analysis. The median age of the population was 12 years; 41 % presented with hemorrhage, 34 % with neurological insult, and 24 % patients were diagnosed incidentally. The median AVM volume was 3.5 cm³. The median radiosurgery-based AVM score (RSBAVMS) was 0.86. The median follow-up period was 32 months.

Results

Single session Gamma Knife radiosurgery resulted in complete AVM obliteration in 40 (68.9 %) patients. There were 35 (60.3 %) excellent outcome (complete obliteration with no new deficits) in this series. During the follow-up period, nine (15.51 %) patients experienced new deficits and three (5.1 %) patients experienced intracranial hemorrhage. The annual rate of developing new deficits and hemorrhage was calculated as 5.45 and 1.8 %, respectively. Volume, gender, RSBAVMS, and nidus type factor were factors associated with excellent outcome.

Conclusions

Radiosurgery was successful in majority of patients with minimal morbidity. Gamma Knife radiosurgery for AVMs can be a safe and successful method in pediatric patients.     

Effectiveness of the Tobacco Tactics Program in the Department of Veterans Affairs

Purpose

The purpose was to determine the effectiveness of the Tobacco Tactics program in three Veterans Affairs hospitals.

Methods

In this effectiveness trial, inpatient nurses were educated to provide the Tobacco Tactics intervention in Ann Arbor and Detroit, while Indianapolis was the control site (N?=?1,070). Smokers were surveyed and given cotinine tests. The components of the intervention included nurse counseling, brochure, DVD, manual, pharmaceuticals, 1-800-QUIT-NOW card, and post-discharge telephone calls.

Results

There were significant improvements in 6-month quit rates in the pre- to post-intervention time periods in Ann Arbor (p?=?0.004) and Detroit (p?Conclusion The Tobacco Tactics program, which meets the Joint Commission standards that apply to all inpatient smokers, has the potential to significantly decrease smoking among Veterans.     

Clustering mild cognitive impairment by mini-mental state examination

We aimed to evaluate whether the performance of the mini-mental state examination (MMSE) could identify risky mild cognitive impairment (MCI). We recruited 122 amnestic MCI-single domain (ASM), 303 amnestic MCI-multiple domains (AMM), and 94 non-amnestic MCI (NAM). Two-step cluster and linear discriminant analyses were used for identifying the clusters of the MMSE with age and education, as well as establishing prediction models for each cluster. Conversion into dementia was compared among clusters. Cluster analyses revealed the following three: cluster 1 = 205 AMM (100 %); cluster 2 = 61 NAM (33.3 %) and 122 ASM (66.7 %); and cluster 3 = 33 NAM (25.2 %) and 98 AMM (74.8 %). Cluster 3 showed a significantly lower ability with regards to orientation to time and place, registration of three words, attention/calculation, language, and copying interlocking pentagons, than clusters 1 and 2. However, for delayed recall, cluster 1 was significantly more impaired than cluster 2. Patients in the cluster 1 showed the most common conversion into dementia [odds ratio (OR) = 2.940 vs. cluster 2, OR = 2.271 vs. cluster 3]. This study showed that clustering by performance in MMSE could help define groups at higher risk for conversion to dementia. Therefore, MMSE can be considered as a promising screening tool including subtyping for MCI when detailed neuropsychological tests are not feasible.     

Evaluation of a psychoeducation programme for parents of children and adolescents with ADHD: immediate and long-term effects using a blind randomized controlled trial

Recent guidelines for the diagnosis and treatment of attention deficit hyperactivity disorder (ADHD) have claimed the possible benefits of psychoeducational techniques in the comprehensive management of ADHD. To evaluate the efficacy of a psychoeducation programme for parents of children and adolescents with ADHD in a clinical setting using a blind randomized trial. 81 children/adolescents with ADHD were randomly assigned for their families to receive either a well-structured psychoeducation programme (intervention group, n = 44), or a parent counselling and support intervention (control group, n = 37). Measures of child ADHD symptoms, psychopathology, quality of life and family stress were taken before and after intervention and after a year follow-up. Parents and evaluators were unaware of the condition received. Compared to the support control group, the psychoeducation group showed ADHD Index and cognitive/inattention levels significantly reduced after the intervention ended (Mann–Whitney U = 3.34; p = 0.001; Mann–Whitney U = 3.47; p = 0.001). An improvement in the pro-social domain was also observed after 1 year follow-up (Mann–Whitney U = ?2.37; p = 0.018), and clinical global impression found a statistically significant effect for severity over the time. Differences were initially found for the impact of the disorder in the family in different domains, including emotional and social functioning; these differences were no longer significant after alpha correction. No significant differences in quality of life or family stress were found in comparison with the control group. This psychoeducation programme is a valuable treatment for parents/carers of children/adolescents with ADHD, which needs to be considered when evaluating different non-pharmacological treatment options. Psychoeducation and other kind of non-pharmacological approaches need to be regarded not as a substitute, but as a complementary treatment to medications; these approaches might help other very crucial aspects of ADHD including social and familiar outcomes.     

