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.

Ethical triage during the COVID-19 pandemic: a toolkit for neurosurgical resource allocation.

BACKGROUND: The COVID-19 pandemic confronts healthcare workers, including neurosurgeons, with difficult choices regarding which patients to treat. METHODS: In order to assist ethical triage, this article gives an overview of the main considerations and ethical principles relevant when allocating resources in times of scarcity. RESULTS: We discuss a framework employing four principles: prioritizing the worst off, maximizing benefits, treating patients equally, and promoting instrumental value. We furthermore discuss the role of age and comorbidity in triage and highlight some principles that may seem intuitive but should not form a basis for triage. CONCLUSIONS: This overview is presented on behalf of the European Association of Neurosurgical Societies and can be used as a toolkit for neurosurgeons faced with ethical dilemmas when triaging patients in times of scarcity.

Prognostic factors for outcome of microvascular decompression in trigeminal neuralgia: A prospective systematic study using independent assessors.

INTRODUCTION: There is a lack of high-quality prospective, systematic studies using independent assessors of outcome of microvascular decompression as treatment for trigeminal neuralgia. METHODS: Clinical characteristics and outcome data were recorded prospectively from consecutive classical trigeminal neuralgia patients, using standardized interviews. Degree of neurovascular contact was evaluated by a 3.0 Tesla MRI blinded to symptomatic side. Patients were assessed before and 12 months after surgery by a neurologist. RESULTS: Twenty-six men and 33 women completed 12 months follow-up. Forty-one patients (69%) had an excellent outcome (no pain, no medication). Ten (18%) patients had a good outcome. Eight (12%) patients had no improvement or had worsening of pain. MRI showed neurovascular contact with morphological changes in 34 patients (58%). Odds ratio between neurovascular contact with morphological changes and excellent outcome was 4.4 (Cl 1.16-16.26), p = 0.029. Odds ratio between male sex and excellent outcome was 11.38 (Cl 2.12-59.52), p = 0.004. No significant association was found between excellent outcome and concomitant persistent pain, current age or disease duration. CONCLUSION: Neurovascular contact with morphological changes and male sex are positive predictive factors for outcome of microvascular decompression. The findings enable clinicians to better inform patients before surgery.

Favourable prognosis of trigeminal neuralgia when enrolled in a multidisciplinary management program - a two-year prospective real-life study.

BACKGROUND: Prognosis of medically treated trigeminal neuralgia patients is assumed to be poor, but the evidence is lacking. Thus, prospective real-life studies of medical management of trigeminal neuralgia are warranted. METHODS: This was an observational study. Patients were consecutively enrolled in a structured management program at a specialist centre for facial pain. Optimisation of medical treatment, physiotherapy, psychotherapy, and advice from trained nurses, were parts of the program. Medically intractable patients were referred for neurosurgery. Data-collection was prospective using standardised schemes and patient surveys. The aim was to describe the two-year outcome of medical treatment at the specialist centre. The primary outcome was a 50% reduction in the overall burden of pain according to a Numerical Rating Scale (NRS) after two years. RESULTS: A total of 186 primary TN patients were enrolled in the program of which 103 patients remained medically managed and completed the two-year follow-up. Fifty patients were treated surgically within the first two years of follow-up. Half of the medically managed patients (53 (51%)), had more than a 50% reduction in the overall burden of pain over the two-year period. The overall burden of pain on NRS decreased from mean 5.34 to 3.00, p < 0.01. There was no significant association between primary outcome and sex, depression and/or anxiety, concomitant persistent pain, or neurovascular contact with morphological changes of the trigeminal nerve. CONCLUSIONS: Patients with trigeminal neuralgia improve over a two-year period when enrolled in a structured medical management program. Optimisation of drug treatment, continuous advice and education and support by the multidisciplinary team, referral of the medically intractable patients for surgery or the natural history of the disease, can be some of the reasons for the improvement. The favourable prognosis provides hope and optimism for medically managed TN patients. TRIAL REGISTRATION: Current study was observational, and patients were offered standard clinical care and laboratory workups according to current American Academy of Neurology and European Federation of Neurological Societies treatment guidelines. The study has been registered at ClincalTrials.gov. ID: NCT03838393 .

Glioma surgery with intraoperative mapping-balancing the onco-functional choice.

