Regression of all untreated lesions in multifocal low-grade meningioma following fractionated stereotactic radiotherapy-abscopal effect or spontaneous regression? : Case report and review of the literature.

PURPOSE: Abscopal effects have been reported predominantly in metastatic cancers, indicating a radiographic response in a lesion that has not been included in the radiotherapy target volume. The response is interpreted as a humoral immune response to radiotherapy-generated tumour-specific antigens. In this case study, we present the first histologically confirmed multifocal low-grade meningioma with spontaneous regression of all other lesions after conventionally fractionated stereotactic radiotherapy (RT). CASE REPORT: Two localisations, right frontal and right spheno-orbital, were resected at the time of the initial diagnosis in a 66-year-old woman. RT was performed 1 year later to a progressive occipital lesion at the cerebral falx. RESULTS: Regular magnetic resonance imaging (MRI) showed slightly decreasing tumour volume in untreated lesions 1 year after RT and continued during further follow-up. Up to > 7 years after treatment, MRI demonstrated an almost complete response of all initial lesions. Two prior reports with meningioma were published in one patient with an atypical meningioma after conventionally fractionated RT and another patient with an intracranial meningiomatosis after radiosurgery. CONCLUSION: This case study supports the concepts of treating only progressive or symptomatic meningioma lesions locally and careful regular MRI surveillance for further assessment. Potential active interventions to trigger an abscopal effect are currently not known. Further research of this beneficial effect for our patients should be supported.

Controlled arterial hypotension during resection of cerebral arteriovenous malformations.

BACKGROUND: Resection of cerebral arteriovenous malformations (AVM) is technically demanding because of size, eloquent location or diffuse nidus. Controlled arterial hypotension (CAH) could facilitate haemostasis. We performed a study to characterize the duration and degree of CAH and to investigate its association with blood loss and outcome. METHODS: We retrospectively analysed intraoperative arterial blood pressure of 56 patients that underwent AVM-resection performed by the same neurosurgeon between 2003 and 2012. Degree of CAH, AVM size, grading and neurological outcome were studied. Patients were divided into two groups, depending on whether CAH was performed (hypotension group) or not (control group). RESULTS: The hypotension group consisted of 28 patients, which presented with riskier to treat AVMs and a higher Spetzler-Martin grading. CAH was achieved by application of urapidil, increasing anaesthetic depth or a combination thereof. Systolic and mean arterial blood pressure were lowered to 82 ± 7 and 57 ± 7 mmHg, respectively, for a median duration of 58 min [25% percentile: 26 min.; 75% percentile: 107 min]. In the hypotension group, duration of surgery (4.4 ± 1.3 h) was significantly (p <  0.001) longer, and median blood loss (500 ml) was significantly (p = 0.002) higher than in the control group (3.3 ± 0.9 h and 200 ml, respectively). No case fatalities occurred. CAH was associated with a higher amount of postoperative neurological deficits. CONCLUSIONS: Whether CAH caused neurological deficits or prevented worse outcomes could be clarified by a prospective randomised study, which is regarded as ethically problematic in the context of bleeding. CAH should only be used after strict indication and should be applied as mild and short as possible.

Saliva molecular inflammatory profiling in female migraine patients responsive to adjunctive cervical non-invasive vagus nerve stimulation: the MOXY Study.

BACKGROUND: Rising evidence indicate that oxytocin and IL-1ß impact trigemino-nociceptive signaling. Current perspectives on migraine physiopathology emphasize a cytokine bias towards a pro-inflammatory status. The anti-nociceptive impact of oxytocin has been reported in preclinical and human trials. Cervical non-invasive vagus nerve stimulation (nVNS) emerges as an add-on treatment for the preventive and abortive use in migraine. Less is known about its potential to modulate saliva inflammatory signaling in migraine patients. The rationale was to perform inter-ictal saliva measures of oxytocin and IL-1ß along with headache assessment in migraine patients with 10 weeks adjunctive nVNS compared to healthy controls. METHODS: 12 migraineurs and 12 suitably matched healthy control were studied with inter-ictal saliva assay of pro- and anti-neuroinflammatory cytokines using enzyme-linked immuno assay techniques along with assessment of headache severity/frequency and associated functional capacity at baseline and after 10 weeks adjunctive cervical nVNS. RESULTS: nVNS significantly reduced headache severity (VAS), frequency (headache days and total number of attacks) and significantly improved sleep quality compared to baseline (p < 0.01). Inter-ictal saliva oxytocin and IL-1ß were significantly elevated pre- as well as post-nVNS compared to healthy controls (p < 0.01) and similarly showed changes that may reflect the observed clinical effects. CONCLUSIONS: Our results add to accumulating evidence for a therapeutic efficacy of adjunct cervical non-invasive vagus nerve stimulation in migraine patients. This study failed to provide an evidence-derived conclusion addressed to the predictive value and usefulness of saliva assays due to its uncontrolled study design. However, saliva screening of mediators associated with trigemino-nociceptive traffic represents a novel approach, thus deserve future targeted headache research. Trial registration This study was indexed at the German Register for Clinical Trials (DRKS No. 00011089) registered on 21.09.2016.

