The effectiveness and cost-effectiveness of intraoperative imaging in high-grade glioma resection; a comparative review of intraoperative ALA, fluorescein, ultrasound and MRI.

BACKGROUND: Surgical resection of high-grade gliomas (HGG) is standard therapy because it imparts significant progression free (PFS) and overall survival (OS). However, HGG-tumor margins are indistinguishable from normal brain during surgery. Hence intraoperative technology such as fluorescence (ALA, fluorescein) and intraoperative ultrasound (IoUS) and MRI (IoMRI) has been deployed. This study compares the effectiveness and cost-effectiveness of these technologies. METHODS: Critical literature review and meta-analyses, using MEDLINE/PubMed service. The list of references in each article was double-checked for any missing references. We included all studies that reported the use of ALA, fluorescein (FLCN), IoUS or IoMRI to guide HGG-surgery. The meta-analyses were conducted according to statistical heterogeneity between studies. If there was no heterogeneity, fixed effects model was used; otherwise, a random effects model was used. Statistical heterogeneity was explored by χ2 and inconsistency (I2) statistics. To assess cost-effectiveness, we calculated the incremental cost per quality-adjusted life-year (QALY). RESULTS: Gross total resection (GTR) after ALA, FLCN, IoUS and IoMRI was 69.1%, 84.4%, 73.4% and 70% respectively. The differences were not statistically significant. All four techniques led to significant prolongation of PFS and tended to prolong OS. However none of these technologies led to significant prolongation of OS compared to controls. The cost/QALY was $16,218, $3181, $6049 and $32,954 for ALA, FLCN, IoUS and IoMRI respectively. CONCLUSIONS: ALA, FLCN, IoUS and IoMRI significantly improve GTR and PFS of HGG. Their incremental cost was below the threshold for cost-effectiveness of HGG-therapy, denoting that each intraoperative technology was cost-effective on its own.

Vagus nerve stimulation for chronic major depressive disorder: 12-month outcomes in highly treatment-refractory patients.

BACKGROUND: There are limited treatment options for patients with chronic, treatment-refractory major depression who do not respond to routinely-available treatments. Vagus Nerve Stimulation (VNS) may represent an alternative to ablative neurosurgery for a specific group of patients. METHODS: 12-month response rates for 28 patients with chronic (≥2 years) major depression who had failed to respond to ≥4 adequate treatment trials in the D03 European open clinical trial of VNS were described along with response rates for 13 consecutive patients who underwent VNS within the neurosurgical treatment programme in Dundee. RESULTS: In the D03 cohort (N=28), the response rate at 12 months (defined as a 50% reduction in symptom score) was 35.7%. In the Dundee VNS case series (N=13), the equivalent response rate was 30.8%. LIMITATIONS: These data are from unblinded and open studies, and there is no control group. Other factors may have contributed to some of the improvement seen, although this is unlikely in very chronic populations. Outcomes are not reported beyond 12 months. CONCLUSION: Response rates at 12 months for patients with chronic and highly-refractory major depression are broadly consistent with previously published results in more heterogeneous and less refractory clinical trial populations. In highly treatment-resistant patients, the rate of response with VNS at 12 m is at least twice that anticipated with 'treatment-as-usual'.

Long term outcome of thermal anterior capsulotomy for chronic, treatment refractory depression.

BACKGROUND: There is very limited evidence for the efficacy of any specific therapeutic intervention in chronic, treatment refractory major depression. Thermal anterior capsulotomy (ACAPS) is a rarely performed but established therapeutic procedure for this patient group. While benefit has been claimed, previous ACAPS reports have provided limited information. Detailed prospective reporting of therapeutic effects and side effects is required. OBJECTIVE: To report a prospective study of therapeutic effect, mental status, quality of life, social functioning and neurocognitive functioning in individuals with chronic treatment refractory major depression, treated with ACAPS. METHOD: A prospective case series of 20 patients treated with ACAPS between 1992 and 1999 were reassessed at a mean follow-up of 7.0±3.4 years. Data were collected preoperatively and at long term follow-up. Structural MRI was performed in 14 participants. RESULTS: According to a priori criteria, at long term follow-up, 50% were classified as 'responders' and 40% as 'remitters'. Fifty-five per cent were classified as 'improved'; 35% were 'unchanged'; and 10% had 'deteriorated'. Neurocognitive and personality testing were not significantly different at follow-up. A trend towards improvement in some aspects of executive neuropsychological functioning was observed. Significant adverse effects were infrequent and there were no deaths. CONCLUSIONS: ACAPS may represent an effective intervention for some patients with chronic, disabling, treatment refractory major depression that has failed to respond to other therapeutic approaches. The adverse effect burden within this population was modest, with no evidence of generalised impairment of neurocognitive functioning.