BACKGROUND: Balancing survival versus risk of inducing functional deficits is a challenge when resecting gliomas in or near eloquent areas. Our objectives were to assess deficits prior to and at 6 and 12 months after awake craniotomies with cortical and subcortical mapping in patients with suspected grade 2 gliomas in eloquent areas. We analyzed whether pre- and intraoperative factors were linked to an increased risk of postoperative deficits. METHOD: Retrospective study of 92 consecutive patients operated between January 2010 and June 2014. All deficits reported by any healthcare professional and KPS-score preoperatively, immediately postoperatively (day 1-10), at 6 months and 12 months, were analyzed. RESULTS: A decrease in neurological and or cognitive function was common in the first days after surgery, with a significant improvement at 6 months after surgery and further improvement at 12 months. Immediately after surgery, 33% of the patients had severe deficits compared to 2% prior to surgery; this improved to 9% at 6 months and 3% at 12 months. However, at 12 months, 18% of the patients had new or worsened minor or moderate deficits and only 10% had no deficits compared to 39% prior to surgery. There were only minor changes in KPS. None of the recorded pre/intraoperative factors were found significantly to influence the risk of moderate/severe late postoperative deficits. CONCLUSION: A significant amount of the patients in this study experienced new or worsened neurological and or cognitive deficits during follow-up. We found a higher frequency of deficits than normally reported. This is due to the inclusion of mild deficits, the use of patient-reported data, and our focus on cognitive deficits. Our study indicates that the impact of awake craniotomy with mapping on patient outcome is larger than expected. This in no way negates the use of the technique.

Persistent idiopathic facial pain - a prospective systematic study of clinical characteristics and neuroanatomical findings at 3.0 Tesla MRI.

Introduction Persistent idiopathic facial pain (PIFP) is a poorly understood chronic orofacial pain disorder and a differential diagnosis to trigeminal neuralgia. To address the lack of systematic studies in PIFP we here report clinical characteristics and neuroimaging findings in PIFP. Methods Data collection was prospective and standardized in consecutive PIFP patients. All patients underwent 3.0 MRI. Results In a cohort of 53 PIFP patients, the average age of onset was 44.1 years. PIFP was found in more women 40 (75%) than men 13 (25%), p < 0.001. There was a high prevalence of bilateral pain 7 (13%), hypoesthesia 23 (48%), depression 16 (30%) and other chronic pain conditions 17 (32%) and a low prevalence of stabbing pain 21 (40%), touch-evoked pain 14 (26%) and remission periods 10 (19%). The odds ratio between neurovascular contact and the painful side was 1.4 (95% Cl 0.4-4.4, p = 0.565) and the odds ratio between neurovascular contact with displacement of the trigeminal nerve and the painful side was 0.2 (95% Cl 0.0-2.1, p = 0.195). Conclusion PIFP is separated from trigeminal neuralgia both with respect to the clinical characteristics and neuroimaging findings, as NVC was not associated to PIFP.

The use of Brainsuite iCT for frame-based stereotactic procedures.

BACKGROUND: Frame-based stereotactic procedures are the gold standard because of their superior stereotactic accuracy. The procedure used to be in multiple steps and was especially cumbersome and hazardous in intubated patients. A single-step procedure using intraoperative CT was created to optimize the procedures. METHODS: A combined fixation and low profile frame holder was designed for the operating table, allowing positioning for the scanning procedure immediately followed by the surgical biopsy procedure with the same positioning and head fixation. For placement of depth electrodes immediate CT control of positioning was feasible. RESULTS: In the first 8 months the procedure was successfully used 65 times including 8 times in pediatric cases. The procedure duration in awake patients was on average 81 min (range 33 to 202) and in intubated patients (children) on average 89 min (median 89, 78-100). DISCUSSION: This study demonstrates that frame-based stereotactic procedures in all brain locations are a feasible and practical technique with improved workflow and added patient safety and comfort.

Primo non nocere or maximum survival in grade 2 gliomas? A medical ethical question.

