Postoperative epilepsy and survival in glioma patients: a nationwide population-based cohort study from 2009 to 2018.

PURPOSE: Postoperative epilepsy is common in glioma patients and has been suggested to indicate disease progression, yet knowledge of its role as a prognostic factor is limited. This study investigates the association between postoperative epilepsy and survival amongst patients with gliomas. METHODS: We included 3763 patients with histopathologically diagnosed grade II, III, and IV gliomas from 2009 to 2018 according to the Danish Neuro-Oncology Registry. Information on epilepsy diagnosis was redeemed from the Danish National Patient Registry, the National Prescription Registry and the Danish Neuro-Oncology Registry. We used Cox proportional hazards models with 95% confidence intervals (CIs) to examine hazard ratios (HRs) for the association between postoperative epilepsy and risk of death. We examined the role of the timing of epilepsy in three different samples: Firstly, in all glioma patients with postoperative epilepsy; secondly, in patients with postoperative de novo epilepsy; thirdly, exclusively in a homogeneous sub-group of grade IV patients with postoperative de novo epilepsy. RESULTS: Glioma patients with postoperative epilepsy had an increased risk of death, regardless of prior epilepsy status (HR = 4.03; CI 2.69-6.03). A similar increase in the risk of death was also seen in patients with postoperative de novo epilepsy (HR = 2.08; CI 1.26-3.44) and in the sub-group of grade IV patients with postoperative de novo epilepsy (HR = 1.83; CI 1.05-3.21). CONCLUSIONS: Postoperative epilepsy may negatively impact survival after glioma diagnosis, regardless of preoperative epilepsy status. Postoperative epilepsy may be an expression of a more invasive growth pattern of the gliomas following primary tumor treatment.

Prediagnosis epilepsy and survival in patients with glioma: a nationwide population-based cohort study from 2009 to 2018.

OBJECTIVE: Considering that epilepsy is common, and knowledge is lacking on its role especially for the prognosis of high-grade gliomas, the objective of this study was to investigate the association between epilepsy prior to glioma diagnosis and survival among glioma patients. METHODS: In a nationwide population-based cohort study, we included 3763 adult glioma patients diagnosed between 2009 and 2018 according to the Danish Neuro-Oncology Registry. Information on epilepsy was redeemed through Danish Neuro-Oncology Registry, National Patient Registry, and National Prescription Registry. Cox proportional hazard models with 95% confidence intervals (CIs) were applied to examine hazard ratios (HRs) for the association between epilepsy (< 1 year prior to glioma including epilepsy at onset; 1-10 years prior to glioma; no prior epilepsy) and risk of death, and whether it differed according to tumor grade and size, performance status, and treatment modalities. RESULTS: A 32% decreased risk of death in patients with epilepsy within 1 year prior to glioma compared to no prior epilepsy was found (HR = 0.68; CI 0.63-0.75). A favorable prognosis was seen for epilepsy in all glioma grades: II (HR = 0.55; CI 0.39-0.77), III (HR = 0.59; CI 0.48-0.73), and IV (HR = 0.85; CI 0.77-0.94). CONCLUSIONS: Patients with epilepsy within 1 year prior to glioma diagnosis had significant survival benefits compared to patients with no prior epilepsy. This association was significant for both low-grade gliomas (grade II) and high-grade gliomas (grade III and IV). Survival benefits in glioma patients with epilepsy at onset are possibly primarily attributable to tumor-specific histopathology, molecular biomarkers, and early diagnosis.

Spontaneous intracranial hypotension presenting with progressive cognitive decline.