Should initial surveillance of vestibular schwannoma be abandoned?

Early diagnosis of vestibular schwannoma (VS) has increased in recent years because of increased longevity and availability of magnetic resonance imaging (MRI). Initial conservative radiological surveillance is often requested by patients and physicians to establish whether these tumors are growing before embarking on intervention. Initial observation of at least 1 year in all small VS was therefore recommended by some authors. We evaluated our prospective skull base database of VSs that were managed with initial radiological surveillance to establish when this policy should be abandoned and what predicts future growth. Fifty-four consecutive patients with VS in our institution who were managed by initial yearly MRI scanning were studied. The MRI data were collected prospectively and analyzed by Kodak CareStream viewing software where VS maximum diameters in three perpendicular planes and volume were calculated. One patient was excluded from the analysis as he had only one MRI follow-up. The median age of the 53 patients was 59 years (range, 26 to 86 years), 25 were males and 28 were females, and 33 were under 65 years of age; 18 VSs were extracanalicular, 18 were intracanalicular, and 17 extended both inside and outside the canal; 21 VSs were 1.2 cm(3) or less, 22 were 1.2 to 4 cm(3), and the rest were >4 cm(3). Using volumetric analysis, 29.72% of conservatively managed VS grew by at least 2 mm per year, and 70.82% did not grow in 5 years. Age, gender, symptoms, and side did not predict future growth. However, growth in the first year was a strong predictor of future growth (p < 0.001) and initial volume was also a strong predictor of future growth (p < 0.05). Twenty-nine percent of observed VSs grew by at least 2 mm per year in the first 5 years of surveillance. As the growth rate is slow, initial radiological surveillance is justified in elderly patients and patients with small VSs and nonserviceable hearing. Growth in the first year was a strong predictor of future growth. The reported treatment effect should be interpreted in the light of 70.24% of VSs that either shrink or do not change in the first 5 years.

Role of craniotomy repair in reducing postoperative headaches after a retrosigmoid approach.

BACKGROUND: The retrosigmoid (RS) approach provides an excellent access corridor to the cerebellopontine angle. However, 80% of patients experience headaches after RS approaches. OBJECTIVE: We reviewed our prospective database to determine the risk factors influencing headaches after RS procedures. METHODS: From 2003, craniotomy, instead of craniectomy, became our standard approach for RS procedures. Patients' demographic, management, and outcome data were collected prospectively. We also retrospectively analyzed similar data collected between 2000 and 2003 to compare headache outcomes after RS approaches. Subgroup analysis of data was performed to identify other risk factors contributing to postoperative headaches. RESULTS: Of 105 patients (mean age, 56 years; 43 men; 62 women) who underwent RS surgery, 30 underwent craniectomy and 75 underwent craniotomy. There were 57 vestibular schwannomas, 40 microvascular decompressions, and 8 other procedures. The patients' age, sex, pathological diagnosis, and length of hospital stay were not statistically different in the 2 subgroups. At discharge, postoperative headache was observed in 43% of patients (13/30) after craniectomy and 19% of patients (14/75) after craniotomy (P = .01). The incidence of headache decreased with further follow-up; 10% of patients (3/30) who underwent craniectomy and 1% of patients (1/75) who underwent craniotomy still had headache at 12 months of follow-up. CONCLUSION: Patients who underwent the RS approach with craniotomy had a significantly lower rate of headache at discharge than did those who underwent craniectomy. These patients continued to have a lower incidence of headache in the long term.

Photodynamic therapy adjuvant to surgery in metastatic carcinoma in brain.