Selective L4 Dorsal Root Ganglion Stimulation Evokes Pain Relief and Changes of Inflammatory Markers: Part I Profiling of Saliva and Serum Molecular Patterns.

OBJECTIVES: Complex regional pain syndrome (CRPS) and associated comorbidities have been linked to a pro-inflammatory state driven by different mediators. Targeted dorsal root ganglion stimulation (DRGSTIM ) suppressed pain levels and improved functional capacity in intractable CRPS. However, clinical trials assessing the impact of DRG stimulation on the neuroimmune axis are lacking. METHODS: This study enrolled 24 subjects (12 refractory CRPS patients plus suitably matched healthy controls) and performed immunoassays of inflammatory mediators in saliva and serum along with score-based assessments of pain, mood, and sleep quality at baseline and after three months of selective L4-DRGSTIM . RESULTS: After three-month L4-DRGSTIM CRPS associated pain significantly decreased. In addition, disturbed sleep and mood improved post-DRGSTIM , although statistically not significant. Significantly increased serum values of pro-inflammatory markers were detected pre- and post L4-DRGSTIM for high-mobility group box 1, tumor-necrosis factor α, interleukin (IL) 6, and leptin. IL-1ß was significantly elevated pre-L4 DRGSTIM , but not posttreatment. Elevated anti-inflammatory IL-10 significantly decreased after three months in serum, while saliva oxytocin concentrations increased in CRPS subjects after L4-DRGSTIM (p = 0.65). No severe implantation and stimulation associated adverse events were recorded. CONCLUSIONS: Selective L4-DRGSTIM improved neuropathic pain and functional impairment in CRPS as previously reported. CRPS patients displayed a pro-inflammatory molecular pattern in serum. Serum anti-inflammatory IL-10 significantly declined, while saliva oxytocin nonsignificantly increased after L4-DRGSTIM . An evidence-based relational interpretation of our study is limited due to the uncontrolled study design. However, molecular profiling of biofluids (saliva, serum) represents a novel and experimental field in applied neuromodulation, which warrant further investigations to unveil mechanisms of neuroimmune modulation.

In vitro analysis of platelet function in acute aneurysmal subarachnoid haemorrhage.

Platelet function might play an essential role in the pathogenesis of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid haemorrhage (SAH). Thus, impaired platelet function and disturbed primary haemostasis induced by intake of acetylsalicylic acid (ASA) might influence the rate of DCI. Primary haemostasis and platelet function can be measured with in vitro diagnosis (platelet function analyser test, PFA 100). The aim of this study is to evaluate the rate of DCI, haemorrhagic complications and the neurological outcome. Two groups were compared (patients with regular platelet function versus patients with impaired platelet function). This is a retrospective observational study. An initial cohort of 787 patients with SAH has been treated from January 2005 to September 2012. Seventy-nine patients (10%) with aneurysmal SAH, a history of ASA medication and PFA testing within the first 24 h after aneurysm rupture have been included. The overall rate of DCI in the present study was 43%. In vitro platelet function testing showed pathological primary haemostasis in 69.6%. The DCI rate was higher in patients with regular tested primary haemostasis (p = 0.02, OR = 3.16, 95%CI = [1.19; 8.83]). However, outcome assessment by mGOS did not show a significant difference between the groups. Patients with impaired primary haemostasis did not display a higher rate of haemorrhagic complications. Impairment of primary haemostasis resulting from an impairment of platelet function at an early stage after SAH might lead to a lower rate of DCI. In vitro testing of platelet function might be useful to predict the occurrence of DCI in the course.

The place for surgical treatment for AVM involving the temporal lobe.

