Current Practice of Neurosurgical Teleconsultation in Germany.

OBJECTIVE: As neurosurgery is a demanding specialty with services in larger medical centers only, consultation over larger distances plays an important role in health care. In times of digitalization, teleconsultation for medical images and cases plays an increasing role in neurosurgical services. However, no standards and demands have been established for its execution in the subfield of neurosurgery, so far. Therefore, as a first step, we performed a survey about the current state of teleconsultation in neurosurgery in Germany. METHODS: A standardized questionnaire consisting of 20 items was used to investigate the frequency of use and the operating conditions of teleconsultation in the field of neurosurgery. The survey was performed during the annual national German Society of Neurosurgery conference in 2017. Participation in the written survey was on voluntary and anonymous basis. RESULTS: In total, 296 individuals took part in the survey (140 specialists in neurosurgery, 77 residents). Among them, 71% were male and 121 worked at a university medical center. In total, 87.5% of all participants indicated that teleconsultation was used in their institutions (n = 113 in university medical centers and n = 76 in hospitals), and a vast majority stated to have had personal experience with it (88.6% of specialists, 85.5% of residents). The most frequent initial request for a consultation was done by phone call (80.3%). Images or data were then primarily transmitted via an electronic system (77.3%), followed by transmissions via CD or by post. The reply to a consultation was also mainly done by phone call (91.3%), followed by fax, or by e-mail. No standard protocol was followed by 78.6% of the respondents, and they stated not to know about the statutory and legal rules. However, it was stated that the protection of patient data was not endangered by using teleconsultation. The usefulness of teleconsultation and its future relevance were rated highly by the participants. The risk of misinterpretation of image data, especially without having direct access to other patient data, seemed to be a critical and unequivocal challenge. CONCLUSION: The results of the survey demonstrate that teleconsultation for medical images and cases is a frequently used and well-accepted tool in neurosurgical health care. However, a standardized neurosurgical procedure is still lacking and the statutory rules for this field of digital medicine are generally not known in our community. Potential misinterpretation and resulting misjudgment seem to be realistic drawbacks. Thus, we see a necessity for elaboration of guidelines for teleconsultation in neurosurgery on national and European basis.

Collision of Priorities in Posttraumatic Coma and Suspected Multiple Injuries: A Prospective Multicenter Trial.

OBJECTIVE: The presence of multiple injuries in addition to a traumatic brain injury (TBI) is initially uncertain in most patients with posttraumatic coma. The interdisciplinary team of physicians in charge of initial treatment after hospital admission may face a collision of vital priorities. The purpose of this study was to analyze which diagnostic and surgical measures were given priority over others in comatose patients after injury and to draw conclusions from these data. METHODS: In this prospective multicenter cohort study, the outcomes of 1,003 comatose patients with suspected multiple injuries were studied. The analysis was divided into an early and a late stage. Diagnostic and surgical measures were analyzed for a 6-month period. The prognostic value of the Glasgow Coma Scale (GCS) and the World Federation of Neurosurgical Societies grading scale were investigated. RESULTS: Removal of intracranial hematomas and decompressive craniotomies were the most frequent procedures within the first 48 hours after admission to the hospital. Prognosis depends on the location and the combination of injuries. Outcome is significantly correlated to initial signs of brainstem dysfunction. The GCS did not adequately predict clinical outcome. CONCLUSION: Comatose patients with suspected multiple injuries should only be admitted to hospitals with a continuous neurosurgical service because intracranial operations are more frequent in the first 48 hours than extracranial operations. Depending on the neurologic status of the patient, an urgent surgical decompression may be essential for a good outcome. The GCS alone is not a sufficient tool for the neurologic assessment and the prognosis of patients with multiple injuries. The onset of clinical signs of brainstem dysfunction indicates a critical deterioration of the functioning of the central nervous system. The priority of surgical measures should be tailored accordingly.

Resolution of Brainstem Edema after Neurosurgical Occlusion of Dural Arteriovenous Fistulas of the Craniocervical Junction: Report of Three Cases and Review.