Posttraumatic growth in the aftermath of a disaster: looking for the role of gender

In the past 10 years, the literature on disasters and mental health has shifted from a focus on psychopathology, to an interest in documenting manifestations of resilience in the face of mass trauma. The Jin et al. study, published in this issue of the Journal, examines gender differences in the relationship between posttraumatic stress disorder (PTSD) and posttraumatic growth (PTG) in the aftermath of the Wenchuan Earthquake in China. The study suggests that the coping response to PTSD may differ between males and females, and raises interesting questions about the types of factors that contribute to the manifestation of high versus low PTG given high levels of PTSD. At the same time, this type of study highlights the need to investigate the long-term impact and meaning of PTG, and to examine whether it reflects an adaptive process with long-term benefits in the face of traumatic exposures, or an illusory type of posttraumatic response.     

Warfarin and Statins are Associated with Hematoma Volume in Primary Infratentorial Intracerebral Hemorrhage

Background and purpose

Despite extensive studies of supratentorial intracerebral hemorrhage (ICH), limited data are available on determinants of hematoma volume in infratentorial ICH. We therefore aimed to identify predictors of infratentorial ICH volume and to evaluate whether location specificity exists when comparing cerebellar to brainstem ICH.

Methods

We undertook a retrospective analysis of 139 consecutive infratentorial ICH cases (95 cerebellar and 44 brainstem ICH) prospectively enrolled in a single-center study of ICH. ICH volume was measured on the CT scan obtained upon presentation to the Emergency Department using an established computer-assisted method. We used linear regression to identify determinants of log-transformed ICH volume and logistic regression to evaluate their role in surgical evacuation.

Results

Median ICH volumes for all infratentorial, cerebellar, and brainstem ICH were nine [interquartile range (IQR), 3–23], ten (IQR, 3–25), and eight (IQR, 3–19) milliliters, respectively. Thirty-six patients were on warfarin treatment, 31 underwent surgical evacuation, and 65 died within 90 days. Warfarin was associated with an increase in ICH volume of 86 % [β = 0.86, standard error (SE) = 0.29, p = 0.003] and statin treatment with a decrease of 69 % (β = ?69, SE = 0.26, p = 0.008). Among cerebellar ICH subjects, those on warfarin were five times more likely to undergo surgical evacuation (OR = 4.80, 95 % confidence interval 1.63–14.16, p = 0.005).

Conclusions

Warfarin exposure increases ICH volume in infratentorial ICH. Further studies will be necessary to confirm the inverse relation observed between statins and ICH volume.     

Induction of Matrix Metalloproteinase-3 (MMP-3) Expression in the Microglia by Lipopolysaccharide (LPS) via Upregulation of Glycoprotein Nonmetastatic Melanoma B (GPNMB) Expression

Substantial evidence suggests that inflammation is an important contributor to many neurodegenerative disorders. Activated microglial cells play an important role in releasing pro-inflammatory factors, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) for inducing inflammation. Recently, some reports have suggested that glycoprotein nonmetastatic melanoma B (GPNMB) is highly expressed in microglia after LPS treatment. However, the role of GPNMB in activated microglia is not clearly understood. In this study, we used RT-PCR and Western blotting to detect GPNMB and matrix metalloproteinase-3 (MMP-3) expressions in activated microglia. GPNMB small interfering RNA (siRNA) or MMP-3 inhibitor was applied on microglial BV2 cells, and ELISA was performed to measure the expressions of TNF-α and IL-1β in BV2 cells. Levels of iNOS and NO in BV2 cells were also determined. We found that the levels of GPNMB and MMP-3 were significantly increased in BV2 cells after LPS treatment. Moreover, we found that GPNMB significantly upregulated the expression of MMP-3 in BV2 cells, and high expression of MMP-3 was dependent on the level of GPNMB. Inhibition of GPNMB or MMP-3 expression by GPNMB siRNA or MMP-3 inhibitor dramatically suppressed the expressions of TNF-α, IL-1β, iNOS, and NO in activated microglia. All of these results suggest that GPNMB is involved in the inflammatory responses of microglia.     

Seroprevalence of n-methyl-d-aspartate glutamate receptor (NMDA-R) autoantibodies in aging subjects without neuropsychiatric disorders and in dementia patients

n-methyl-d-aspartate glutamate receptors (NMDA-R) play a key role in learning and memory. Therefore, they may be involved in the pathophysiology of dementia. NMDA-R autoantibodies directed against the NR1a subunit of the NMDA-R, which were first identified as a specific marker for a severe form of encephalitis, cause a decrease in NMDA-Rs, resulting in cognitive impairment and psychosis. We examined the prevalence of NR1a NMDA-R autoantibodies in the serum and cerebrospinal fluid (CSF) of 24 patients with Alzheimer’s disease (AD), 20 patients with subcortical ischemic vascular dementia (SIVD), and 274 volunteers without neuropsychiatric disorder. The latter cases showed an association of seropositivity with age. Notably, the overall seroprevalence was not statistically different between dementia patients and matched controls. Further analysis of the patient samples showed that four patients with AD and three patients with SIVD had positive NMDA-R IgM, IgG, and/or IgA autoantibody titers in serum. These patients suffered from psychosis (with the exception of one case). CSF samples were negative for NMDA-R autoantibodies. We conclude that the seroprevalence of NMDA-R-directed autoantibodies is age-related. It has to be clarified by larger studies whether NMDA-R autoantibodies in peripheral blood may predispose patients with AD and SIVD to susceptibility for psychotic episodes if disturbances of blood–brain-barrier integrity occur.     

