Investigating survival, quality of life and cognition in PROton versus photon therapy for IDH-mutated diffuse grade 2 and 3 GLIOmas (PRO-GLIO): a randomised controlled trial in Norway and Sweden.

INTRODUCTION: The use of proton therapy increases globally despite a lack of randomised controlled trials demonstrating its efficacy and safety. Proton therapy enables sparing of non-neoplastic tissue from radiation. This is principally beneficial and holds promise of reduced long-term side effects. However, the sparing of seemingly non-cancerous tissue is not necessarily positive for isocitrate dehydrogenase (IDH)-mutated diffuse gliomas grade 2-3, which have a diffuse growth pattern. With their relatively good prognosis, yet incurable nature, therapy needs to be delicately balanced to achieve a maximal survival benefit combined with an optimised quality of life. METHODS AND ANALYSIS: PRO-GLIO (PROton versus photon therapy in IDH-mutated diffuse grade 2 and 3 GLIOmas) is an open-label, multicentre, randomised phase III non-inferiority study. 224 patients aged 18-65 years with IDH-mutated diffuse gliomas grade 2-3 from Norway and Sweden will be randomised 1:1 to radiotherapy delivered with protons (experimental arm) or photons (standard arm). First intervention-free survival at 2 years is the primary endpoint. Key secondary endpoints are fatigue and cognitive impairment, both at 2 years. Additional secondary outcomes include several survival measures, health-related quality of life parameters and health economy endpoints. ETHICS AND DISSEMINATION: To implement proton therapy as part of standard of care for patients with IDH-mutated diffuse gliomas grade 2-3, it should be deemed safe. With its randomised controlled design testing proton versus photon therapy, PRO-GLIO will provide important information for this patient population concerning safety, cognition, fatigue and other quality of life parameters. As proton therapy is considerably more costly than its photon counterpart, cost-effectiveness will also be evaluated. PRO-GLIO is approved by ethical committees in Norway (Regional Committee for Medical & Health Research Ethics) and Sweden (The Swedish Ethical Review Authority) and patient inclusion has commenced. Trial results will be published in international peer-reviewed journals, relevant conferences, national and international meetings and expert forums. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05190172).

Coping strategies in patients with good outcome but chronic fatigue after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Fatigue is a highly prevalent and debilitating symptom among patients in the chronic phase of aneurysmal subarachnoid haemorrhage (aSAH) with no identified effective treatment. Cognitive therapy has been shown to have moderate effects on fatigue. Delineating the coping strategies used by patients with post-aSAH fatigue and relating them to fatigue severity and emotional symptoms could be a step towards developing a behavioural therapy for post-aSAH fatigue. METHODS: Ninety-six good outcome patients with chronic post-aSAH fatigue answered the questionnaires Brief COPE, (a questionnaire defining 14 coping strategies and three Coping Styles), the Fatigue Severity Scale (FSS), Mental Fatigue Scale (MFS), Beck Depression Inventory (BDI-II) and Beck Anxiety Inventory (BAI). The Brief COPE scores were compared with fatigue severity and emotional symptoms of the patients. RESULTS: The prevailing coping strategies were "Acceptance", "Emotional Support", "Active Coping" and "Planning". "Acceptance" was the sole coping strategy that was significantly inversely related to levels of fatigue. Patients with the highest scores for mental fatigue and those with clinically significant emotional symptoms applied significantly more maladaptive avoidant strategies. Females and the youngest patients applied more "Problem-Focused" strategies. CONCLUSION: A therapeutic behavioural model aiming at furthering "Acceptance" and reducing passivity and "Avoidant" strategies may contribute to alleviate post-aSAH fatigue in good outcome patients. Given the chronic nature of post-aSAH fatigue, neurosurgeons may encourage patients to accept their new situation so that they can start a process of positive reframing instead of being trapped in a spiral of futile loss of energy and secondary increased emotional burden and frustration.

(-)-OSU6162 in the treatment of fatigue and other sequelae after aneurysmal subarachnoid hemorrhage: a double-blind, randomized, placebo-controlled study.