A 63-year-old woman presented with headache, progressive somnolence, neurocognitive decline and urinary incontinence through a year. Medical history was unremarkable except for hypertension and hypercholesterolaemia. Neurological examination was normal. Brain MRI showed findings typical for spontaneous intracranial hypotension (subdural fluid collection, pachymeningeal enhancement, brain sagging) and pituitary tumour. The patient's complaints improved dramatically but temporarily after treatment with each of repeated targeted as well as non-targeted blood patches and a trial with continuous intrathecal saline infusion. Extensive work up including repeated MRI-scans, radioisotope cisternographies, CT and T2-weighted MR myelography could not localise the leakage, but showed minor root-cysts at three levels. Finally, lateral decubitus digital subtraction dynamic myelography with subsequent CT myelography identified a tiny dural venous fistula at the fourth thoracic level. After surgical venous ligation, the patient fully recovered. Awareness of spontaneous dural leaks and their heterogeneous clinical picture are important and demands an extensive workup.

Depressive Symptoms in Danish Patients With Glioma and a Cancer-Free Comparison Group.

BACKGROUND: It is well established that patients with glioma may experience adverse general (eg, headache) or focal symptoms (eg, personality changes) and neurocognitive deficits (eg, planning), but they may also experience severe emotional distress. We investigated the prevalence of depressive symptoms in patients with newly diagnosed glioma and in matched cancer-free persons. METHODS: For this study, we recruited patients with glioma diagnosed within 12 months at all 4 neurosurgical clinics in Denmark. The cancer-free comparison group was identified through the Danish Central Person Register and matched on sex and age. Participants' depressive symptoms were evaluated using the Center for Epidemiologic Studies Depression Scale (CES-D; score range, 0-60), with a cutoff score ≥16 indicating moderate-to-severe depressive symptoms. RESULTS: In this study, 363 of 554 patients with glioma and 481 of 1,304 cancer-free persons participated. Mean age of all patients was 55 years and 60% of the population was male. Mean scores for depressive symptoms were statistically significantly higher among patients with glioma, with a mean CES-D score of 10.9 (95% CI, 10.1-11.8) compared with 5.3 (95% CI, 4.7-5.8) among cancer-free persons (P<.0001). Overall, 92 patients with glioma (25%) and 30 cancer-free persons (6%) had moderate-to-severe depressive symptoms. After adjustment for marital status, education level, and comorbidity, the prevalence of depressive symptoms was 5 times higher among patients with glioma compared with cancer-free persons. CONCLUSIONS: A substantially higher prevalence of moderate-to-severe depressive symptoms was identified in patients with glioma compared with cancer-free persons. This indicates the importance of programs to systematically identify and manage depressive symptoms in patients with glioma.

[Rare occurence of dural sinus cavernous fistula as the cause of oculomotor palsy].

In this case report we describe the presence of a dural sinus cavernosus fistula presenting with unilateral oculomotor palsy. Dural arterio-venous fistula is a rare abnormal connection between dural arteries and the venous system. Venous stasis, infarctions and intracranial haemorrhage might arise. Hence, timely diagnosis and intervention is crucial. Symptoms involve focal neurological deficits, cognitive impairment, movement disorders, seizures, symptoms of elevated intracranial or intraocular pressure and bruits or pulsatile tinnitus, which may be heard by auscultation of the skull. Invasive angiography is diagnostic.

Treatment and survival of glioblastoma patients in Denmark: The Danish Neuro-Oncology Registry 2009-2014.