Subthreshold attention-deficit/hyperactivity disorder is associated with functional impairments across domains: a comprehensive analysis in a large-scale community study

This study compared children who experience attention-deficit/hyperactivity disorder (ADHD) symptoms but do not meet criteria (i.e., subthreshold ADHD) with those with the full syndrome and healthy controls. Presence of ADHD symptoms was determined in a nationwide community sample of 921 children, aged 8–11 years. The main outcome measures comprised attentional symptoms, comorbidity profiles, academic performance, and neurocognitive ability (i.e., ADHD Rating Scale, Child Behavior Checklist, Learning Disability Evaluation Scale, and Stroop Color-Word Test, respectively). Subthreshold ADHD was equally prevalent in boys and girls, and more prevalent in low-income families. Throughout all the outcome measurements, subthreshold ADHD was both a significantly milder condition than full syndrome ADHD and a significantly more severe condition than non-ADHD status. The findings were consistent across the total as well as the subtest scores, and after correction for multiple comparisons (p < 0.0017). Children with subthreshold ADHD were found to experience significant symptoms and functional impairments. The results of this study support the clinical relevance of subthreshold ADHD in a childhood population. Subthreshold diagnostic criteria for ADHD may be more sensitive in detecting ADHD symptoms in girls than the full syndrome criteria, and subthreshold clinical, cognitive, and behavioral symptoms of ADHD may occur in a subset of children who are possibly more sensitive to their environment. Further consideration about the diagnostic threshold for ADHD may particularly benefit girls and children in low-income families.     

Caloric restriction can improve learning ability in C57/BL mice via regulation of the insulin-PI3K/Akt signaling pathway

To identify the molecular mechanism underlying improved spatial learning ability of C57/BL mice on a caloric restricted (CR) diet. Seven-week-old male C57/BL mice were randomly divided into three groups: normal control group (NC group, n = 10), high energy group (n = 10), and low energy group (CR group, n = 10). Body mass and levels of blood glucose were measured every 2 weeks over the course of 30 weeks. After 30 weeks, metabolic parameters, serum total cholesterol, and insulin-like growth factor 1 (IGF-1) were measured, and learning and memory ability of animals were tested using the Morris water maze. The expression of insulin signaling pathway-related proteins in the brain tissues also were tested for molecular mechanism. When compared with the NC group, body weight, and levels of serum glucose decreased in the CR group and increased in the high energy group at all time points tested. Average escape latency and swimming distance were lower in the CR group as compared to the control group after 30 weeks. The serum cholesterol level of the high energy group was significantly higher than that of the control group. The expressions of IGF-1, IR, IRS-1, PI3K, Akt/PKB, and p-CREB protein in the CR group were significantly lower and the expressions of PI3K and Akt/PKB protein in the high energy group were significantly lower than those of the control group at post 30 weeks treatment. Our findings demonstrate that the low energy diet may improve hippocampus-dependent spatial learning ability in C57/BL mice, possibly through a regulatory mechanism of the insulin-PI3K/Akt signaling pathway.     

Teriflunomide reduces relapses with sequelae and relapses leading to hospitalizations: results from the TOWER study

Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing–remitting multiple sclerosis. This post hoc analysis of the Phase III TOWER study evaluated the effects of teriflunomide treatment on five severe relapse outcomes: relapses with sequelae defined by an increase in Expanded Disability Status Scale (EDSS)/functional system (FS) score (sequelae-EDSS/FS) 30 days post relapse; relapses with sequelae defined by the investigator (sequelae-investigator); relapses leading to hospitalization; relapses treated with intravenous corticosteroids; and intense relapses using the definition of Panitch et al. from the EVIDENCE study based on specified increases in EDSS for severe relapses. Adjusted annualized rates for the five severe relapse outcomes were derived using a Poisson model with robust error variance, with treatment, baseline EDSS strata and region as covariates. Compared with placebo, teriflunomide significantly reduced annualized rates of relapses with sequelae-EDSS/FS [14 mg, 36.6 % (p = 0.0021); 7 mg, 31.3 % (p = 0.0104)] and sequelae-investigator [14 mg only, 53.5 % (p = 0.0004)], relapses leading to hospitalization [14 mg only, 33.6 % (p = 0.0155)], relapses requiring intravenous corticosteroids [14 mg, 35.7 % (p = 0.0002); 7 mg, 21.5 % (p = 0.0337)], and intense relapses [14 mg only, 52.5 % (p = 0.0015)]. Patients treated with teriflunomide 14 mg spent significantly fewer nights in hospital for relapse (p = 0.009) and had lower annualized rates of all hospitalizations (p = 0.030). Taken together, the positive effects of teriflunomide on severe relapses indicate that teriflunomide may reduce relapse-related healthcare costs.