OBJECTIVE: Fatigue after aneurysmal subarachnoid hemorrhage (aSAH) is common and usually long-lasting, and it has a considerable negative impact on health-related quality of life (HRQOL), social functioning, and the ability to return to work (RTW). No effective treatment exists. The dopaminergic regulator (-)-OSU6162 has shown promising results regarding the mitigation of fatigue in various neurological diseases, and therefore the authors aimed to investigate the efficacy of (-)-OSU6162 in alleviating fatigue and other sequelae after aSAH. METHODS: A double-blind, randomized, placebo-controlled, single-center trial was performed in which 96 participants with post-aSAH fatigue were administered 30-60 mg/day of (-)-OSU6162 or placebo over a period of 12 weeks. Efficacy was assessed using the Fatigue Severity Scale (FSS), the Mental Fatigue Scale (MFS), the Beck Anxiety Inventory (BAI), the Beck Depression Inventory II (BDI-II), the SF-36 questionnaire, and a neuropsychological test battery. Assessments were performed at baseline, after 1, 4, 8, and 12 weeks of treatment, and at follow-up, 8 weeks after treatment. RESULTS: The 96 participants with post-aSAH fatigue were randomized to treatment with (-)-OSU6162 (n = 49) or placebo (n = 47). The FSS, MFS, and BDI scores improved significantly in both groups after 12 weeks of treatment, whereas the BAI scores improved in the placebo group only. HRQOL improved significantly in the SF-36 domain "Vitality" in both groups. Neuropsychological test performances were within the normal range at baseline and not affected by treatment. The FSS score was distinctly improved in patients with complete RTW upon treatment with (-)-OSU6162. Concomitant use of antidepressants improved the efficacy of (-)-OSU6162 on the FSS score at week 1 beyond the placebo response, and correspondingly the use of beta- or calcium-channel blockers improved the (-)-OSU6162 efficacy beyond the placebo response in MFS scores at week 4 of treatment. There was a significant correlation between improvement in FSS, BAI, and BDI scores and the plasma concentration of (-)-OSU6162 at the dose of 60 mg/day. No serious adverse events were attributable to the treatment, but dizziness was reported more often in the (-)-OSU6162 group. CONCLUSIONS: Fatigue and other sequelae after aSAH were similarly alleviated by treatment with (-)-OSU6162 and placebo. (-)-OSU6162 improved fatigue, as measured with the FSS score, significantly in patients with complete RTW. There seemed to be synergetic effects of (-)-OSU6162 and medications interfering with dopaminergic pathways that should be explored further. The strong placebo response may be exploited in developing nonpharmacological treatment programs for post-aSAH fatigue.

Fatigue After Aneurysmal Subarachnoid Hemorrhage: Clinical Characteristics and Associated Factors in Patients With Good Outcome.

Fatigue after aneurysmal subarachnoid hemorrhage (post-aSAH fatigue) is a frequent, often long-lasting, but still poorly studied sequel. The aim of the present study was to characterize the nature of post-aSAH fatigue with an itemized analysis of the Fatigue Severity Scale (FSS) and Mental Fatigue Scale (MFS). We further wanted to assess the association of fatigue with other commonly observed problems after aSAH: mood disorders, cognitive problems, health-related quality of life (HRQoL), weight gain, and return to work (RTW). Ninety-six good outcome aSAH patients with fatigue completed questionnaires measuring fatigue, depression, anxiety, and HRQoL. All patients underwent a physical and neurological examination. Cognitive functioning was assessed with a neuropsychological test battery. We also registered prior history of fatigue and mood disorders as well as occupational status and RTW. The patients experienced fatigue as being among their three most disabling symptoms and when characterizing their fatigue they emphasized the questionnaire items "low motivation," "mental fatigue," and "sensitivity to stress." Fatigue due to exercise was their least bothersome aspect of fatigue and weight gain was associated with depressive symptoms rather than the severity of fatigue. Although there was a strong association between fatigue and mood disorders, especially for depression, the overlap was incomplete. Post-aSAH fatigue related to reduced HRQoL. RTW was remarkably low with only 10.3% of patients returning to their previous workload. Fatigue was not related to cognitive functioning or neurological status. Although there was a strong association between fatigue and depression, the incomplete overlap supports the notion of these two being distinct constructs. Moreover, post-aSAH fatigue can exist without significant neurological or cognitive impairments, but is related to reduced HRQoL and contributes to the low rate of RTW.

Effectiveness of Combining Compensatory Cognitive Training and Vocational Intervention vs. Treatment as Usual on Return to Work Following Mild-to-Moderate Traumatic Brain Injury: Interim Analysis at 3 and 6 Month Follow-Up.