UNLABELLED: Cerebral metastases occur in 15-40% of cancers and their incidence is increasing. We have studied the use of fluorescence image-guided surgery and repetitive photodynamic therapy in 14 metastatic brain cancers. METHODS: Case note review of prospectively collected data on patients who were treated with PDT at the time of surgery for brain metastases. Patients were consented for the surgery and PDT. Patients were given 2 mg/kg body weight of Photofrin IV 48 h before the surgery and 20 mg/kg 5-aminolevulenic acid orally 3h before surgery. Following resection of the tumor using fluorescence, microsurgical and image guidance techniques, the post-excision cavity is filled with a balloon using 0.32% intralipid solution and up to five consecutive PDT treatments were given using 100 J/cm(2) Diode Laser 630 nm. Patients were followed up clinically and by brain imaging every 3 months till their death. RESULTS: Seven were lung in origin and seven of variable sources. One patient with lung metastases died of unrelated cause while the remaining six had remained free from brain disease till their death. Two of the remaining seven patients died of local brain recurrence, one bowel after 4 weeks and one of unknown primary after 70 weeks. CONCLUSION: Adjuvant repetitive PDT seems to offer an excellent local control of metastatic brain carcinomas with about 79% of patients succumb to the primary and only two out of fourteen died of brain recurrence with the best results obtained in lung cancer.

Intraoperative optical identification of pituitary adenomas.

INTRODUCTION: The main goals of transsphenoidal pituitary surgery are total removal of pituitary adenomas (PAs) and preservation of normal pituitary functions. Achieving these goals is dependent upon the precise localisation of PAs during surgery, particularly secreting microadenomas. However, some microadenomas are invisible on preoperative imaging and during surgery, leading some surgeons to perform total hypophysectomy in many patients to achieve cure at the expense of panhypopituitrism. We have examined optical detection systems to identify PAs intraoperatively. This paper reports our preliminary findings. METHODS: A prospective observational study design. TECHNIQUE: Patients were given 20 mg/kg body weight 5-aminolevulinic acid (ALA) mixed in 30 ml of orange juice, orally 3 h before surgery. Surgery was performed in the supine position, under image guidance, through the right nostril using Storz 0 degree endoscope assisted with microsurgery as required. The endoscope was attached to photodiagnostic filters (PD) allowing switching the light from white to blue at the flick of a foot pedal. After the dura of the floor of the sella was incised a laser probe was inserted into the pituitary gland to identify the ALA-induced protoporphyrin IX spectroscopy at 632 nm, using an optical biopsy system (OBS). Once the adenoma was identified by the OBS it was exposed and examined by the PD system to detect fluorescence. The PA was removed and its type was confirmed by histopathology and correlated to the OBS and PD system findings. PATIENTS: Thirty consecutive patients were studied: 14 were non-functioning macroadenomas (NFA), 12 were secreting PAs and 4 pituitary cysts. The secreting PAs were GH (2), ACTH (3), prolactin (2) and gonadotrophins (5). Six were microadenomas (3 ACTH, 1 GH, 2 prolactin) and 20 were macroadenomas, of which 12 were invading macroadenomas. Twenty-four of these were examined by the OBS and the PD systems and six were examined by the PD system only. The true positive (sensitivity) of the PD and OBS systems were 80.8% (21/26) and 95.5% (21/22) respectively. The true negative (specificity) of PD and OBS were 75% (3/4) and 100% (2/2) respectively. The false negative rate of PD was 19.2% (5/26) and for OBS was 4.5% (1/22), while the false positive rate for PD was 25% (1/4) and for OBS was 0. CONCLUSION: Intraoperative optical identification of pituitary adenomas is a feasible and reliable way to localize pituitary adenomas during transsphenoidal surgery and it may lead to improved cure rate and preservation of normal pituitary functions.

Spinal cord stimulation in the first two trimesters of pregnancy: case report and review of the literature.