OBJECTIVE: The objective of this study was to analyze preoperative symptoms and late clinical outcomes in patients who underwent surgical treatment of arterio-venous malformations (AVMs) of the temporal lobe, including those involving the Sylvian fissure (SF) and the lateral wall of the inferior ventricular horns-with special respect to postoperative hemiparesis and visual field defects (VFD). METHODS: Between 1990 and 2007, 44 patients (n = 22 women, n = 22 men) with a mean age of 41 (12-67) years were operated on an AVM of the temporal lobe. All data had been collected prospectively. Patients' charts, as well as surgical reports and outpatient files, were analyzed. Thirteen patients showed an involvement of the SF, and six were localized partially in the lateral wall of the temporal horn. Eight AVMs were located in the temporo-mesial region. Fourteen patients had an AVM located mainly within the visual pathway. In 24 cases, the AVM was located in the dominant hemisphere. The AVMs were classified by the Spetzler-Martin grading system (SM). Visual fields were assessed in all patients pre- and postoperatively by independent ophthalmological examiners. RESULTS: The initial symptoms leading to the diagnosis of the AVM were seizures in 20 cases (45%), headache without hemorrhage in six cases (14%), incidental finding in five cases (11%), and tinnitus in two cases (5%). Hemorrhage had occurred in 15 cases (34%). Based on SM, 7 AVMs were grade I, 17 grade II, 17 grade III, and 3 grade IV. Preoperatively, seven patients presented with a VFD and two with a hemiparesis. Postoperatively, 8 of 44 (18%) patients presented with a new hemiparesis, remaining permanent in 3 of 44 (7%). In two of these patients, the AVMs were localized temporo-mesially (n = 2/8, 25%). Seven patients (19%) showed a new significant postoperative VFD, and in addition, three patients had worsening of their preexisting VFD (3/7, 43%). Postoperative angiography verified complete AVM occlusion in 43 of 44 (98%) cases. One patient needed reoperation for residual AVM; hence, in all patients, complete occlusion before discharge was achieved. CONCLUSION: Treatment of temporal lobe AVMs is demanding due to their close spatio-anatomical relationship with important neurovascular structures and the optic radiation. In this surgically treated series, morbidity for a new permanent hemiparesis was 7% and preservation of the visual field could be achieved in almost 90% of all cases. This is a calculable risk for most patients that renders microsurgical resection a justifiable option, even in light of other treatment modalities. The risk for new permanent motor deficits is elevated in temporo-mesial AVMs, and these patients have to be advised accordingly for surgical treatment.

Surgical treatment of choroid plexus tumors.

PURPOSE: The purpose of this study is to evaluate the results of microsurgical treatment for choroid plexus tumors (CPT) in adult patients. METHODS: From 1990 to 2008, 14 patients >18 years were treated at our institution for CPT, including seven males and seven females with a mean age of 46 years. Mean follow-up was 40 months. We reviewed the respective patients' charts, operative, and follow-up notes. Telephone interviews were performed as necessary. Neurological status was determined using the Karnofsky performance index pre- and post-operatively and at last follow-up. RESULTS: This series includes 12 plexus papillomas (CPP) and two atypical plexus papillomas (APP). Ten tumors were located in the fourth ventricle, two tumors in the cerebellopontine angle, one growth each in the third and lateral ventricle. In 12 cases, a complete tumor resection was achieved. No recurrence was observed in these cases. Two recurrent CPP were diagnosed 11 and 25 years after the initial surgery. Brain stem infiltration prevented a complete tumor removal in one case. In the other, the degree of resection after the first operation could not be ascertained. None of the patients received adjuvant chemo- or radiotherapy. In four patients (29%), a permanent ventricular-peritoneal shunt was necessary. Three patients initially presented with a Karnofsky index of 60 or below. During follow-up, three patients (21%) never improved beyond a Karnofsky index of 60. CONCLUSIONS: Surgery aiming radical excision is the key to successful treatment of CPP and APP in adults. Postoperative outcomes may be less than satisfactory in some patients.

Health Economic Aspects of Aneurysmal Subarachnoid Hemorrhage: Factors Determining First Year In-Hospital Treatment Expenses.

BACKGROUND: Spontaneous aneurysmal subarachnoid hemorrhage (SAH) is a common neurosurgical emergency with a high case fatality rate. The clinical course of SAH generates high health economic expenses. Here we highlight possible cost-driving factors for in-hospital care expenses for the first year. Furthermore, results are compared with ischemic stroke treatment. METHODS: One hundred and one patients with aneurysmal SAH treated in our hospital from 2007 through 2009 were included. The Hunt and Hess (HH) scale, World Federation of Neurosurgical Societies (WFNS) scale, Fisher Scale, and further outcome-relevant data were recorded. Expenses were calculated using the German fixed case rate classification system consisting of Diagnosis-Related Groups (DRG) and the Operation and Procedure catalogue (OPS). Overall acute length of stay (LOS) and LOS on the intensive care unit (ICU) were separately evaluated. Expenses were compared with formerly published first-year costs of ischemic stroke. RESULTS: Fifty-four percent of the patients (median age 52 years, 69% females) received coiling and 46% clipping. Acute in-hospital treatment accounted for 82% of total in-hospital expenses, while consequential in-hospital treatment accounted only for 18%. Altogether, the total first-year in-hospital expenses for all patients were as high as €2,650,002, resulting in average SAH in-hospital treatment expenses of €26,238 per patient for the first year. Poor clinical condition on admission and longer stay in ICU are the main cost-driving factors. The impact of the aneurysm treatment method is debatable. Only a poor HH grade and longer ICU stay are independent cost-driving factors. SAH treatment expenses are far higher than treatment costs for ischemic stroke in the literature (€6,731 for first-year inpatient and €3,287 for outpatient treatment). CONCLUSIONS: Clinical condition and LOS determine in-hospital expenses after SAH. Aneurysmal SAH prevalently results in a relevant economic impact on the health system exceeding formerly published treatment expenses for ischemic stroke.