BACKGROUND: As many glioblastoma patients are in a poor condition they are unable to undergo the full treatment documented in clinical trials. We aimed to examine the survival and its relationship to clinical characteristics and treatment in a nationwide population of glioblastoma patients in Denmark. METHODS: We included prospectively recorded clinical data from 1364 adult patients with histologically verified glioblastoma from the Danish Neuro-Oncology Registry, 2009-2014. RESULTS: The age standardized incidence rate was 6.3/100,000 person-years for males and 3.9 for females and the median age was 66 years. The median overall survival was 11.2 months. There was an independently significant prognostic effect of age, performance status, cognitive symptoms, tumor diameter, multifocality, crossing midline, and contrast enhancement. For partial and total resection compared to biopsy only, the adjusted risk of dying was reduced by 43% (HR [CI] 0.57 [0.48-0.68]) and 51% (0.49 [0.40-0.60]), respectively. For patients receiving a partial and full radiochemotherapy regimen compared to no postsurgical treatment, the risk reduction was 56% (HR [CI] 0.44 [0.37-0.53]) and 70% (0.30 [0.25-0.35]), respectively. The full radiochemotherapy regimen was only allocated to 50% of the patients, 29% among the oldest (70+ years) and 60% among the younger (18-69 years). CONCLUSIONS: Glioblastoma patients had a poor overall survival but with several specific independent prognostic factors. Extensive cancer treatment was associated with an increasing survival in all age groups, but only half of the patients were sufficiently fit for a full regimen of postoperative combined radiochemotherapy.

Early incidence of glucocorticoid-induced diabetes in patients with brain tumors: a retrospective study of the first 7 days of treatment.

BACKGROUND: Hyperglycemia or diabetes is a well-known side effect of treatment with glucocorticoids. In patients with brain tumors, glucocorticoids are widely used to treat symptoms of peritumoral edema. We conducted a retrospective study of patients with suspected brain tumor to determine the incidence of and risk factors for glucocorticoid-induced diabetes. METHODS: This was a retrospective study of patients referred with suspected brain tumor to a neurological department, using data from a clinical database, electronic medical records, the laboratory system, and the pathology information bank. . Nondiabetic patients with a neuroimaging-verified brain tumor treated with high-dose glucocorticoid and monitored with glucose measurements were included in the study. RESULTS: Among 809 patients referred with suspected brain tumor, 171 were eligible for the study. Thirty-eight (22%) patients developed glucocorticoid-induced diabetes, defined as 2 glucose measurements ≥200 mg/dl (11.1 mmol/l) within the first week of treatment, and 4 of the patients were treated with insulin. The majority of patients with glucocorticoid-induced diabetes were identified on days 2, 3, and 4, and glucose levels were highest in the afternoon and evening. We were not able to identify any risk factors for glucocorticoid-induced diabetes and glucocorticoid-induced diabetes had no influence on survival in our cohort. CONCLUSIONS: Glucocorticoid-induced diabetes is frequent in the first 7 days of treatment in patients with brain tumors. The results emphasize the need for screening for glucocorticoid-induced diabetes in this group of patients to avoid comorbidity expected to arise from hyperglycemia.

Epidemiology of glioma: clinical characteristics, symptoms, and predictors of glioma patients grade I-IV in the the Danish Neuro-Oncology Registry.

In this national population-based study of glioma, we present epidemiologic data on incidence, demographics, survival, clinical characteristics and symptoms, and evaluate the association of specific indicators with the grade of glioma. We included 1930 patients registered in the Danish Neuro-Oncology Registry (DNOR) from 2009 to 2014. DNOR is a large-scale national population-based database including all adult glioma patients in Denmark. The age-adjusted annual incidence of histologic verified glioma was 7.3 cases pr. 100,000 person-years. High-grade gliomas were present in 85% and low-grade glioma in 15%. The overall male:female ratio was 3:2 and the mean age at onset was 60 years. Data for WHO grade I, II, III and IV glioma showed several important differences regarding age and sex distribution and symptomatology at presentation. The mean age increased with the grade of glioma and males predominated in all grades. Focal deficits were the most frequent presenting symptom, but among patients with glioma, grade II epileptic seizures were the most frequent symptom. Headache was a rare mono-symptomatic onset symptom. At presentation, higher age, focal deficits and cognitive change for <3 months duration, and headache <1 month were significant independent indicators of high-grade gliomas. Younger age and epileptic seizures for more than 3 months were indicative for low-grade gliomas. Survival rates for glioma grade I-IV showed decreasing survival with increasing grade. Glioma grade I-IV showed high diversity regarding several demographic and clinical characteristics emphasizing the importance of individually tailored disease treatments and support.

