Impact of extent of resection on outcome from glioblastoma using the RANO resect group classification system: a retrospective, population-based cohort study.

Background: Extent of resection (EOR) is associated with survival in glioblastoma. A standardized classification for EOR was lacking until a system was recently proposed by the response assessment in neuro-oncology (RANO) resect group. We aimed to assess EOR in an unselected glioblastoma cohort and use this classification system to evaluate the impact on survival in a real-world setting. Methods: We retrospectively identified all patients with histologically confirmed glioblastoma in Western Norway between 1.1.2007 and 31.12.2014. Volumetric analyses were performed using a semi-automated method. EOR was categorized according to the recent classification system. Kaplan-Meier method and Cox proportional hazard ratios were applied for survival analyses. Results: Among 235 included patients, biopsy (EOR class 4) was performed in 50 patients (21.3%), submaximal contrast enhancement (CE) resection (EOR class 3) in 66 patients (28.1%), and maximal CE resection (EOR class 2) in 119 patients (50.6%). Median survival was 6.2 months, 9.2 months, and 14.9 months, respectively. Within EOR class 2, 80 patients underwent complete CE resection (EOR class 2A) and had a median survival of 20.0 months, while 39 patients had a near-total CE resection, with ≤1 cm3 CE residual volume (EOR class 2B), and a median survival of 11.1 months, P < 0.001. The 2-year survival rate in EOR class 2A was 40.0%, compared to 7.7% in EOR class 2B. Conclusions: RANO resect group classification for the extent of resection reflected outcome from glioblastoma in a real-world setting. There was significantly superior survival after complete CE resection compared to near-total resection.

Butterfly glioblastoma: Clinical characteristics, treatment strategies and outcomes in a population-based cohort.

Background: Butterfly glioblastoma is a rare subgroup of glioblastoma with a bihemispheric tumor crossing the corpus callosum, and is associated with a dismal prognosis. Prognostic factors are previously sparsely described and optimal treatment remains uncertain. We aimed to analyze clinical characteristics, treatment strategies, and outcomes from butterfly glioblastoma in a real-world setting. Methods: This retrospective population-based cohort study included patients diagnosed with butterfly glioblastoma in Western Norway between 01/01/2007 and 31/12/2014. We enrolled patients with histologically confirmed glioblastoma and patients with a diagnosis based on a typical MRI pattern. Clinical data were extracted from electronic medical records. Molecular and MRI volumetric analyses were retrospectively performed. Survival analyses were performed using the Kaplan-Meier method and Cox proportional hazards regression models. Results: Among 381 patients diagnosed with glioblastoma, 33 patients (8.7%) met the butterfly glioblastoma criteria. Median overall survival was 5.5 months (95% CI 3.1-7.9) and 3-year survival was 9.1%. Hypofractionated radiation therapy with or without temozolomide was the most frequently used treatment strategy, given to 16 of the 27 (59.3%) patients receiving radiation therapy. Best supportive care was associated with poorer survival compared with multimodal treatment [adjusted hazard ratio 5.11 (95% CI 1.09-23.89)]. Conclusion: Outcome from butterfly glioblastoma was dismal, with a median overall survival of less than 6 months. However, long-term survival was comparable to that observed in non-butterfly glioblastoma, and multimodal treatment was associated with longer survival. This suggests that patients with butterfly glioblastoma may benefit from a more aggressive treatment approach despite the overall poor prognosis.

CSF neurofilament light chain predicts 10-year clinical and radiologic worsening in multiple sclerosis.