Introduction. Spinal cord stimulation (SCS) is an accepted cost-effective therapy for many chronic pain syndromes. Its effects on pregnancy have not been studied because of stringent regulation and manufacturers' recommendations. However, childbearing women who had SCS become or choose to become pregnant despite these policies. It is paramount to monitor, document, and report these effects of SCS during pregnancy to build clinical experience and guide recommendations and management. Methods. We reviewed the literature for SCS in pregnancy and added new case report of a young woman who had SCS implanted for chronic pain, became pregnant and at the end of the second trimester the lead extender had to be divided to relief pain at the lead site. Results. We found only one previous case report in this field and we add another case. Discussion. Our case is different from the previously reported case in that the implantable pulse generator (IPG) of our case was implanted in the anterior abdominal wall, while the previously reported case was implanted in the subclavicular fossa. Therefore our case highlights the need to implant the IPG in a way that avoids stretching the lead extender by the expanding abdomen. Conclusion. SCS seems to be safe in the first two trimesters of pregnancy based on these two case reports and the abdominal wall should be avoided as a site for IPG implantation in these patients. However, more cases are required to establish the safety of SCS in pregnancy.

Ablative neurosurgery for mental disorders: is there still a role in the 21st century? A personal perspective.

OBJECT: The author presents his personal perspective on ablative neurosurgical techniques used to perform bilateral anterior cingulotomy (BACI) and bilateral anterior capsulotomy (BACA) for ameliorating the symptoms of refractory obsessive-compulsive disorder (OCD) and treatment refractory depression (TRD). With depression predicted to be the second most common cause of disability in the world by the year 2020 and the birth of electric neurostimulation representing an attractive alternative treatment option for TRD and OCD, it is desirable to revisit the pros and cons of these treatment options. METHODS: The author reviewed the surgical methods and outcome (including neuroimaging findings) in all cases in which ablative neurosurgery was performed at Ninewells Hospital and Medical School over the last 2 decades. RESULTS: The advantages of ablative procedures (BACI and BACA) from patients' and psychiatrists' perspectives are that the ablative procedures are one-off procedures that do not require lifelong commitment to program the stimulation devices, fix hardware failures, or change exhausted batteries. From the perspective of healthcare funding bodies, the relatively low cost of these treatments is an advantage. The main disadvantages of BACI and BACA are the perceived higher complication rates, the irreversibility of the surgical lesions, and the stigma associated with brain destruction in psychiatric patients that are still unpalatable in the community at large. However, some patients still choose a one-off procedure in preference to any other options presented to them. CONCLUSIONS: There is still place for BACI and BACA in modern neurosurgery for mental disorders, at least in the short term for those who do not want to commit to lifelong device programming and maintenance.

Lymphocytic hypophysitis occurring simultaneously with a functioning pituitary adenoma.

Lymphocytic Hypophysitis (LH) is a rare and previously under-recognised disorder, most commonly affecting young females in the post-partum period. It presents clinically with symptoms and signs related to either a pituitary mass or hypopituitarism, frequently mimicking a pituitary adenoma; the diagnosis of LH can only be made histologically with the presence of a dense lymphocytic infiltration usually confined to the anterior pituitary. We present two case histories of patients who presented with symptoms suggestive of a functioning pituitary adenoma who also had concomitant LH confirmed histologically. The first case was a 39 year old lady, with a history of primary hypothyroidism, who presented with weight gain and hirsutism and clinical and biochemical features of Cushing's syndrome. The second case was a 61 year old male, also with a history of primary hypothyroidism, who presented with visual field loss and biochemically with hyperprolactinaemia. In both patients, magnetic resonance (MR) imaging of the pituitary demonstrated an enlarged partially cystic pituitary mass with slight suprasellar extension. Both patients were treated surgically with transphenoidal drainage and excision and histological examination of the surgical specimens demonstrated a mixture of pathologies with fragments of adenohypophyseal tissue (staining positive for ACTH and prolactin respectively) with a dense chronic inflammatory cell infiltrate suggestive of LH in nearby normal anterior pituitary. In both cases a joint diagnosis of a functioning pituitary adenoma with LH was made. There have been only several reported cases of this combination of pathologies but LH even in isolation is becoming increasingly recognised.

ALA and Photofrin fluorescence-guided resection and repetitive PDT in glioblastoma multiforme: a single centre Phase III randomised controlled trial.