Aims: Knowledge regarding the most effective return to work (RTW) approaches after traumatic brain injury (TBI) is lacking. This trial aimed to compare the effectiveness of a combined cognitive and vocational intervention to treatment as usual (TAU) on RTW and work stability after TBI. Methods: We performed a parallel-group randomized controlled trial (RCT) at a TBI outpatient clinic at Oslo University Hospital (OUH), Norway. Patients with a history of mild-to-moderate TBI (n = 116) aged 18-60 were randomized (1:1) by an independent investigator to receive group-based compensatory cognitive training (CCT) and supported employment (SE) (n = 60) or TAU consisting of individualized multidisciplinary treatment (n = 56). Participants were enrolled 2-3 months post-injury. The nature of the intervention prevented blinding of patients and therapists, however, outcome assessors were blinded to group allocation. The primary outcome measure was RTW at 3 and 6 months following study inclusion. Secondary outcomes were work percentage, stability, and productivity. The present study provides results from an interim analysis from the first two planned follow ups, while subsequent publications will present results up to 12 months following study inclusion. Results: Mixed effects models showed no between-group differences in the RTW proportion, work percentage, and hours worked between CCT-SE and TAU from baseline to 6 months. A significantly higher proportion of participants in CCT-SE had returned to work at 3 months when adjusting for baseline differences. The majority of participants who were employed at 3 and 6 months were stably employed. There was a statistically significant within-group improvement on RTW proportion, hours worked and work percentage in both groups. Conclusion: The results revealed no difference between CCT-SE and TAU on work-related outcomes from baseline to 6 months. However, there was a higher RTW proportion in the CCT-SE group compared to TAU at 3 months. Future publications will assess the effectiveness of CCT-SE vs. TAU up to 12 months. Clinical Trial Registration: US National Institutes of Health ClinicalTrials.gov, identifier #NCT03092713.

Prevalence and predictors of fatigue after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Fatigue is a common and disabling sequel after aneurysmal subarachnoid hemorrhage (aSAH). At present, prevalence estimates of post-aSAH fatigue in the chronic phase are scarce and vary greatly. Factors from the acute phase of aSAH have hitherto barely been associated with post-aSAH fatigue in the chronic phase. METHODS: Prospective study assessing prevalence of fatigue using the Fatigue Severity Scale (FSS) in patients who were living independently 1 to 7 years after aSAH. We compared demographic, medical, and radiological variables from the acute phase of aSAH between patients with and without fatigue (FSS ≥ 4 versus < 4) and searched for predictors of fatigue among these variables applying univariable and multivariable regression analyses. RESULTS: Of 726 patients treated for aSAH in the period between January 2012 and December 2017, 356 patients completed the assessment. The mean FSS score was 4.7 ± 1.7, and fatigue was present in 69.7%. The frequency of patients with fatigue did not decline significantly over time. Univariable analysis identified nicotine use, loss of consciousness at ictus (LOCi), rebleed prior to aneurysm repair, reduced consciousness to Glasgow Coma Scale (GCS) < 14, large amounts of subarachnoid blood, the presence of acute hydrocephalus, and severe vasospasm as factors that were significantly associated with fatigue. In multivariable analysis, nicotine use, reduced GCS, and severe vasospasm were independent predictors that all more than doubled the risk to develop post-aSAH fatigue. CONCLUSIONS: Fatigue is a frequent sequel persisting several years after aSAH. Nicotine use, reduced consciousness at admission, and severe vasospasm are independent predictors of fatigue from the acute phase of aSAH. We propose inflammatory cytokines causing dopamine imbalance to be a common denominator for post-aSAH fatigue and the presently identified predictors.

Combined cognitive and vocational interventions after mild to moderate traumatic brain injury: study protocol for a randomized controlled trial.