Prognostic Factors for Functional Outcome of Patients with Optic Nerve Sheath Meningiomas Treated with Stereotactic Radiotherapy-Evaluation of Own and Meta-Analysis of Published Data.

OBJECTIVE: To evaluate prognostic factors for a favorable outcome (improvement of the visual acuity or visual fields) after fractionated stereotactic radiotherapy (fSRT) of optic nerve sheath meningioma (ONSM). METHODS: We performed a database search for ONSM treatments during the period from April 2008 to September 2019 in the prospective database for stereotactic radiosurgery/radiotherapy (SRS/SRT) of the Robert Janker Clinic Bonn (Department of Radiotherapy) and performed a literature review and meta-analysis of published data on ONSM between 2010 and 2019. Ophthalmic status before and after treatment was evaluated and the collective was dichotomized into two groups: functional improvement (FI; improvement of either visual acuity or visual fields) and non functional improvement (NFI; with stable or deteriorating visual acuity or visual fields). The two groups were compared regarding different variables: pretreatment visual acuity, age, gender, gross tumor volume (GTV), follow up (FU) time, tumor localization, and maximal retina dose. RESULTS: Overall, 13 stereotactic radiotherapies were performed for ONSM (12 × fSRT, 1 × SRS). Mean follow up was 3 years (range: 1-5 years). The total dose was 50.4 Gy (5 × 1.8 Gy/week) in 12 patients treated with fSRT and 1 × 14 Gy in one SRS case. Mean GTV was 1.13 ccm (range: 0.44-2.20 ccm). During follow up, all tumors were stable or showed shrinkage of tumor volume (100% tumor control), no adverse events were observed, 53% of the patients achieved either better visual acuity or visual fields. Pretreatment visual acuity was significantly different between the FI and the NFI group (0.17 vs. 0.63, p = 0.03) in our series and in the meta analysis (p < 0.01). Moreover, shorter FU time and lower retinal dose were significantly linked (p < 0.05 and p < 0.01, respectively) with a better outcome in the meta-analysis but not in our patient cohort. Intracranial tumor localization, gender, and age were not significantly different between the two outcome groups. CONCLUSION: FSRT for ONSM achieves in over 50% of cases an improvement of the ophthalmic status with low morbidity and excellent tumor control in our series and the meta analysis. Patients with a favorable outcome had in all analysis a significantly higher visual acuity before treatment start. Therefore, we advocate using fSRT as early as possible before vision deterioration occurs.

Spinal glomus-type arteriovenous malformations: microsurgical treatment in 20 cases.

OBJECT: Glomus-type spinal arteriovenous malformations (AVMs) are rare. In the literature only small series and anecdotal reports can be found, and there are no prospective series elucidating the natural course or the superiority of 1 treatment regimen over another (such as surgery versus embolization versus conservative treatment). Microsurgical treatment of spinal AVMs often seems difficult because many lesions are not anatomically suitable for primary microsurgical occlusion and are therefore treated with first-line neuroradiological interventions or not at all. METHODS: Between 1989 and 2005, 20 patients with glomus-type AVMs underwent microsurgical treatment at 2 major neurosurgical centers in Germany. The history of symptoms in these patients ranged from 2 days to 11 years. Four patients presented with subarachnoid hemorrhage, 2 with intramedullary hematoma, 4 with paresthesia or pain, and 10 with clinical signs of myelopathy. Seven patients underwent partial embolization prior to microsurgery. The authors only operated on AVMs accessible from a dorsal or dorsolateral approach. Neurological status was assessed with the McCormick classification scheme. Follow-up data were obtained from outpatient records. Three patients were interviewed over the telephone and 4 patients were not available for follow-up evaluation. RESULTS: Surgery was performed via a laminectomy in 14 and hemilaminectomy in 6 patients. The microsurgical technique used consisted of retrograde dissection of the AVM from the venous side in most cases. Four (20%) of 20 patients showed worsening of neurological symptoms to a worse McCormick grade, probably caused by suspected venous stasis directly after surgery, however only 1 patient (5%) suffered permanent deterioration after surgery. In 14 patients postoperative angiography proved complete occlusion in 11 patients, including the presence of a remnant requiring a second operation with complete occlusion thereafter in 1 patient. In 3 patients occlusion was incomplete: a small residual AVM remained in 1 patient, and a discrete feeding vessel without a vein was evident in 2 patients. CONCLUSIONS: Spinal cord AVMs are rare. If embolization is not possible, surgery may be indicated in selected cases. Spinal AVMs behave differently after incomplete occlusion either surgically or with embolization. A postoperative reduction in symptoms is frequent despite the presence of small remnants, and the risk of neurological deficits seems relatively low even in residual AVMs. Therefore, treatment need not necessarily aim at complete occlusion if that would be associated with an unacceptably high risk of neurological deficits.