BACKGROUND: Neurofilament light chain (NfL) is an attractive biomarker of disease activity and progression in MS, but there is a lack in long-term prognostic data. OBJECTIVE: To test the long-term clinical and radiological prognostic value of cerebrospinal fluid (CSF)-NfL among newly diagnosed patients with MS. METHODS: Newly diagnosed MS patients where followed prospectively with baseline CSF-NfL and repeated MRI and clinical assessments for up to 10 years. Associations between baseline CSF-NfL and longitudinal MRI and clinical assessments were found by Generalized Estimating Equations analysis. RESULTS: Forty-two participants were included. CSF-NfL at baseline was significantly associated with the rate of atrophy in globus pallidus (p = 0.009) and hippocampus (p = 0.001) as evaluated by MRI. Baseline volumes of thalamus (ß -0.33; 95% CI -0.57 to -0.10, p = 0.006), T1 (ß 0.28; 95% CI 0.11 to 0.44, p = 0.001) and T2 (ß 0.16; 95% CI 0.04 to 0.27, p = 0.008) lesions and baseline levels of CSF-NfL (ß 0.9; 95% CI 0.3 to 1.5, p = 0.002) significantly predicted EDSS worsening over 10 years. Baseline CSF-NfL gave a comparable prediction to the best MRI volumetric predictors. CONCLUSION: CSF-NfL predicted the clinical and radiological course of newly diagnosed patients with MS over a 10-year period, underlining its prognostic role.

Treatment approach and survival from glioblastoma: results from a population-based retrospective cohort study from Western Norway.

OBJECTIVES: To evaluate treatment and survival from glioblastoma in a real-world setting. DESIGN AND SETTINGS: A population-based retrospective cohort study from Western Norway. PARTICIPANTS: 363 patients aged 18 years or older diagnosed with glioblastoma between 1 January 2007 and 31 December 2014. PRIMARY AND SECONDARY OUTCOME MEASURES: Overall survival and survival rates determined by Kaplan-Meier method, groups compared by log-rank test. Associations between clinical characteristics and treatment approach assessed by logistic regression. Associations between treatment approach and outcome analysed by Cox regression. RESULTS: Median overall survival was 10.2 months (95% CI 9.1 to 11.3). Resection was performed in 221 patients (60.9%), and was inversely associated with age over 70 years, higher comorbidity burden, deep-seated tumour localisation and multifocality. Median survival was 13.7 months (95% CI 12.1 to 15.4) in patients undergoing tumour resection, 8.3 months (95% CI 6.6 to 9.9) in patients undergoing biopsy and 4.5 months (95% CI 4.0 to 5.1) in patients where no surgical intervention was performed. Chemoradiotherapy according to the Stupp protocol was given to 157 patients (43%). Age over 70 years, higher comorbidity burden and cognitive impairment were associated with less intensive chemoradiotherapy. Median survival was 16.3 months (95% CI 14.1 to 18.5), 7.9 months (95% CI 6.7 to 9.0) and 2.0 months (95% CI 0.9 to 3.2) in patients treated according to the Stupp protocol, with less intensive chemoradiotherapy and with best supportive care, respectively. Surgical resection (HR 0.61 (95% CI 0.47 to 0.79)) and chemoradiotherapy according to the Stupp protocol (HR 0.09 (95% CI 0.06 to 0.15)) were strongly associated with favourable overall survival, when adjusted for clinical variables. CONCLUSIONS: In a real-world setting, less than half of the patients received full-course chemoradiotherapy, with a median survival comparable to results from clinical trials. Survival was considerably worse in patients receiving less intensive treatment. Our results point out a substantial risk of undertreating glioblastoma, especially in elderly patients.

Brain atrophy and clinical characteristics predicting SDMT performance in multiple sclerosis: A 10-year follow-up study.

OBJECTIVES: To identify Magnetic Resonance Imaging (MRI), clinical and demographic biomarkers predictive of worsening information processing speed (IPS) as measured by Symbol Digit Modalities Test (SDMT). METHODS: Demographic, clinical data and 1.5 T MRI scans were collected in 76 patients at time of inclusion, and after 5 and 10 years. Global and tissue-specific volumes were calculated at each time point. For the primary outcome of analysis, SDMT was used. RESULTS: Worsening SDMT at 5-year follow-up was predicted by baseline age, Expanded Disability Status Scale (EDSS), SDMT, whole brain volume (WBV) and T2 lesion volume (LV), explaining 30.2% of the variance of SDMT. At 10-year follow-up, age, EDSS, grey matter volume (GMV) and T1 LV explained 39.4% of the variance of SDMT change. CONCLUSION: This longitudinal study shows that baseline MRI-markers, demographic and clinical data can help predict worsening IPS. Identification of patients at risk of IPS decline is of importance as follow-up, treatment and rehabilitation can be optimized.