BACKGROUND: A considerable proportion of patients with mild to moderate traumatic brain injury (TBI) experience long-lasting somatic, cognitive, and emotional symptoms that may hamper their capacity to return to work (RTW). Although several studies have described medical, psychological, and work-related factors that predict RTW after TBI, well-controlled intervention studies regarding RTW are scarce. Furthermore, there has traditionally been weak collaboration among health-related rehabilitation services, the labor and welfare sector, and workplaces. METHODS/DESIGN: This study protocol describes an innovative randomized controlled trial in which we will explore the effect of combining manualized cognitive rehabilitation (Compensatory Cognitive Training [CCT]) and supported employment (SE) on RTW and related outcomes for patients with mild to moderate TBI in real-life competitive work settings. The study will be carried out in the southeastern region of Norway and thereby be performed within the Norwegian welfare system. Patients aged 18-60 years with mild to moderate TBI who are employed in a minimum 50% position at the time of injury and sick-listed 50% or more for postconcussive symptoms 2 months postinjury will be included in the study. A comprehensive assessment of neurocognitive function, self-reported symptoms, emotional distress, coping style, and quality of life will be performed at baseline, immediately after CCT (3 months after inclusion), following the end of SE (6 months after inclusion), and 12 months following study inclusion. The primary outcome measures are the proportion of participants who have returned to work at 12-month follow-up and length of time until RTW, in addition to work stability as well as work productivity over the first year following the intervention. Secondary outcomes include changes in self-reported symptoms, emotional and cognitive function, and quality of life. Additionally, a qualitative RTW process evaluation focused on organizational challenges at the workplace will be performed. DISCUSSION: The proposed study will combine cognitive and vocational rehabilitation and explore the efficacy of increased cross-sectoral collaboration between specialized health care services and the labor and welfare system. If the intervention proves effective, the project will describe the cost-effectiveness and utility of the program and thereby provide important information for policy makers. In addition, knowledge about the RTW process for persons with TBI and their workplaces will be provided. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03092713 . Registered on 10 March 2017.

Effect of early mobilization and rehabilitation on complications in aneurysmal subarachnoid hemorrhage.

OBJECTIVE Early rehabilitation is effective in an array of acute neurological disorders but it is not established as part of treatment guidelines after aneurysmal subarachnoid hemorrhage (aSAH). This may in part be due to the fear of aggravating the development of cerebral vasospasm, which is the most feared complication of aSAH. The aim of this study was to evaluate the effect of early rehabilitation and mobilization on complications during the acute phase and within 90 days after aSAH. METHODS This was a prospective, interventional study that included patients with aSAH at the neuro-intermediate ward after aneurysm repair. The control group received standard treatment, whereas the early rehab group underwent early rehabilitation and mobilization in addition to standard treatment. Clinical and radiological characteristics of patients with aSAH, progression in mobilization, and treatment variables were registered. The frequency and severity of cerebral vasospasm, cerebral infarction acquired in conjunction with the aSAH, and acute and chronic hydrocephalus, as well as pulmonary and thromboembolic complications, were compared between the 2 groups. RESULTS Clinical and radiological characteristics of patients with aSAH were similar between the groups. The early rehab group was mobilized beginning on the first day after aneurysm repair. The significantly quicker and higher degree of mobilization in the early rehab group did not increase complications. Clinical cerebral vasospasm was not as frequent in the early rehab group and it also tended to be less severe. Each step of mobilization achieved during the first 4 days after aneurysm repair reduced the risk of severe vasospasm by 30%. Acute and chronic hydrocephalus were similar in both groups, but there was a tendency toward earlier shunt implantation among patients in the control group. Pulmonary infections, thromboembolic events, and death before discharge or within 90 days after the ictus were similar between the 2 groups. CONCLUSIONS Early rehabilitation of patients after aSAH is safe and feasible. The earlier and higher degree of mobilization does not increase neurosurgical complications. Rather, the frequency and severity of cerebral vasospasm following aSAH are alleviated and are not aggravated by early rehabilitation. Clinical trial registration no.: NCT01656317 ( www.clinicaltrials.gov ).

Impact of early mobilization and rehabilitation on global functional outcome one year after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: To assess the impact of early mobilization and rehabilitation on global functional outcome one year after aneurysmal subarachnoid haemorrhage. METHODS: Prospective, controlled, interventional study comprising patients managed in the neuro-intermediate ward following repair of a ruptured intracranial aneurysm. Patients in the Control group (n = 76) received standard treatment, whereas those in the Early Rehab group (n = 92) in addition underwent early mobilization and rehabilitation. Demographic, clinical and intervention data were registered. Global functional outcome was assessed using the modified Rankin Scale and the Glasgow Outcome Scale Extended. RESULTS: The 2 groups were similar in their demographic and clinical characteristics. Early Rehab group patients were mobilized more quickly (p < 0.001), median 1.4 days (range 0-23 days) after aneurysm repair. After 1 year, 47% of the patients had made a good recovery, whereas 6.5% had died. Regression analysis did not reveal any significant effect of early rehabilitation on functional outcome. However, in poor-grade patients, early rehabilitation more than doubled the chance of a favourable outcome (adjusted odds ratio = 2.33; confidence interval 1.04-5.2, p = 0.039). CONCLUSION: Early mobilization and rehabilitation probably increases the chance of a good functional outcome in poor-grade aneurysmal subarachnoid haemorrhage patients.