Hyponatremia After Spontaneous Aneurysmal Subarachnoid Hemorrhage-A Prospective Observational Study.

OBJECTIVE: Hyponatremia has been frequently observed after aneurysmal subarachnoid hemorrhage (SAH), and some data have suggested a correlation with symptomatic cerebral vasospasm and poor outcomes. The present prospective study investigated sodium and water disturbances after aneurysmal SAH with regard to symptomatic vasospasm and patient outcomes. METHODS: Data from all patients with aneurysmal SAH treated in our department during a 2-year period were collected. Daily natriuresis, sodium levels, water balance, and serum and urine osmolality were measured at 4 different points: day 1 of admission or bleeding, day 3, day 7, and day 14-21 or discharge. The clinical parameters (i.e., Hunt and Hess grade, aneurysm location and treatment, onset of vasospasm) were reviewed. The patients' outcome was assessed using the Glasgow outcome score and modified Rankin scale. RESULTS: A total of 101 patients (70 women; median age, 52 years) were enrolled in the present study. Of these 101 patients, 59.4% had a good grade SAH (Hunt and Hess grade 1-3). The most common aneurysm location was the anterior communicating artery (37%). The results from an electrolyte analysis were available for ≤91 patients at days 1 and 78 at discharge. In 33 patients (32.7%), hyponatremia had been diagnosed at any time point. Hyponatremia was most frequently observed at day 1 and later at days 7-10. A location in the anterior communicating artery resulted in hyponatremia more frequently only at day 1 (P = 0.007). The main causes of hyponatremia were cerebral salt-wasting syndrome (early onset) and syndrome of inappropriate antidiuretic hormone secretion (early and late onset). CONCLUSION: Distinguishing early- and late-onset hyponatremia is of major relevance, because different therapeutic approaches are required. Only hyponatremia at discharge resulted in less favorable outcomes.

Spontaneous Aneurysmal Subarachnoid Hemorrhage and Related Cortisol and Immunologic Alterations: Impact on Patients' Health-related Quality of Life.

OBJECTIVE: To highlight the impact of aneurysmal subarachnoid hemorrhage (SAH) on surviving patients' health-related quality of life (HRQoL) with respect to cortisol and interleukin (IL)-6 alterations and also to identify possible clinical predictors for a better HRQoL. METHODS: Fifty surviving patients treated in our hospital for aneurysmal SAH in a 2-year period with sufficient HRQoL data were enrolled. A good clinical outcome was represented by the modified Rankin Scale (mRS) 0 to 2. The patient's HRQoL was assessed using the Short Form health survey questionnaire, the Beck Depression Inventory, and the Daily Fatigue Impact Scale at 6 and 12 months. The results were analyzed regarding possible correlation to 24-hour urinary free cortisol, serum, and cerebrospinal fluid IL-6 levels. RESULTS: A reduction of HRQoL in up to 35% of survivors was observed at 6 months and in a high proportion of patients (47.2%) with an assumable good outcome (mRS 0-2). Reduced HRQoL in survivors was found in terms of SF-36 (34.9%), depression (26.8%), and fatigue (14%) at 6 months and 18.4%, 39.4%, and 18.9% at 12 months, respectively. Improvement was recorded at 12 months, mainly in SF-36. Early elevated 24-hour urinary free cortisol and IL-6 levels showed a significant positive impact on HRQoL. CONCLUSIONS: Early cortisol and IL-6 levels may predict patients' HRQoL after SAH. Twelve months after SAH, a considerable percentage of patients with a presumably good outcome (mRS 0-2) had a lower HRQoL compared with the general population. Implementing corresponding tests at discharge and 12-month follow-up is recommended.

Microsurgery for cerebral arteriovenous malformations: subgroup outcomes in a consecutive series of 288 cases.