BACKGROUND: Maximum safe resection is the "gold standard" in surgical treatment of grade 2 gliomas (G2Gs), aiming to achieve maximal survival benefit with minimal risk of functional deficit. OBJECTIVE: To investigate the attitude of patients and experts towards more extensive surgery with a trade-off between neurological function and survival time. METHODS: Eight patients and seven experts participated in semi-structured focus group interviews. RESULTS: Both patients and experts accepted the premise of balancing neurological function versus longevity. Some patients would accept an increased risk of permanent neurological deficits in order to obtain a chance of increased survival. There was a significant variance in what constituted "quality of life" both between patients and for the individual patient over time. CONCLUSIONS: In important life-changing decisions there is no "one size fits all". We find that it is ethically acceptable to offer more extensive surgery than is possible within the concept of maximal safe surgery as a treatment option, when balancing the principles of beneficence, non-maleficience, autonomy and justice supports the decision. At the same time it must be remembered that even when the patients have made a well-informed decision, some will regret it. In that situation it will be our job as healthcare professionals to support them and help carry some of this burden.

Pyogenic brain abscess, a 15 year survey.

BACKGROUND: Brain abscess is a potentially fatal disease. This study assesses clinical aspects of brain abscess in a large hospital cohort. METHODS: Retrospective review of adult patients with pyogenic brain abscess at Rigshospitalet University Hospital, Denmark between 1994 and 2009. Prognostic factors associated with Glasgow Outcome Score (GOS) (death, severe disability or vegetative state) were assessed by logistic regression. RESULTS: 102 patients were included. On admission, only 20% of patients had a triad of fever, headache and nausea, 39% had no fever, 26% had normal CRP and 49% had no leucocytosis. Median delay from symptom onset to antibiotic treatment was 7 days (range 0-97 days). Source of infection was contiguous in 36%, haematogenous in 28%, surgical or traumatic in 9% and unknown in 27% of cases. Abscess location did not accurately predict the portal of entry. 67% were treated by burr hole aspiration, 20% by craniotomy and 13% by antibiotics alone. Median duration of antibiotic treatment was 62 days. No cases of recurrent abscess were observed. At discharge 23% had GOS ≤3. The 1-, 3- and 12-month mortality was 11%, 17% and 19%. Adverse outcome was associated with a low GCS at admission, presence of comorbidities and intraventricular rupture of abscess. CONCLUSIONS: The clinical signs of brain abscess are unspecific, many patients presented without clear signs of infection and diagnosis and treatment were often delayed. Decreased GCS, presence of comorbidities and intraventricular rupture of brain abscess were associated with poor outcome. Brain abscess remains associated with considerable morbidity and mortality.

A randomised double-blind controlled study of Deep Brain Stimulation for dystonia in STN or GPi - A long term follow-up after up to 15 years.

AIM: This is a long-term open follow-up of a prospective double-blind crossover study, where electrodes were bilaterally implanted in both the Subthalamic nucleus (STN) and internal pallidum (GPi) in patients with isolated dystonia. METHODS: Patients with isolated dystonia were included to undergo surgery with Deep Brain stimulation (DBS) and after randomization, in a double-blind cross-over study, receiving bilateral stimulation of either STN or GPi for 6 months in each target. Preoperative and postoperative assessments with the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the 36-item Short Form Health Survey (SF-36) were performed. In this long-term follow-up (LFU), these ratings were repeated, and patients were evaluated with cognitive tests. RESULTS: 21 patients were included in the protocol, 9 patients with generalized dystonia, 12 with a diagnosis of cervical dystonia. The mean duration of disease was 19.3 years, age at time of surgery 50.1 years. Fourteen patients participated in the LFU. At a mean follow-up of 10.2 years (range 4.8-15.4), BFMDRS movement score was improved with a mean of 36% (p < 0.05) compared with baseline. At LFU both a statistically significant improvement of stimulation in STN on BFMDRS movement score (p = 0.029) and Gpi (p = 0.008) was demonstrated, no significant difference was found between the two targets (p = 0.076). SF-36 improved for both targets. CONCLUSION: In this study we performed a long-term follow-up in 14 patients with cervical or generalized dystonia, who received stimulation in GPi, STN or both. The mean follow-up time was more than 10 years. Our data support a long-term effect of both STN-DBS and GPi-DBS in dystonia with equal effect and safety for up to 15 years. STN has been proven a viable safe and effective target and may be used as an alternative to GPi in both adult-onset cervical dystonia and generalized dystonia.

Tumor mutational burden and purity adjustment before and after treatment with temozolomide in 27 paired samples of glioblastoma: a prospective study.