Walking ability in patients with glioblastoma: prognostic value of the Berg Balance Scale and the 10 meter walk test.

Primary brain tumors frequently cause considerable functional impairments and the survival time when diagnosed with glioblastoma is 14.6 months. The aim of this study was to examine if baseline postural control and walking ability in patients with glioblastoma could predict long term walking ability and 1 year mortality. Data were gathered from prospective recordings in a brain cancer database supplemented by retrospective review of electronic patient records. We included 109 patients with glioblastoma, 47 women and 62 men with mean age 65 years. At admission 84 patients were tested with Berg Balance Scale and 57 were tested with 10 meter walk test. Binary logistic regression analysis showed no statistical significance in favour of the 10 meter walk test. Berg Balance Scale showed an ability to predict walking ability 4-8 months after admission. The risk of dying within a year was 6.9 times higher in patients who lost their ability to walk within 4-8 months of the first admission. This study showed that Berg Balance Scale has some ability to predict the loss of walking ability 4-8 months after admission. This could be an important indicator pin pointing patients most in need of more intensive specialized neurorehabilitation efforts early in the disease course.

The Danish Neuro-Oncology Registry: establishment, completeness and validity.

BACKGROUND: The Danish Neuro-Oncology Registry (DNOR) is a nationwide clinical cancer database that has prospectively registered data on patients with gliomas since January 2009. The purpose of this study was to describe the establishment of the DNOR and further to evaluate the database completeness of patient registration and validity of data. METHODS: The completeness of the number of patients registered in the database was evaluated in the study period from January 2009 through December 2014 by comparing cases reported to the DNOR with the Danish National Patient Registry and the Danish Pathology Registry. The data validity of important clinical variables was evaluated by a random sample of 100 patients from the DNOR using the medical records as reference. RESULTS: A total of 2241 patients were registered in the DNOR by December 2014 with an overall patient completeness of 92 %, which increased during the study period (from 78 % in 2009 to 96 % in 2014). Medical records were available for all patients in the validity analyses. Most variables showed a high agreement proportion (56-100 %), with a fair to good chance-corrected agreement (k = 0.43-1.0). CONCLUSIONS: The completeness of patient registration was very high (92 %) and the validity of the most important patient data was good. The DNOR is a newly established national database, which is a reliable source for future scientific studies and clinical quality assessments among patients with gliomas.

A brain cancer pathway in clinical practice.

INTRODUCTION: Danish healthcare seeks to improve cancer survival through improved diagnostics, rapid treatment and increased focus on cancer prevention and early help-seeking. In neuro-oncology, this has resulted in the Integrated Brain Cancer Pathway (IBCP). The paper explores how the pathway works in the initial phase in a clinical setting with emphasis on pathway criteria. MATERIAL AND METHODS: All patients admitted during the first two-year period to a regional neurology department in Denmark and fulfilling the IBCP inclusion criteria were included. Data regarding onset symptoms, diagnosis and time for diagnostic work-up were obtained and supplemented by a retrospective review of patient records. Sensitivities, specificities and positive predictive values of the inclusion criteria were calculated with magnetic resonance imaging scan of the cerebrum as index of validity. RESULTS: The strength of the pathway inclusion criteria was determined largely by the number of criteria fulfilled and by the type of predominant symptoms. The criteria identified the majority of patients with symptomatic brain malignancy and were also highly predictive of general structural brain lesions. CONCLUSION: The introduction of the pathway is a major step forward in the efforts to optimize brain cancer patients' illness trajectory. FUNDING: This study was funded by a grant from the Danish Ministry of Health and Interior Affairs 2009 and the Helen Rude Foundation and has been approved by the Danish Data Protection Agency. TRIAL REGISTRATION: not relevant.

Work-up times in an integrated brain cancer pathway.