OBJECTIVE The objective of this study was to review the outcomes after microsurgical resection of cerebral arteriovenous malformations (AVMs) from a consecutive single-surgeon series. Clinical and imaging data were analyzed to address the following questions concerning AVM treatment in the post-ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations) era. 1) Are the patients who present with unruptured or ruptured AVMs doing better at long-term follow-up? 2) Is the differentiation between Ponce Class A (Spetzler-Martin Grade I and II) patients versus Ponce Class B and C patients (Spetzler-Martin Grade III and IV) meaningful and applicable to surgical practice? 3) How did the ARUBA-eligible patients of this surgical series compare with the results reported in ARUBA? METHODS Two hundred eighty-eight patients with cerebral AVMs underwent microsurgical resection between 1983 and 2012 performed by the same surgeon (J.S.). This is a prospective case collection study that represents a consecutive series. The results are based on prospectively collected, early-outcome data that were supplemented by retrospectively collected, follow-up data for 94% of those cases. The analyzed data included the initial presentation, Spetzler-Martin grade, obliteration rates, surgical and neurological complications, and frequency of pretreatment with embolization or radiosurgery. The total cohort was compared using "small-AVM," Spetzler-Martin Grade I and II, and ARUBA-eligible AVM subgroups. RESULTS The initial presentation was hemorrhage in 50.0% and seizures in 43.1% of patients. The series included 53 Spetzler-Martin Grade I (18.4%), 114 Spetzler-Martin Grade II (39.6%), 90 Spetzler-Martin Grade III (31.3%), 28 Spetzler-Martin Grade IV (9.7%), and 3 Spetzler-Martin Grade V (1.0%) AVMs. There were 144 unruptured and 104 ARUBA-eligible cases. Preembolization was used in 39 cases (13.5%). The occlusion rates for the total series and small AVM subgroup were 99% and 98.7%, respectively. The mean follow-up duration was 64 months. Early neurological deterioration was seen in 39.2% of patients, of which 12.2% had permanent and 5.6% had permanent significant deficits, and the mortality rate was 1.7% (n = 5). Outcome was better for patients with AVMs smaller than 3 cm (permanent deficit in 7.8% and permanent significant deficit in 3.2% of patients) and Ponce Class A status (permanent deficit in 7.8% and significant deficit in 3.2% of patients). Unruptured AVMs showed slightly higher new deficit rates (but 0 instances of mortality) among all cases, and in the small AVM and Ponce Class A subgroups. Unruptured Spetzler-Martin Grade I and II lesions had the best outcome (1.8% permanent significant deficit), and ARUBA-eligible Spetzler-Martin Grade I and II lesions had a slightly higher rate of permanent significant deficits (3.2%). CONCLUSIONS Microsurgery has a very high cure rate. Focusing microsurgical AVM resection on unruptured lesions smaller than 3 cm or on Spetzler-Martin Grade I and II lesions is a good strategy for minimizing long-term morbidity. Well-selected microsurgical cases lead to better outcomes than with multimodal interventions, as in the ARUBA treatment arm, or conservative treatment alone. Long-term prospective data collection is valuable.

Health Care Costs of Spontaneous Aneurysmal Subarachnoid Hemorrhage for Rehabilitation, Home Care, and In-Hospital Treatment for the First Year.

BACKGROUND: Given the young age of onset and high probability of long-term disability after subarachnoid hemorrhage (SAH), the financial impact is expected to be substantial. Our primary objective was to highlight subsequent treatment costs after the acute in-hospital stay, including rehabilitation and home care, compared with costs for ischemic stroke. METHODS: The study included 101 patients (median age 52 years, 70 women) with aneurysmal SAH treated from July 2007 to April 2009. In-hospital costs were calculated using German diagnosis related groups. Rehabilitation costs depended on rehabilitation phase/grade and daily rate. Level of severity of care requirements determined the costs for home care. RESULTS: Of patients, 54% received coiling and 46% received clipping. The clipping group included more poor-grade patients than the coiling group (P = 0.039); 23 patients died. Of 78 surviving patients, 70 received rehabilitation treatment (68 in Germany). Mean rehabilitation costs were €16,030 per patient. Patients in the clipping group generated higher rehabilitation costs and longer treatment periods in rehabilitation facilities (P = 0.001 for costs [€20,290 vs. €11,771] and P = 0.011 for duration (54.4 days vs. 40.5 days). Of surviving patients, 32% needed home care, of whom 52% required constant care. Multivariate regression analysis identified longer intensive care unit stay and poor Hunt and Hess grade as independent predictors of higher costs. CONCLUSIONS: Aneurysmal SAH prevalently affects working individuals with long-term occupational disability necessitating long-term medical rehabilitation for most patients and subsequent nursing care in one third of survivors. Overall, SAH treatment generates far higher costs than reported for ischemic stroke.

NOTCH4 gene polymorphisms as potential risk factors for brain arteriovenous malformation development and hemorrhagic presentation.