Brain atrophy and employment in multiple sclerosis patients: a 10-year follow-up study.

BACKGROUND: Multiple sclerosis is often associated with unemployment. The contribution of grey matter atrophy to unemployment is unclear. OBJECTIVES: To identify magnetic resonance imaging biomarkers of grey matter and clinical symptoms associated with unemployment in multiple sclerosis patients. METHODS: Demographic, clinical data and 1.5 T magnetic resonance imaging scans were collected in 81 patients at the time of inclusion and after 5 and 10 years. Global and tissue-specific volumes were calculated at each time point. Statistical analysis was performed using a mixed linear model. RESULTS: At baseline 31 (38%) of the patients were unemployed, at 5-year follow-up 44 (59%) and at 10-year follow-up 34 (81%) were unemployed. The unemployed patients had significantly lower subcortical deep grey matter volume (P < 0.001), specifically thalamus, pallidus, putamen and hippocampal volumes, and cortical volume (P = 0.011); and significantly greater T1 (P < 0.001)/T2 (P < 0.001) lesion volume than the employed patient group at baseline. Subcortical deep grey matter volumes, and to a lesser degree cortical volume, were significantly associated with unemployment throughout the follow-up. CONCLUSION: We found significantly greater atrophy of subcortical deep grey matter and cortical volume at baseline and during follow-up in the unemployed patient group. Atrophy of subcortical deep grey matter showed a stronger association to unemployment than atrophy of cortical volume during the follow-up.

Neurofilaments and 10-year follow-up in multiple sclerosis.

BACKGROUND: The role of biomarkers to predict clinical outcome in multiple sclerosis (MS) is still debated. OBJECTIVE: To test whether cerebrospinal fluid (CSF) light-chain neurofilament (NfL) levels in newly diagnosed patients with MS could predict clinical outcome over a 10-year period. METHODS: Patients with newly diagnosed MS underwent standardized clinical assessments at baseline and 5 and 10 years of follow-up. Expanded Disability Status Scale (EDSS) progression between assessments was defined as an increase in one point or more if <6 and 0.5 or more if ≥6. CSF obtained at baseline was analyzed for levels of NfL using enzyme-linked immunosorbent assay technology. RESULTS: A total of 44 patients were included. In all, 35 patients (80%) had relapsing-remitting multiple sclerosis (RRMS). Patients who progressed in EDSS showed a trend for higher median baseline CSF-NfL levels than patients who did not progress after 5 years (947 ng/L vs 246 ng/L, p = 0.05), and although not statistically significant, after 10 years (708 ng/L vs 265 ng/L, p = 0.28). Patients who converted from RRMS to secondary-progressive multiple sclerosis (SPMS) at 5 years had a statistical significant higher median CSF level of NfL (2122 ng/L vs 246 ng/L, p = 0.01). CONCLUSION: CSF levels of NfL at the time of diagnosis seems to be an early predictive biomarker of long-term clinical outcome and conversion from RRMS to SPMS.

The influence of coping styles on long-term employment in multiple sclerosis: A prospective study.