Treatment of glioblastoma (GBM) remains a challenging task, with limited treatment options, none offering a cure. Immune therapy has proven effective across different cancers with remarkable response rates. Tumor mutational burden (TMB) is a marker of response, but technical and methodological differences in TMB estimates have made a proper assessment and comparison challenging. Here, we analyzed a prospective collection of paired samples from 35 patients with newly diagnosed GBM, all of whom were wild-type (WT) for isocitrate dehydrogenase, before and after treatment with radiotherapy and temozolomide. Seven patients (20%) had O6-methylguanine-DNA methyltransferase-methylated tumors. Six patients (17%) had two relapse surgeries, and tissue from all three surgeries was collected. We found that accurate evaluation of TMB was confounded by high variability in the cancer cell fraction of relapse samples. To ameliorate this, we developed a model to adjust for tumor purity based on the relative density distribution of variant allele frequencies in each primary-relapse pair. Additionally, we examined the mutation spectra of shared and private mutations. After tumor purity adjustment, we found TMB comparison reliable in tumors with tumor purity between 15% and 40%, resulting in 27/35 patients (77.1%). TMB remained unchanged from 0.65 mutations per megabase (Mb) to 0.67/Mb before and after treatment, respectively. Examination of the mutation spectra revealed a dominance of C > T transitions at CpG sites in both shared and relapse-private mutations, consistent with cytosine deamination and the clock-like mutational signature 1. We present and apply a cellularity correction approach that enables more accurate assessment of TMB in paired tumor samples. We did not find a significant increase in TMB after correcting for cancer cell fraction. Our study raises significant concerns when determining TMB. Although a small sample size, corrected TMB can have a clinical significance when stratifying patients to experimental treatment, for example, immune checkpoint therapy.

Automated ictal EEG source imaging: A retrospective, blinded clinical validation study.

OBJECTIVE: EEG source imaging (ESI) is a validated tool in the multimodal workup of patients with drug resistant focal epilepsy. However, it requires special expertise and it is underutilized. To circumvent this, automated analysis pipelines have been developed and validated for the interictal discharges. In this study, we present the clinical validation of an automated ESI for ictal EEG signals. METHODS: We have developed an automated analysis pipeline of ictal EEG activity, based on spectral analysis in source space, using an individual head model of six tissues. The analysis was done blinded to all other data. As reference standard, we used the concordance with the resected area and one-year postoperative outcome. RESULTS: We analyzed 50 consecutive patients undergoing epilepsy surgery (34 temporal and 16 extra-temporal). Thirty patients (60%) became seizure-free. The accuracy of the automated ESI was 74% (95% confidence interval: 59.66-85.37%). CONCLUSIONS: Automated ictal ESI has a high accuracy for localizing the seizure onset zone. SIGNIFICANCE: Automating the ESI of the ictal EEG signals will facilitate implementation of this tool in the presurgical evaluation.

Pain treatment after craniotomy: where is the (procedure-specific) evidence? A qualitative systematic review.

CONTEXT AND OBJECTIVE: Pain following craniotomy has been demonstrated to be frequent and moderate-to-severe in nature. In recent years, the focus on the challenges in treatment of postoperative pain following craniotomy has increased. Fear of using opioids because of their wide array of side-effects has led to the search for alternative analgesic options. The objective of this systematic review was to evaluate current evidence about analgesic therapy following craniotomy. DATA SOURCES: PubMed database, Embase, Cochrane library, Google scholar and the Cumulative Index to Nursing and Allied Health Literature. ELIGIBILITY CRITERIA: Randomised double-blinded placebo-controlled trials (RCTs) with pain or supplemental postoperative analgesic consumption as an endpoint were included in the analysis. RESULTS: A total of 34 RCTs were identified, and nine RCTs were included in the final analysis, with a total of 519 patients (251 control vs. 268 active treatment). Four treatment modalities - scalp infiltration (five RCTs), nerve scalp block (two RCTs), parecoxib (one RCT) and patient-controlled analgesia with morphine (one RCT) - were evaluated. Scalp infiltration with local anaesthetic may provide adequate analgesia in the first few postoperative hours, and nerve scalp block may provide longer lasting analgesia for about 6 h. Morphine was found to reduce total analgesic rescue doses with no significant effect on nausea and no other side-effects. No significant evidence was found to support the use of parecoxib in the treatment of postcraniotomy pain. CONCLUSION: No firm recommendations on analgesic therapy following craniotomy can be given because the number of well performed RCTs is limited and the study populations are very small. However, evidence on scalp infiltration suggests an analgesic effect in the first few postoperative hours. There is an urgent need for well performed RCTs on pain therapy following craniotomy.