INTRODUCTION: The integrated brain cancer pathway (IBCP) aims to ensure fast-track diagnostics and treatment for brain cancers in Denmark. This paper focuses on the referral pattern and the time frame of key pathway elements during the first two years following implementation of the IBCP in a regional neurology department. MATERIAL AND METHODS: All patients (n = 241) enrolled in the IBCP during the two-year period were included. Times from admission to completion of the key elements of the IBCP were used. The referral manner and changes in total neurology work-up time over eight quarters were assessed. RESULTS: The monthly patient enrollment decreased over the eight quarters studied. Primary care physicians accounted for nearly half of referrals, while one-third were referred from other hospital departments. The mean time from admission to end of diagnostic work-up fell from three days (0-10 days) to two days (0-6 days). Within 24 hours of admission, all patients were seen by a specialist in neurology, 90% had an electrocardiogram and 93% had the required blood-work performed. 94% of the included patients had magnetic resonance imaging of the cerebrum performed. CONCLUSION: The diagnostic process which was accelerated in the study-period and the total work-up time were generally low throughout. Key work-up items are currently being completed timely. Further improvements are possible. The enrollment rate has fallen to what we expect will be a steady level. FUNDING: This study was funded by a grant from the Danish Ministry of Health and Interior Affairs 2009 and the Helen Rude Foundation and was approved by the Danish Data Protection Agency. TRIAL REGISTRATION: not relevant.

Prognosis of migraine and tension-type headache: a population-based follow-up study.

OBJECTIVE: To determine the prognosis of migraine and tension-type headache and to identify prognostic factors. METHODS: Of 740 persons (aged 25 to 64 years) examined in a 1989 Danish cross-sectional headache study, 673 were eligible for follow-up in 2001. All interviews at baseline and at follow-up were conducted by medical doctors and based on the 1988 IHS-criteria. RESULTS: A total of 549 persons (81.6%) participated in the follow-up study. Of 64 migraineurs at baseline, 42% had experienced remission, 38% had low migraine frequency, and 20% had more than 14 migraine days per year (poor outcome) at follow-up. Poor outcome was associated with high migraine frequency at baseline and age at onset younger than 20 years. Among 146 subjects with frequent episodic tension-type headache and 15 with chronic tension-type headache at baseline, 45% experienced infrequent or no tension-type headache (remission), 39% had frequent episodic tension-type headache, and 16% experienced chronic tension-type headache (poor outcome) at follow-up. Poor outcome was associated with baseline chronic tension-type headache, coexisting migraine, not being married, and sleeping problems. CONCLUSIONS: The prognosis of migraine, frequent episodic tension-type headache, and chronic tension-type headache was favorable.

Burden of headache.

Although headache is the most prevalent pain disorder, the substantial societal and individual burden associated with it has been previously overlooked. The primary headaches including migraine, tension-type and cluster are the most prevalent forms but also a very high number of headaches secondary to analgesic overuse and various brain diseases are ignored without any specific acknowledgement or treatment. Migraine is listed as number 20 of all diseases with regard to years lived with disability, and headache accounts for approximately 20% of lost work days. Chronic headaches (occurring for more than half of all days per month) affects 4-5% of the general population and differs not only from the episodic forms in frequency, but also in respect to lack of effect of most treatment strategies, more medication overuse and more loss of quality of life than the episodic forms. The burden of headache disorders remains substantial and is estimated to cost a minimum of US$100 million per million inhabitants per year. As most headache disorders remain prevalent, disabling, underdiagnosed and undertreated, public health initiatives to improve prevention and treatment are urgently required. Considerable benefits for society can be gained by specific strategies leading to reductions in the amount of sickness absence and impaired working abilities. The burden on affected individuals and their families quality of life may be improved by a general acceptance of the impact of headache disorders and the development of specific treatment strategies.

Migraine and tension-type headache in a general population: precipitating factors, female hormones, sleep pattern and relation to lifestyle.