BACKGROUND: The aim was to investigate predictive values of coping styles, clinical and demographic factors on time to unemployment in patients diagnosed with multiple sclerosis (MS) during 1998-2002 in Norway. METHOD: All patients ( N = 108) diagnosed with MS 1998-2002 in Hordaland and Rogaland counties, Western Norway, were invited to participate in the long-term follow-up study in 2002. Baseline recordings included disability scoring (Expanded Disability Status Scale (EDSS)), fatigue (Fatigue Severity Scale (FSS)), depression (Beck Depression Inventory (BDI)), and questionnaire assessing coping (the Dispositional Coping Styles Scale (COPE)). Logistic regression analysis was used to identify factors associated with unemployed at baseline, and Cox regression analysis to identify factors at baseline associated with time to unemployment during follow-up. RESULTS: In all, 41 (44%) were employed at baseline. After 13 years follow-up in 2015, mean disease duration of 22 years, 16 (17%) were still employed. Median time from baseline to unemployment was 6 years (±5). Older age at diagnosis, female gender, and depression were associated with patients being unemployed at baseline. Female gender, long disease duration, and denial as avoidant coping strategy at baseline predicted shorter time to unemployment. CONCLUSION: Avoidant coping style, female gender, and longer disease duration were associated with shorter time to unemployment. These factors should be considered when advising patients on MS and future employment.

Preclinical disease activity in multiple sclerosis: A prospective study of cognitive performance prior to first symptom.

OBJECTIVE: To prospectively investigate potential signs of preclinical multiple sclerosis (MS) activity and when they are present prior to first symptom using data from a historical cohort. METHODS: We linked the cognitive performance of all Norwegian men born 1950-1995 who underwent conscription examination at age 18 to 19 years to the Norwegian MS registry to identify those later developing MS, and randomly selected controls frequency-matched on year of birth from the Norwegian Conscript Service database. In this nested case-control study, cognitive test scores were available for 924 male cases and 19,530 male controls. We estimated mean score differences among cases and controls (Student t test) and the risk of developing MS comparing lower to higher scores (Cox regression) in strata of years to clinical onset. RESULTS: Men developing first clinical MS symptoms up to 2 years after the examination scored significantly lower than controls (Δ = 0.80, p = 0.0095), corresponding to a 6 intelligence quotient (IQ)-point difference. Those scoring lowest, that is, >1 standard deviation below the controls' mean, had an increased MS risk during the 2 following years (relative risk = 2.81, 95% confidence interval = 1.52-5.20). Whereas results were similar for relapsing-remitting MS cases (RRMS), those developing primary-progressive MS (PPMS) scored a significant 4.6 to 6.9 IQ points lower than controls up to 20 years prior to first progressive symptoms. INTERPRETATION: RRMS may start years prior to clinical presentation, and disease processes in PPMS could start decades prior to first apparent progressive symptoms. Cognitive problems could be present in both MS forms before apparent symptoms. Apart from potential implications for clinical practice and research, these findings challenge our thinking about the disease. Ann Neurol 2016;80:616-624.

Guillain Barré syndrome--Incidence and clinical course in Southern Rogaland, Norway.

OBJECTIVE: To establish the incidence and clinical course of Guillain Barré syndrome (GBS) in a well-defined geographical area. PATIENTS AND METHODS: All patients older than 16 years of age diagnosed with GBS were prospectively invited to join a follow-up study for two years. RESULTS: Seventeen patients were diagnosed with GBS; an incidence rate of 2.28/100,000 in 2006/2007, and 3.19/100,000 in 2007/2008 with an equal gender distribution. Eleven patients accepted follow up, and more than 50% had milder forms of GBS with preserved walking ability and a Hughes score ≤ 2. None required assisted ventilation in this period, and only one patient had a MRC score <40. Three patients were simultaneously diagnosed with SIADH. Nine patients received IvIg treatment and clinical improvement measured by MRC and INCAT was seen during the first three months, but the patients subjective perceptions of health and symptoms measured using VAS, FSS, and SF-36 were reduced the first 12 months after diagnosis. CONCLUSION: Incidence of GBS in a well-defined area varied between 2.28-3.19/100 000, and more than 50% of patients were mildly affected. Despite a good clinical recovery after three months and subsequent improvement on self-assessed health items, patients with GBS rated their health lower than expected after one year.

Wernicke's Encephalopathy Mimicking Acute Onset Stroke Diagnosed by CT Perfusion.