OBJECTIVE Arteriovenous malformations (AVMs) of the brain are a frequent and important cause of intracranial hemorrhage in young adults. Little is known about the molecular-genetic pathomechanisms underlying AVM development. Genes of the NOTCH family control the normal development of vessels and proper arteriovenous specification. Transgenic mice with constitutive expression of active NOTCH4 frequently develop AVMs. Here, the authors report a genetic association study investigating possible associations between NOTCH4 gene polymorphisms and formation and clinical presentation of AVMs. METHODS After PCR amplification and direct DNA sequencing or restriction digests, 10 single-nucleotide polymorphisms (SNPs) of the NOTCH4 gene were used for genotyping 153 AVM patients and 192 healthy controls (i.e., blood donors). Pertinent clinical data were available for 129 patients. Uni- and multivariate single-marker and explorative haplotype analyses were performed to identify potential genetic risk factors for AVM development and for hemorrhagic or epileptic presentation. RESULTS Eleven calculated haplotypes consisting of 3-4 SNPs (most of which were located in the epidermal growth factor-like domain of the NOTCH4 gene) were observed significantly more often among AVM patients than among controls. Univariate analysis indicated that rs443198_TT and rs915895_AA genotypes both were significantly associated with hemorrhage and that an rs1109771_GG genotype was associated with epilepsy. The association between rs443198_TT and AVM bleeding remained significant in the multivariate regression analysis. CONCLUSIONS The authors' results suggest NOTCH4 SNPs as possible genetic risk factors for the development and clinical presentation of AVMs and a role of NOTCH4 in the pathogenesis of this disease.

Association of a polymorphism of the ACVRL1 gene with sporadic arteriovenous malformations of the central nervous system.

OBJECT: Important central nervous system (CNS) manifestations in patients with hereditary hemorrhagic telangiectasia (HHT) include arteriovenous malformations (AVMs) and dural arteriovenous fistulas (DAVFs). Hereditary hemorrhagic telangiectasia is caused by germline mutations of two genes: ENG (HHT Type 1) and ACVRL1 (HHT Type 2). The ENG gene variations have been associated with the formation of intracranial aneurysms. The authors studied whether sequence variations in ACVRL1 or ENG are associated with the development of clinically sporadic arteriovenous dysplasias and aneurysms of the CNS. METHODS: The coding sequence (in 44 patients with AVMs and 27 with aneurysms) and the 5' end and the polyA site (in 53 patients with AVMs) of the ACVRL1 gene were analyzed for sequence variations using direct sequencing and single-strand conformational polymorphism analysis. One ENG and three ACVRL1 gene polymorphisms were genotyped using restriction enzyme-based analysis in 101 patients with sporadic AVMs and DAVFs of the CNS, 79 patients treated for intracranial aneurysms, and 202 control volunteers. The authors identified a statistically significant association between the IVS3 -35A/T polymorphism in intron 3 of the ACVRL1 gene and the development of AVMs and DAVFs (p = 0.004; odds ratio [OR] 1.73; 95% confidence interval [CI] 1.19-2.51; after adjustments for age and sex), but not aneurysms (crude OR 0.82; 95% CI 0.55-1.18). CONCLUSIONS: The results of this study link ACVRL1 (HHT Type 2 gene) to the formation of the clinically sporadic variants of vascular malformations of the CNS most commonly seen in patients with HHT, that is, AVMs and DAVFs.

Treatment of Cerebral Arteriovenous Malformations with Radiosurgery or Hypofractionated Stereotactic Radiotherapy in a Consecutive Pooled Linear Accelerator Series.

OBJECTIVE: To review outcomes after linear accelerator stereotactic radiosurgery (SRS) and hypofractionated stereotactic radiotherapy (hfSRT) of arteriovenous malformations (AVMs) from a consecutive and pooled series of 2 Novalis centers and to analyze the influence of AVM size, Spetzler-Martin (SM) grade, pretreatment, and hemorrhagic versus nonhemorrhagic presentation. A subgroup analysis of A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA)-eligible patients also was performed. METHODS: Prospectively collected treatment and outcome data were supplemented by retrospectively collected follow-up data for 93.8% of all patients. A total of 129 patients with AVM had SRS or hfSRT between 2000 and 2014 with the same linear accelerator system in 2 centers. Data analysis included initial presentation, SM grade, occlusion rates assessed by magnetic resonance and/or digital subtraction angiography, neurologic and therapeutic complications, and pretreatments. Statistical analysis was performed for patient demographic data and for factors potentially influencing outcome. RESULTS: Initial presentation was hemorrhage in 43.8% or seizures/neurologic deficits in 46.2%. The series included 6 SM grade I (5%), 26 SM II (21.5%), 55 SM III (45.5%), 28 SM IV (23%), and 6 SM V cases (5%). Pre-embolization was used in 36 patients (29.8%), 8 patients had previous surgery (6.6%), and 6 patients were irradiated before elsewhere (5%); 5 patients (4.2%) received multimodal pretreatment. Mean follow-up was 43 months. The occlusion rate for the total series was 71.1%, for SM I/II cases 80.6%, and 67.4% for the SM ≥ subgroup. The occlusion rate was 75.0% for the small volume (<4 cc) and 55.6% for the large volume (>10 cc) subgroup. There was no statistical difference between the occlusion rate of patients with or without pretreatment if taken all modalities together (72.7% and 69.7%, respectively). There was only a trend of a belated occlusion of pre-embolized AVMs. The occlusion rate for hemorrhagic AVM was with 77.4% better than for nonhemorrhagic (66.2%) or ARUBA-eligible AVMs (64.8%) but without reaching statistical significance. Neurologic deterioration was seen in 13.2% of the patients. There were 2 re-bleedings within 17-18 months (1.7%), 1 of them without a new neurologic deficit and total occlusion after re-SRS. One patient with pre-existing epilepsy died a sudden unexpected death (mortality rate: 0.8%). CONCLUSIONS: Overall SRS and hfSRT are valuable therapy options, especially in symptomatic patients with AVM, with a low rate of morbidity and mortality and an acceptable overall complete occlusion rate of >70% and >80% for SM I/II AVMs.