OBJECTIVE: Dural arteriovenous fistulas of the craniocervical junction are rare but the most dangerous of spinal fistulas. The concurrent brainstem edema has been attributed to increased pressure within the venous outflow of the brainstem and upper cord, but the differential diagnosis of brainstem edema is demanding. This report presents the details of clinical findings, magnetic resonance imaging (MRI) , surgical techniques, and follow-up of these fistulas. METHODS: Three cases with dural arteriovenous fistulas and edema of the brainstem and upper cord are described plus a review of the literature. Clinical presentation, radiologic findings, and a follow-up of outcomes are presented. RESULTS: All three cases with misleading diagnoses at the time of referral experienced variable degrees of tetraparesis with brainstem edema on MRI. Congested veins on MRI raised the suspicion of a vascular origin of the edema. The diagnosis was established with highly specific angiography with microcatheters identifying a feeder from the ascending pharyngeal artery in two cases and a tentorial feeder from the carotid artery in one case. The operation included temporary clipping of the fistula and neuromonitoring. Follow-up confirmed improvement of clinical signs and resolution of the brainstem edema on MRI. CONCLUSION: Edema of the brainstem and cervical cord may be caused by a dural arteriovenous fistula of the craniocervical junction. Surgical occlusion may be an efficient option for the complete resolution of radiologic and clinical symptoms.

Altered expression of E-Cadherin-related transcription factors indicates partial epithelial-mesenchymal transition in aggressive meningiomas.

E-Cadherin has been suggested to be involved in meningioma progression but is also known as a key player of epithelial to mesenchymal transition (EMT). We wondered whether the adherens junction protein E-Cadherin, the tight junction protein Zo-1, and transcription factors suppressing E-Cadherin expression (Slug, Snail, Twist, Zeb-1) are differentially expressed between histopathological subtypes of meningioma, and if the expression of these factors is related to biological features of meningiomas. Analyzing 85 meningiomas of various histopathological subtypes and grades of malignancy by immunohistochemistry and 50 of them in addition by real-Time-PCR, we observed significantly reduced expression of Zeb-1, Twist and Slug, together with slightly increased expression levels for E-Cadherin and Zo- 1 in fibroblastic WHO-grade I tumors compared to meningothelial WHO grade I tumors, contradicting the hypothesis of EMT in the fibroblastic meningiomas characterized by mesenchymal appearance. However, comparing aggressive WHO grade II or III meningiomas with WHO-grade I tumors, we observed altered expression levels (loss of E-Cadherin and Zo-1, increased expression of Zeb-1 and Slug) indicating molecular features of EMT in aggressive meningiomas. This was supported by reduced E-Cadherin and increased Slug levels in recurrent compared to non-recurrent meningiomas. The expression levels of E-cadherin and Zo-1 were positively correlated with expression of NF2 mRNA. In primary meningioma cultures and IOMM-Lee meningioma cells, EMT induction by TGF-ß resulted in altered morphology and increased expression of EMT associated transcription factors. Meningioma cells with allelic losses of NF2 showed generally higher levels of various EMT relevant proteins, but were unresponsive to TGF-ß treatment. Our data indicate that aggressive meningiomas of WHO grade II/III are characterized by molecular alterations indicating partial EMT. This might contribute to the aggressive biology of these tumors.

Coma After Acute Head Injury.

BACKGROUND: Coma after acute head injury is always alarming. Depending on the type of injury, immediate treatment may be life-saving. About a quarter of a million patients are treated for traumatic brain injury in Germany each year. Treatment recommendations must be updated continually in the light of advancing knowledge. METHODS: This review of treatment recommendations, prognostic factors, and the pathophysiology of coma after acute head injury is based on a 2015 German guideline for the treatment of head injury in adults and on pertinent publications retrieved by a selective search in PubMed for literature on post-traumatic coma. RESULTS: As soon as the vital functions have been secured, patients with acute head injury should undergo cranial computed tomography, which is the method of choice for identifying intracranial injuries needing immediate treatment. Patients who have an intracranial hematoma with mass effect should be taken to surgery at once. The prognosis is significantly correlated with the patient's age, the duration of coma, accompanying neurological manifestations, and the site of brain injury. The case fatality rate of patients who have been comatose for 24 hours and who have accompanying lateralizing signs, a unilaterally absent pupillary light reflex, or hemiparesis lies between 30% and 50%. This figure rises to 50-60% in patients with abnormal extensor reflexes and to over 90% in those with bilaterally absent pupillary light reflexes. Current neuropathological and neuroradiological studies indicate that coma after acute head injury is due to reversible or irreversible dysfunction of the brainstem. CONCLUSION: Brain tissue can tolerate ischemia and elevated pressure only for a very limited time. Comatose head-injured patients must therefore be evaluated urgently to determine whether they can be helped by the surgical removal of a hematoma or by a decompressive hemicraniectomy.

Clinical, Radiologic, and Legal Significance of "Extensor Response" in Posttraumatic Coma.