Background. Metabolic syndromes such as Wernicke's encephalopathy may present with a sudden neurological deficit, thus mimicking acute onset stroke. Due to current emphasis on rapid admission and treatment of acute stroke patients, there is a significant risk that these stroke mimics may end up being treated with thrombolysis. Rigorous clinical and radiological skills are necessary to correctly identify such metabolic stroke mimics, in order to avoid doing any harm to these patients due to the unnecessary use of thrombolysis. Patient. A 51-year-old Caucasian male was admitted to our hospital with suspicion of an acute stroke due to sudden onset dysarthria and unilateral facial nerve paresis. Clinical examination revealed confusion and dysconjugate gaze. Computed tomography (CT) including a CT perfusion (CTP) scan revealed bilateral thalamic hyperperfusion. The use of both clinical and radiological findings led to correctly diagnosing Wernicke's encephalopathy. Conclusion. The application of CTP as a standard diagnostic tool in acute stroke patients can improve the detection of stroke mimics caused by metabolic syndromes as shown in our case report.

Brain atrophy and disability progression in multiple sclerosis patients: a 10-year follow-up study.

OBJECTIVES: To identify MRI biomarkers associated with long-term disability progression in patients with multiple sclerosis (MS), and to define the rate of evolution of global, tissue-specific and regional atrophy in patients with MS over long-term. METHODS: MRI of the brain and clinical neurological assessment was performed in 81 patients at time of first visit and after 5 and 10 years of follow-up. MRI was acquired on 1.5 T scanners. T1-lesion and T2-lesion volumes (LVs) were calculated. Global and tissue-specific atrophy changes were longitudinally assessed, using a direct measurement approach, by calculating percentage volume changes between different time points. Regional tissue volumes for the subcortical deep grey matter (SDGM) structures were also obtained. Disability progression was defined as an increase in Expanded Disability Status Scale of ≥ 1.0 compared to baseline at 5-year and 10-year follow-up. RESULTS: Over 5 years, patients with disability progression showed significantly increased loss of whole brain (-3.8% vs -2.0%, p<0.001), cortical (-3.4% vs -1.8%, p=0.009) and putamen volume changes (-10.6% vs -3.8%, p=0.003) compared to patients with no disability progression. No significant change in white matter (WM) volume was observed when comparing progressing and non-progressing patients. Over 10 years, there was a trend for greater decrease in whole brain volume (-5.5% vs -3.7%, p=0.015) in the progressing patients. No significant changes in LV measures were detected between the patients with and without disability progression. CONCLUSION: This long-term study shows that whole brain, cortical and putamen atrophy occurs throughout the 10-year follow-up of this MS cohort and is more pronounced in the group that showed disability progression at 5, but not at 10 years of follow-up. Overall, GM atrophy showed better association with disease progression than WM atrophy over 5-year and 10-year follow-up.

Risk of MS is not associated with exposure to crude oil, but increases with low level of education.

BACKGROUND: Offshore workers in the Norwegian upstream petroleum industry are exposed to a number of chemicals such as organic solvents, mineral oils and other hydrocarbons, possibly contributing to an increased risk of multiple sclerosis (MS). OBJECTIVE: To estimate the risk of MS in this population compared with the general working population in Norway, adjusting for education. METHODS: Using the Norwegian Registry of Employers and Employees we included all 27,900 offshore workers registered from 1981 to 2003 and 366,805 referents from the general working population matched by gender, age and community of residence. The cohort was linked to the Norwegian MS Registry and the Norwegian Education Registry. RESULTS: There was no increased risk of MS among the offshore workers. We found a marked and linear inverse relationship between level of education and the risk of MS in the total study population, with a rate ratio of 0.48 (95% CI, 0.53 to 0.88) for workers with a graduate degree compared to workers with elementary school only. CONCLUSIONS: These findings do not support a major aetiological role of petroleum-based products, but rather point to smoking and other lifestyle factors related to the level of education as being important for the risk of MS.

Update on current and emerging treatment options for post-polio syndrome.