In a cross-sectional epidemiological study of headache disorders information on precipitating factors, age at onset, influence of menstruation and pregnancy and use of oral contraceptives was collected. The presence of migraine and tension-type headache was ascertained by a clinical interview and examination using the operational diagnostic criteria of the International Headache Society. The prevalence of migraine and tension-type headache was also analysed in relation to variables of lifestyle: physical activity, smoking, consumption of coffee, alcohol intake and sleep pattern. In both migraine and tension-type headache, the most conspicuous precipitating factor was stress and mental tension. Other common precipitants were alcohol, weather changes and menstruation. Disappearance or substantial improvement of the headache during pregnancy was more frequent in migraineurs than in tension-type headache sufferers. The age at onset of both migraine and tension-type headache differs between men and women. Female hormones may be an important factor responsible for the sex difference of headache disorders. The level of physical activity showed no association with migraine, but a significantly higher prevalence of tension-type headache in men with exclusively sedentary activity emerged. Smoking, coffee and alcohol consumption showed no significant associations with the headache disorders. Sleep pattern was significantly associated with migraine and tension-type headache in both univariate and multivariate analyses. In conclusion, migraine and tension-type headache seem to be different with regard to a number of endogenous and exogenous factors.

Muscle tenderness and pressure pain thresholds in headache. A population study.

Tenderness and pain thresholds in pericranial muscles were studied in a random sample of 735 adults aged 25-64 years. This study was a part of a multifaceted, epidemiological study of different headache disorders. Manual palpation and pressure pain threshold were performed by observers blinded to the persons' history of headache. The aim of the study was to evaluate the possible role of pericranial myofascial nociception in headache pathogenesis. Tenderness in migraineurs did not differ from non-migraineurs. Subjects with episodic tension-type headache and females with chronic tension-type headache were more tender than the rest of the population, and males without any experience of headache were less tender than the rest of the male population. A strong positive correlation between tenderness and frequency of tension-type headache was found (males: P < 10(-4); females: P < 10(-5)), while no relation between tenderness and migraine frequency was seen (P = 0.43). In subjects having actual headache at the day of examination tenderness was 32% increased compared to a matched group with identical usual frequency of headache, but without headache during the examination. A significant relation of tenderness to the recency of last episode of headache was detected in both sexes after control for usual frequency and actual headache (males: P < 10(-3); females: P < 10(-4)). Pressure pain thresholds were largely normal indicating normal pain processing and contradicting the idea that tension-type headache mainly is due to generally increased pain sensitivity. This study supports the pathogenetic importance of muscular factors in tension-type headache, while muscular factors are of no primary importance in migraine.

Cephalic muscle tenderness and pressure pain threshold in a general population.

Tenderness and pain thresholds in pericranial muscles were studied in a general population. A random sample of 1000 adults aged 25-64 years was drawn as part of the Glostrup Population Studies, and 740 adults were examined. This study was part of a multifacetted, epidemiological study of different headache disorders according to the new headache classification. Manual palpation and pressure pain threshold with an electronic pressure algometer were performed by observers blinded to other information such as the person's history of headache, previous illness and mental state. The muscles most commonly tender to manual palpation were the lateral pterygoid (55%), the trapezius (52%), and the sternocleido-mastoid muscles (51%). Females were more tender than men in all the muscles examined by manual palpation. In total, the young age group was more tender than the old age group (P = 0.03). Pressure pain thresholds on temporal muscles showed lower thresholds in women than in men (P less than 10(-3)), and in the total population thresholds increased with age (P less than 0.05). No side-to-side difference in tenderness by manual palpation was found, while the right side showed increased pain thresholds in right-handed individuals (P less than 10(-4)). No side-to-side difference was found in left-handed persons. This study provides data about the normal population and forms the necessary basis for evaluating the importance of muscle tenderness in headache subjects and other selected groups.