Glioblastoma multiforme (GBM) carries dismal prognosis and cannot be eradicated surgically because of its wide brain invasion. The objective of this prospective randomised controlled trial was to evaluate ALA and Photofrin fluorescence-guided resection (FGR) and repetitive photodynamic therapy (PDT) in GBM. We recruited 27 patients; 13 were in the study group and 14 were in the control group. The mean survival of the study group was 52.8 weeks compared to 24.6 weeks in the control group (p<0.01). The study group gained on average 20 points on the Karnofsky performance score (p<0.05). There were no differences in complications or hospital stay between the two groups. The mean time to tumour progression was 8.6 months in the study group compared to 4.8 months in the control group (p<0.05). Therefore, ALA and Photofrin fluorescence-guided resection and repetitive PDT offered a worthwhile survival advantage without added risk to patients with GBM. A multicentre randomized controlled trial is warranted to confirm these results.

Anterior cingulotomy for major depression: clinical outcome and relationship to lesion characteristics.

BACKGROUND: Anterior cingulotomy (ACING) is a neurosurgical treatment for chronic refractory depression, pain, and obsessive-compulsive disorder. Anterior cingulotomy involves the placement of bilateral lesions in the anterior cingulate under stereotactic guidance. Although a long-established therapeutic intervention, the optimal location and volume of lesions are not known, but it is generally believed that efficacious lesions interrupt the fibers of the cingulum bundle. METHODS: Using T2-weighted magnetic resonance imaging, we tested the hypothesis that lesions placed more anteriorly would be associated with a better clinical response. We also tested a secondary hypothesis that a superior clinical response would be associated with larger lesion volumes. RESULTS: When assessed 12 months following surgery, a superior clinical response was associated with more anterior lesions but, unexpectedly, with smaller lesion volumes. Specifically, the best clinical response was associated with total (right plus left hemisphere) lesion volumes of 1000 to 2000 mm(3) centered at Montreal Neurological Institute (MNI) coordinates (+/- 9,19,30). CONCLUSIONS: There is considerable evidence from neuroimaging studies that more rostral areas within the anterior cingulate cortex are functionally and structurally abnormal in patients with major depressive disorder. Anteriorly placed ACING lesions would target and modify function within such regions. It should not be assumed that larger lesions are associated with a better response. These findings of relationships between lesion characteristics and clinical response argue against the suggestion that ACING represents a placebo treatment.

Brain photodiagnosis (PD), fluorescence guided resection (FGR) and photodynamic therapy (PDT): past, present and future.

Intracranial tumours are an excellent target for photodiagnosis (PD), fluorescence guided resection (FGR) and photodynamic therapy (PDT), because the tumour to brain ratio of photosensitizers' concentration is very high. However, several attempts of proving the value of PDT in the most malignant type of brain tumours, gliobastoma multeforme (GBM) failed to demonstrate any significant worthwhile survival advantage in the past because of the very nature of this cancer and several compounding factors that led to this apparent disappointing outcome; variations in the photosensitizer and light dosages, variations in the photosensitizer administration to treatment time-intervals, and variations in photosensitizers used are just few to mention in this article. However, after a very long gestation period of brain PD, FGR and PDT, three randomized controlled trials (RCT) in brain PD, FGR and PDT were concluded by 2007. The first trial demonstrated that time to tumour progression (TTP) was significantly longer in patients who had PD and FGR compared to standard surgical resection but this difference did not translate into survival advantage in GBM due to the variability in the management of recurrent tumours and significant residual tumour cells left after FGR in about a third of patients leading to GBM relapse. The second trial compared single shot PDT in GBM and standard therapy. Neither the treatment nor the control group received PD or FGR. Again this RCT did not provide any survival advantage in patients who had had PDT due to the fact that standard surgical resection had left significant residual tumour in a large number of patients canceling any potential benefit from PDT. The last trial compared combined PD, FGR and repetitive PDT and standard therapy and confirmed that TTP was significantly longer in the treatment group and demonstrated that the treatment group had significant survival advantage in GBM. In conclusion, PD, FGR and PDT need to be combined to be effective in brain tumours and in the future, we will see more and more scientific evidence accumulating in support of brain PD, FGR and PDT. The next decade will see further refinement and evolution of the techniques and technology employed and expansion of the indications of brain PD, FGR and PDT.

Fluorescence image-guided surgery of brain tumors: explained step-by-step.

Fluorescence image-guided surgery (FIGS) and fluorescence-guided resection (FGR) are surgical techniques used to maximise tumor excision and minimise collateral damage. FIGS and FGR combine preoperative photosensitizer-administration and fluorescence detection during surgery, by illumination of the surgical field using the appropriate wavelength and observing the fluorescence via a long-pass filter that allows fluorescent tumor to be seen by the surgeon. Commercially available technology has led to gross total resection of enhancing brain tumors in 65% of patients compared to merely 35% under standard white light surgery. This is a step-by-step synopsis of the techniques of FIGS in brain.