Post-polio syndrome (PPS) refers to the clinical deterioration experienced by many polio survivors several decades after their acute illness. The symptoms are new muscle weakness, decreased muscle endurance, fatigue, muscle pain, joint pain, cold intolerance, and this typical clinical entity is reported from different parts of the world. The pathophysiology behind PPS is not fully understood, but a combination of distal degeneration of enlarged motor units caused by increased metabolic demands and the normal aging process, in addition to inflammatory mechanisms, are thought to be involved. There is no diagnostic test for PPS, and the diagnosis is based on a proper clinical workup where all other possible explanations for the new symptoms are ruled out. The basic principle of management of PPS lies in physical activity, individually tailored training programs, and lifestyle modification. Muscle weakness and muscle pain may be helped with specific training programs, in which training in warm water seems to be particularly helpful. Properly fitted orthoses can improve the biomechanical movement pattern and be energy-saving. Fatigue can be relieved with lifestyle changes, assistive devices, and training programs. Respiratory insufficiency can be controlled with noninvasive respiratory aids including biphasic positive pressure ventilators. Pharmacologic agents like prednisone, amantadine, pyridostigmine, and coenzyme Q10 are of no benefit in PPS. Intravenous immunoglobulin (IVIG) has been tried in three studies, all having positive results. IVIG could probably be a therapeutic alternative, but the potential benefit is modest, and some important questions are still unanswered, in particular to which patients this treatment is useful, the dose, and the therapeutic interval.

Late-onset familial amyloid polyneuropathy (FAP) Val30Met without family history.

Familial amyloid polyneuropathy (FAP) is rare and most commonly caused by the Val30Met mutation of the transthyretin (TTR) gene. Beside polyneuropathy, other complications due to amyloid deposits occur, but may vary in phenotype. The mutation tends to occur in endemic clusters. We describe a 65-year-old man from a non-endemic FAPVal30Met area who developed a progressive generalized painless axonal sensorimotor polyneuropathy with mild autonomic involvement and absent FAP symptoms in the family. Nerve biopsy showed amyloid deposits, staining with TTR-antibodies on immunohistochemistry. After DNA-sequencing of the TTR gene, the diagnosis of FAP Val30Met was made. Late-onset FAP Val30Met is a progressive and fatal disorder with varying penetrance, and may occur in non-endemic areas and cases without a family history.

Perceived disability, fatigue, pain and measured isometric muscle strength in patients with post-polio symptoms.

BACKGROUND AND PURPOSE: Several years after the acute polio illness, patients may develop new post-polio symptoms. The purpose of the present study was to evaluate patients with post-polio symptoms with regard to perceived fatigue, functional ability, muscle strength, pain and with regard to measured physical fitness and isometric muscle strength. In addition, the relationship between the results of these subjective and objective measurements was investigated. METHOD: This was a prospective cross-sectional study in which 32 patients with post-polio symptoms were included. Main outcome measures were the Fatigue Severity Scale (FSS), the Disability Rating Index (DRI), pain intensity, pain distribution, self-reported and measured muscle strength and oxygen uptake. RESULTS: A marked reduction in isometric muscle strength compared to normal data, high scores in fatigue, widespread pain, low oxygen uptake and difficulties in performing some daily activities were found. Self-reported general muscle strength, pain intensity and pain distribution correlated significantly with patients' perceived fatigue and function at the activity level. There was no significant correlation between self-reported and measured results except for that found between isometric muscle strength in the legs and patients' perceived general muscle strength and oxygen uptake. CONCLUSIONS: Evaluation of pain intensity, pain distribution, perceived muscle strength, fatigue and ability to perform daily tasks reveals important aspects of health status in patients with post-polio symptoms. Reduction in isometric muscle strength was not reflected in those tests or in reported symptoms, and should be monitored independently using a sensitive assessment tool. Accurate screening of isometric muscle strength in isolated muscle groups contributes to therapeutic management in making a functional diagnosis at the level of body function and structure when designing specific training programmes and in motivating patients. An evaluation combining self-reports with sensitive muscle strength measures provide supplementary information and is appropriate for evaluating these patients in physiotherapy practice.