OBJECTIVE: The timely detection of neurologic deterioration can be critical for the survival of a neurosurgical patient following head injury. Because little reliable evidence is available on the prognostic value of the clinical sign "extensor response" in comatose posttraumatic patients, we investigated the correlation of this clinical sign with outcome and with early radiologic findings from magnetic resonance imaging (MRI). METHODS: This retrospective analysis of prospectively obtained data included 157 patients who had remained in a coma for a minimum of 24 hours after traumatic brain injury. All patients received a 1.5-T MRI within 10 days (median: 2 days) of the injury. The correlations between clinical findings 12 and 24 hours after the injury-in particular, extensor response and pupillary function, MRI findings, and outcome after 1 year-were investigated. Statistical analysis included contingency tables, Fisher exact test, odds ratios (ORs) with confidence intervals (CIs), and weighted κ values. RESULTS: There were 48 patients with extensor response within the first 24 hours after the injury. Patients with extensor response (World Federation of Neurosurgical Societies coma grade III) statistically were significantly more likely to harbor MRI lesions in the brainstem when compared with patients in a coma who had no further deficiencies (coma grade I; p = 0.0004 by Fisher exact test, OR 10.8 with 95% CI, 2.7-42.5) and patients with unilateral loss of pupil function (coma grade II; p = 0.0187, OR 2.8 with 95% CI, 1.2-6.5). The correlation of brainstem lesions as found by MRI and outcome according to the Glasgow Outcome Scale after 1 year was also highly significant (p ≤ 0.016). CONCLUSION: The correlation of extensor response and loss of pupil function with an unfavorable outcome and with brainstem lesions revealed by MRI is highly significant. Their sudden onset may be associated with the sudden onset of brainstem dysfunction and should therefore be regarded as one of the most fundamental warning signs in the clinical monitoring of comatose patients.

Coma and cerebral imaging.

The clinical sign of coma is a common feature in critical care medicine. However, little information has been put forth on the correlations between coma and cerebral imaging methods. The purpose of the article is to compile the available information derived from various imaging methods and placing it in a context of clinical knowledge of coma and related states. The definition of coma and the cerebral structures responsible for consciousness are described; the mechanisms of cerebral lesions leading to impaired consciousness and coma are explained. Cerebral imaging methods provide a large array of information on the structural changes of brain tissue in the various diseases leading to coma. Circumscript lesions produce space-occupying masses that displace the brain, ultimately leading to various types of herniation. Generalized disease of the brain usually leads to diffuse brain swelling which also can cause herniation. Epileptic states, however, rarely are detectable by imaging methods and mandate EEG examinations. Another important aspect of imaging in coma is the increasing use of functional imaging methods, which can detect the function of loss of function in various areas of the brain and render information on the extent and severity of brain damage as well as on the prognosis of disease. The MRI methods of (1)H-spectroscopy and diffusion tensor imaging may provide more functional information in the future.

Changes in gray matter volume after microsurgical lumbar discectomy: a longitudinal analysis.

People around the world suffer chronic lower back pain. Because spine imaging often does not explain the degree of perceived pain reported by patients, the role of the processing of nociceptor signals in the brain as the basis of pain perception is gaining increased attention. Modern neuroimaging techniques (including functional and morphometric methods) have produced results that suggest which brain areas may play a crucial role in the perception of acute and chronic pain. In this study, we examined 12 patients with chronic low back pain and sciatica, both resulting from lumbar disc herniation. Structural magnetic resonance imaging (MRI) of the brain was performed 1 day prior to and about 4 weeks after microsurgical lumbar discectomy. The subsequent MRI revealed an increase in gray matter volume in the basal ganglia but a decrease in volume in the hippocampus, which suggests the complexity of the network that involves movement, pain processing, and aspects of memory. Interestingly, volume changes in the hippocampus were significantly correlated to preoperative pain intensity but not to the duration of chronic pain. Mapping structural changes of the brain that result from lumbar disc herniation has the potential to enhance our understanding of the neuropathology of chronic low back pain and sciatica and therefore may help to optimize the decisions we make about conservative and surgical treatments in the future. The possibility of illuminating more of the details of central pain processing in lumbar disc herniation, as well as the accompanying personal and economic impact of pain relief worldwide, calls for future large-scale clinical studies.

Structural brain alterations in patients with lumbar disc herniation: a preliminary study.