Hypopituitarism is uncommon after aneurysmal subarachnoid haemorrhage.

OBJECTIVE: Aneurysmal subarachnoid haemorrhage (SAH) has recently been reported as a common cause of chronic hypopituitarism, and introduction of routine neuroendocrine screening has been advocated. We aimed at estimating the risk of hypopituitarism after SAH using strict criteria including confirmatory testing in case of suggested insufficiency. DESIGN: Cross-sectional evaluation with a nested prospective subgroup. Patients and measurements Endocrine evaluation was performed at a median of 14 months (range 11-26) post-SAH in 62 patients with SAH and 30 healthy controls. Twenty-six patients were followed prospectively (median 7 days, and 12 months post-SAH). Endocrine evaluation included baseline evaluation, which was combined with an insulin tolerance test (ITT) or, if contraindicated, GHRH + arginine tests and a standard ACTH test at evaluation 1-2 years post-SAH. Pituitary insufficiencies were confirmed by re-evaluation. RESULTS: Early post-SAH hormone alterations mimicking central hypogonadism were present in 58% of the patients and associated with a worse clinical state (P < 0.05). One to 2 years post-SAH, initial neuroendocrine evaluation identified seven patients (11%) with abnormal results; three had free T4 and TSH suggestive of central hypothyroidism, three men had testosterone below 10 nm, and one had an insufficient GH and cortisol response to the ITT. None of these abnormalities was confirmed upon confirmatory testing. CONCLUSION: In the largest reported cohort of patients with SAH to date, with early and late endocrine evaluation, none of the patients had chronic hypopituitarism. Based on these findings, the introduction of routine neuroendocrine screening is not justified, and the data suggest the importance of using strict diagnostic criteria in patients with a low pretest probability of hypopituitarism.

Surgical treatment of trigeminal neuralgia. Results from the use of glycerol injection, microvascular decompression, and rhizotomia.

PURPOSE: The study aims to assess the efficacy and safety of surgical treatment of trigeminal neuralgia (TN) in our department and to identify prognostic factors. METHODS: Seventy patients receiving surgical treatment for TN during the period 2003-2004 were included in this retrospective study. The surgical procedures used were glycerol injection (GI), microvascular decompression (MVD), or rhizotomia (RIZ). All patients were divided into spontaneous onset TN type1 (brief lancinating pain) or TN type 2 (continuous pain component). Two patients had bilateral TN; each side was regarded as a separate case. These 70 patients had a total of 160 interventions (110 GI, 40 MVD, and ten RIZ) performed in the period 1998-2007. Data were obtained by chart review and telephone interview. Patients provided information about pre- and postoperative pain characteristics including subtype, duration, intensity, and the use of antiepileptic drugs. Outcome was evaluated using a pain vector diagram. RESULTS: To quantify self-reported pain, we developed a new vector-based pain diagram. The subtype of TN was shown to be a very important prognostic factor. One year after MVD, 90% of patients with type 1 TN still had positive effect, whereas this was only true in 73% of patients with type 2 TN. After RIZ, the results were 71% and 33% for types 1 and 2, respectively. For comparison, GI had a significant lower effect but if the treatment led to hypoesthesia, 41% continued to have a positive effect 1 year after surgery, compared to only 24% if postoperative sensation was normal. Type 2 TN was found to be dominated by women with left-sided TN outside the V2 dermatome and with a lower probability of a neurovascular conflict. As expected, 1/5 of the cases developed postoperative hypoesthesia in the face following a nerve destructive procedure (RIZ and GI). Using MVD, the risk of serious side effects was about 4%. Complementary and alternative treatment had no general or permanent effect in the investigated population-quite the contrary. CONCLUSIONS: Regarding prognosis and outcome, we find that it is very important to classify TN in subgroups (types 1 and 2). Dealing with medically treatment-resistant type 1 TN, MVD and RIZ are reasonably safe and effective interventions. The surgical results dealing with type 2 TN are still very poor. All patients with medically treatment-resistant TN should be offered referral to a neurosurgical unit with experience in treating this painful disease. We recommend using a vector-based pain diagram when evaluating the outcome of multiple interventions.