Fluorescence image-guided surgery and repetitive Photodynamic Therapy in brain metastatic malignant melanoma.

UNLABELLED: Metastatic brain melanoma occurs in about 3.5% of patients suffering from malignant melanoma. It has disabling effects on cognition, memory, language and mobility. We studied the use of fluorescence image-guided resection and repetitive Photodynamic Therapy in six consecutive metastatic brain melanomas. Three were males and the mean age of the group was 52.8 years. RESULTS: All six patients (100%) remained free of brain disease till death, 50% died of malignant melanoma elsewhere, and 50% died of unrelated causes. CONCLUSION: Adjuvant fluorescence image-guided resection and repetitive Photodynamic Therapy offers an excellent local control of metastatic brain melanoma.

Spinal cord stimulation for chronic pain: causes of long-term paddle-lead failure.

Objectives. This study is to evaluate long-term lead failure in spinal cord stimulation. Materials and Methods. One hundred and seven patients with permanently implanted spinal cord stimulators were studied for 14 years. All suspected paddle-lead failures were studied prospectively using preoperative radiography and intraoperative electric interrogation. Lead failure was defined as complete loss of electric stimulation due to lead malfunction. Primary lead failure was defined as first lead failure after permanent implantation of a new lead and recurrent lead failure was defined as any lead failure after any lead replacement. Results. Primary lead failure occurred in 14.9% and recurrent lead failure in 56.2%. Two (12.5%) of the primary failures and two (22.2%) of the recurrent failures were due to lead fractures. The mean time to primary lead failure was 37.9 months and to recurrent lead failure was 23.7 months. Conclusion. The incidence of primary lead failure remains low at 14.9% in the long run, but it is a significant adverse risk factor for recurrent paddle-lead failure. Great care should be undertaken to prevent lead failures by appropriate anchoring.

A simple stereotactic method for frameless deep brain stimulation.

BACKGROUND: Deep brain stimulation (DBS) is widely used to treat advanced Parkinson's disease, other movement and psychiatric disorders. DBS implantation requires application of a stereotactic frame throughout a lengthy procedure, making it uncomfortable and tiring. We designed a stereotactic cube to stage the operation, perform frameless microelectrode recording (MER) and fix the DBS. METHODS: The 15-mm cube is implanted in a burr hole using bone cement. It contains 5 parallel trajectories (central + 4 around). It is aligned by stereotactic frame so that central trajectory reaches the target. Frameless MER is performed by attaching a micro-driver to the cube using 2-5 cannulae (4 cm). The DBS is fixed to the cube by a mini-plate and 1 screw. Ninety-six cubes were compared with 43 Bennet spheres (BS). RESULTS: No cube moved compared to 2 (5%) BS (p < 0.05). The final trajectory was central in 64.4% of cubes compared to 47.5% of BS, and the final target was >2 mm out in no cubes compared to 12.5% of BS (p < 0.01). Infection and haemorrhage were observed in 2.5% and 3.3% of cubes, respectively, while 5% of BS developed infection, 5% haemorrhage and 7.5% skin erosion. CONCLUSIONS: This method is simple and effective in staging DBS procedures, performing frameless MER and DBS implantation, fixation and revision.

Photodynamic assisted surgical resection and treatment of malignant brain tumours technique, technology and clinical application.

Malignant brain tumours have a dismal prognosis with current state of the art technology. The main reasons for this lost battle in the battlefield of cancer are tumour cell invisibility to the surgical microscope and brain invasion. However, the vast majority of these tumours relapse locally making local radical removal the main strategy in their successful eradication. PDD and PDT combined with new technology stands a very good chance of achieving this goal by maximising tumour resection (PDD) and selective tumour kill (PDT). The aim of this paper is to explain how this is done at Ninewells Hospital and Medical School, Dundee, Scotland. The technique and technology described in this paper, provide a means of diffusing the light to the periphery of the tumour cavity with subsequent therapeutic sessions and treatment dose escalation at the bedside, saving time and resources.