Chronic pain is one of the most common health complaints in industrial nations. For example, chronic low back pain (cLBP) disables millions of people across the world and generates a tremendous economic burden. While previous studies provided evidence of widespread functional as well as structural brain alterations in chronic pain, little is known about cortical changes in patients suffering from lumbar disc herniation. We investigated morphometric alterations of the gray and white matter of the brain in patients suffering from LDH. The volumes of the gray and white matter of 12 LDH patients were determined in a prospective study and compared to the volumes of healthy controls to distinguish local differences. High-resolution MRI brain images of all participants were performed using a 3 Tesla MRI scanner. Voxel-based morphometry was used to investigate local differences in gray and white matter volume between patients suffering from LDH and healthy controls. LDH patients showed significantly reduced gray matter volume in the right anterolateral prefrontal cortex, the right temporal lobe, the left premotor cortex, the right caudate nucleus, and the right cerebellum as compared to healthy controls. Increased gray matter volume, however, was found in the right dorsal anterior cingulate cortex, the left precuneal cortex, the left fusiform gyrus, and the right brainstem. Additionally, small subcortical decreases of the white matter were found adjacent to the left prefrontal cortex, the right premotor cortex and in the anterior limb of the left internal capsule. We conclude that the lumbar disk herniation can lead to specific local alterations of the gray and white matter in the human brain. The investigation of LDH-induced brain alterations could provide further insight into the underlying nature of the chronification processes and could possibly identify prognostic factors that may improve the conservative as well as the operative treatment of the LDH.

Resveratrol decreases B-cell lymphoma-2 expression and viability in GH3 pituitary adenoma cells of the rat.

OBJECTIVE: Resveratrol is a phytoestrogen with various antiproliferative and proapoptotic effects. This in vitro study aimed to analyze the effect of resveratrol on the viability and expression of modulators of apoptosis in GH3 pituitary adenoma cells of the rat. METHODS: GH3 cells were incubated with resveratrol concentrations from 20 to 100 µM for 48-72 hours. Cell viability was quantified using a hemocytometer. We assessed the ability of resveratrol to kill GH3 cells by an enzyme-linked immunosorbent assay (ELISA) of nucleosome liberation and by DNA degradation (unidimensional gel electrophoresis). Relative messenger RNA (mRNA) expression of survivin, B-cell lymphoma-2 protein (BCL-2) and BCL-2-associated X protein (BAX) normalized to ß2 microglobulin was measured using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: GH3 cell survival significantly decreased with increasing concentrations of resveratrol. In GH3 cells treated with 100 µM resveratrol, ELISA demonstrated a significant rise of nucleosome liberation, which typically occurs during apoptosis. In parallel, gel electrophoresis showed degradation of DNA into random fragments, pointing to a necrotic mode of cell death in most GH3 cells. In GH3 cells treated with 100 µM resveratrol, qRT-PCR detected a significant decrease of BCL-2 mRNA expression and a decrease of survivin mRNA expression, whereas a change of BAX mRNA expression could not be found. The BAX/BCL-2 ratio was significantly increased in GH3 cells after resveratrol treatment. CONCLUSIONS: Resveratrol reduces GH3 cell viability in a dose-dependent manner by inducing nonapoptotic cell death and apoptosis. Apoptosis in GH3 cells is probably mediated by resveratrol-dependent downregulation of apoptosis inhibitors, namely BCL-2 and possibly survivin. Further investigation of the potential effects of resveratrol on pituitary adenoma cells is warranted.

Controversies of diffusion weighted imaging in the diagnosis of brain death.

Imaging techniques as confirmatory tests may add safety to the diagnosis of brain death, but are partly not accepted either because they are too invasive, such as conventional arterial angiography, or because there is still lack of evidence of its reliability, such as magnetic resonance angiography. In this study the reliability of diffusion weighted imaging for the diagnosis of brain death was evaluated according in terms of its sensitivity and specificity. The apparent diffusion coefficients (ADC) of 18 brain dead patients were registered from 14 distinct brain areas. The mean ADC values of the brain dead patients were compared with normal controls of physiological ADC values of unaffected brain tissue. Despite a highly significant decrease of the mean ADC value in 16 patients, two patients showed mean ADC values that were within normal physiological range. An explanation may be the pseudonormalization of ADC values seen in stroke patients that depends on the time of the onset of the brain damage. We conclude, diffusion-weighted imaging may provide additional information on damage of the brain tissue but is not a practicable confirmatory test for the reliable diagnosis of brain death.

Early survival of comatose patients after severe traumatic brain injury with the dual cannabinoid CB1/CB2 receptor agonist KN38-7271: a randomized, double-blind, placebo-controlled phase II trial.