Seizure Outcomes in Patients With Surgically Treated Cerebral Arteriovenous Malformations.

BACKGROUND: Epilepsy is the second most common symptom in cerebral arteriovenous malformation (AVM) patients. The consecutive reduction of life quality is a clinically underrated problem because treatment usually focuses on the prevention of intracerebral hemorrhage. OBJECTIVE: To evaluate postoperative seizure outcome with the aim of more accurate counseling for postoperative seizure outcome. METHODS: From 1985 to 2012, 293 patients with an AVM were surgically treated by J.S. One hundred twenty-six patients with preoperative seizures or epilepsy could be identified; 103 of 126 had a follow-up of at least 12 months and were included in the analysis. The different epilepsy subtypes were categorized (sporadic seizures, chronic epilepsy, drug-resistant epilepsy [DRE]). Preoperative workup and surgical technique were evaluated. Seizure outcome was analyzed by using International League Against Epilepsy classification. RESULTS: Sporadic seizures were identified in 41% of patients (chronic epilepsy and DRE were identified in 36% and 23%, respectively). Detailed preoperative epileptological workup was done in 13%. Seizure freedom was achieved in 77% (79% at 5 years, 84% at 10 years). Outcome was significantly poorer in DRE cases. More extensive resection was performed in 11 cases with longstanding symptoms (>24 months) and resulted in better seizure outcome as well as the short duration of preoperative seizure history. CONCLUSION: Patients presenting with AVM-associated epilepsy have a favorable seizure outcome after surgical treatment. Long-standing epilepsy and the progress into DRE markedly deteriorate the chances to obtain seizure freedom and should be considered an early factor in establishing the indication for AVM removal.

Management and outcome in adult intramedullary spinal cord tumours: a 20-year single institution experience.

BACKGROUND: Several uncertainties remain concerning the management of intramedullary spinal cord tumours (IMSCTs). These include the timing and extent of resection, its interrelated functional outcome, and the adequate use and timing of radiation therapy and/or chemotherapy. In this retrospective study we report on all adult cases involving IMSCTs treated from 1987 to 2007 in our institution to validate our treatment strategy for IMSCTs. Pre- and post-operative functional performance was classified according to the McCormick scale. RESULTS: A total of 70 adult cases with IMSCTs consisting of ependymoma (39), astrocytoma (11), carcinoma metastasis (8), haemangioblastoma (5), cavernoma (3) and others (4) were reviewed. Mean age was 46.8 years (range, 18-79 years), and mean follow-up was 4.5 years (range, 1-195 months). The proportion of localisation in descending order was thoracic (36%), cervical (33%), cervicothoracic (19%) and conus region (13%), with 45 gross total resections, 22 partial resections and three biopsies. Surgery-related morbidity with worsening postoperative symptoms occurred immediately in 13 patients (18.6%). The preoperative McCormick grade correlated significantly with the early postoperative grade and the grade at follow-up (χ2-test; p=0.001). None of the patients with preserved intraoperative evoked potentials exhibited significant postoperative deterioration. The degree of resection was correlated with progression-free survival (Duncan test; p=0.05). Most patients with malignant tumours, namely anaplastic ependymoma (3), astrocytoma (2) or metastatic lesions (5), underwent postoperative radiation therapy. Six patients (one anaplastic ependymoma, two anaplastic astrocytomas and three metastatic lesions) received postoperative chemotherapy. CONCLUSIONS: IMSCTs should be operated on when symptoms are mild. We recommend evoked potential-guided microsurgical total resection of ependymomas and other benign lesions; partial resection or biopsy followed by adjuvant therapy should be confined to patients with high-grade astrocytomas, whereas resection or biopsy with adjuvant therapy is the best option for metastatic lesions.