UNLABELLED: BACKGROUND AND STUDY OBJECT: Despite many drug trials, no substance has yet been identified that improves the outcome of severe head injury. The dual cannabinoid CB1/CB2 receptor agonist KN38-7271 mediates potent neuroprotection in animal models. We describe here the first randomized, double-blind, prospective, placebo-controlled clinical phase IIa proof-of-concept trial to investigate the safety, pharmacokinetics, and potential efficacy of a cannabinoid receptor agonist in humans. PATIENTS AND METHODS: Out of the 439, 97 comatose patients at 14 European neurosurgical centers met the inclusion criteria. KN38-7271 was administered within 4.5 hours of the injury, and the patients received 1000, 500 µg, or placebo. The primary analysis was pharmacokinetic; efficacy was measured by survival and by neurological improvement or deterioration 7 and 14 days and 1, 3, and 6 months after the injury. Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were analyzed from start of treatment to end of day 7. RESULTS: Survival rates within 1 month of the injury were significantly better in the treatment groups than in the placebo group (high-dose, Kaplan-Meier difference on day 30 + 0.12 with p = 0.043; low-dose, difference +0.15 with p = 0.011) but this effect was not seen after 6 months. Critical ICP and CPP were less extreme and less frequent in the treatment group. There were no severe and no serious adverse effects that could be attributed to KN38-7271. CONCLUSIONS: KN38-7271 appeared beneficial in the acute early phase of the comatose patient after a head injury. Its use was safe and well tolerated by patients. These results may provide the basis for further phase II/III trials in larger study populations.

Noninvasive assessment of intracranial pressure with venous ophthalmodynamometry. Clinical article.

OBJECT: Venous ophthalmodynamometry is a technique used to register the pressure within the central retinal vein. Because the outflow of the central retinal vein is exposed to the intracranial pressure (ICP), the pressure of the central retinal vein may be correlated with the ICP. In the absence of adequate statistical evidence, the authors compared the pressure of the central retinal vein with results of simultaneous invasive monitoring of ICP in neurosurgical patients. METHODS: The pressure within the central retinal vein was recorded in 102 patients, in whom invasive continuous monitoring of ICP had become necessary for various reasons, mostly because of suspected hydrocephalus and intracranial hemorrhage. RESULTS: A highly significant correlation of the pressure in the central retinal vein and the intracranial cavity was confirmed statistically. An increased pressure of the central retinal vein indicated an elevated ICP, with a probability of 84.2%, whereas a normal pressure of the central retinal vein indicated a normal ICP in 92.8% of patients. Conclusions Venous ophthalmodynamometry is a valuable technique for the noninvasive assessment of ICP.

Cytotoxic effect of different statins and thiazolidinediones on malignant glioma cells.

PURPOSE: Glioblastoma multiforme is still a tumor with very poor prognosis. Statins are actually used for the treatment of dyslipidemias and thiazolidinediones for improving insulin sensitivity in diabetes. Statins are inhibitors of the cholesterol pathway, while thiazolidinediones are peroxisomal proliferator activator receptor γ (PPAR) agonists. For both, a potent pro-apoptotic activity has been suggested. METHODS: We compared the antiglioma effect of simvastatin, atorvastatin, lovastatin, pravastatin, rosuvastatin, rosiglitazone, pioglitazone and their combinations at several concentrations on human glioblastoma cell lines U87, U 138, LN 405 and rat RG II. The cytotoxic effect was assessed using a cell proliferation assay after 48 and 144 h. Caspase 3 activity and the addition of isoprenoids and PPAR-y inhibitor GW9662 were assessed. Experiments were as well conducted under hypoxia for 24 h. RESULTS: We demonstrated a significant cytotoxic effect with a combination of statins plus pioglitazone. The effect was observed after 48 h and dramatically increased after 144 h. The combination of 2 types of statins (synthetic and natural) allowed a fivefold dose reduction. Statin effect was reversed with isoprenoids and partially with PPAR-γ antagonists, while thiazolidinediones effect was slightly affected by PPAR-γ antagonists. A marked increase in caspase 3 activity was achieved by combining atorvastatin with lovastatin. Cytotoxicity of the combination of statins and thiazolidinediones did not decrease under hypoxia. CONCLUSION: The assessed combination of statins with thiazolidinediones shows a synergistic cytotoxic effect against glioblastoma cells in vitro, which could represent a feasible therapeutic schema.