Proteins of the Lectin Pathway of complement activation at the site of injury in subarachnoid hemorrhage compared with peripheral blood.

BACKGROUND: A subarachnoid hemorrhage (SAH) is a debilitating stroke. Activation of the lectin pathway (LP) of the complement system in SAH patients could worsen the prognosis; however, conflicting results have been reported. This potentially reflects that pathological changes at the site of injury are not reflected in peripheral blood. AIMS OF THE STUDY: To measure the concentration of LP proteins in blood from the site of brain injury compared with peripheral blood in SAH patients, and to determine the concentration of LP proteins in cerebrospinal fluid (CSF). METHODS: We included 11 SAH patients undergoing aneurysm clipping or external ventricular drainage. Blood was collected from the site of injury and from a peripheral artery and/or CSF simultaneously. LP proteins were measured using time-resolved immunofluorometric assays. RESULTS: In all patients, the cerebral blood concentration of mannan-binding lectin, collectin liver-1 and collectin kidney-1, and mannan-associated serine proteases 1 and 2 were lower than in peripheral blood. The LP proteins were almost undetectable in CSF. CONCLUSION: Lectin pathway protein concentrations measured in peripheral blood do not always reflect changes at the site of injury. For some proteins, more information could be obtained in blood from the site of injury when investigating pathogenic mechanisms.

Plasma Neurofilament Light Chain Is Associated with Poor Functional Outcome and Mortality Rate After Spontaneous Subarachnoid Hemorrhage.

The initial clinical status after subarachnoid hemorrhage (SAH) is an important outcome predictor, but the mechanisms behind the early brain injury (EBI) remains incompletely understood. Elevated neurofilament levels in the cerebrospinal fluid at protracted stages after SAH are associated with poor outcome, but the potential association between plasma neurofilament (pNfL) levels during EBI, disease severity on admission, and poor outcome remains unaddressed. Plasma NfL (pNfL) was measured by single molecule array in 44 SAH patients on admission and 24 h after ictus, as well as in 44 controls. Disease severity on admission was assessed by validated scoring systems, and day 30 modified Rankin Scale (mRS) score was registered. Admission levels of pNfL correlated with clinical disease severity scores (rho = 0.43, p < 0.01 and rho = 0.48, p < 0.001) as well as day 30 mRS score (rho = 0.53, p < 0.001). Each quartile increase in pNfL was independently associated with poor functional status (mRS > 4) [odds ratio = 1.98, 95% confidence interval (CI): 1.01-3.88, p = 0.05]. Non-survivors had higher pNfL than survivors; on admission [17.6 pg/mL (IQR 11.4) vs. 8.4 pg/mL (IQR: 8.9), p < 0.01] and 24 h after ictus [29.9 pg/mL (IQR 90.4) vs 7.8 pg/mL (IQR 26.9), p = 0.01]. Each quartile increase in pNfL was independently associated with reduced survival rate [log-rank = 0.02, hazard ratio = 2.29 (95% CI): 1.15-4.57), p = 0.02]. PNfL levels are associated with disease severity during the EBI phase of SAH. Higher pNfL levels during EBI are associated with poor functional outcome on day 30 after ictus and increased mortality rate.

Thromboelastometry Shows Early Hypercoagulation in Patients with Spontaneous Subarachnoid Hemorrhage.

BACKGROUND: The ability to achieve hemostasis after spontaneous subarachnoid hemorrhage (SAH) plays a pivotal role in outcome. Changes in coagulation in the early hours after SAH have been only sparsely investigated. OBJECTIVE: To investigate changes in coagulation after SAH and illuminate underlying mechanisms. METHODS: We enrolled 46 patients with spontaneous aneurysmal SAH. Blood samples were collected at admission and 24 hours after symptom onset. Thromboelastometry (ROTEM) was performed using the standard assays EXTEM, INTEM, and FIBTEM. Platelet maximum clot elasticity was calculated based on ROTEM results. Thrombin generation, levels of thrombin-antithrombin complex, fibrinogen, and coagulation factor XIII were measured. All data were compared with a gender-matched healthy control group. RESULTS: At admission (median, 3 hours 39 minutes from symptom onset), maximum clot firmness (EXTEM, P < 0.0001; INTEM, P = 0.08; FIBTEM, P < 0.0001) and platelet maximum clot elasticity (P < 0.0001) were higher in patients with SAH than in healthy controls. Thrombin generation showed higher, although nonsignificant, endogenous thrombin potential in patients with SAH than in healthy controls (P = 0.06), and thrombin-antithrombin complex levels were above the reference interval. Median fibrinogen and coagulation factor XIII levels were both within the reference parameters and remained increased 24 hours after symptom onset, whereas endogenous thrombin potential (P = 0.01) and thrombin-antithrombin complex levels decreased (P < 0.0001). CONCLUSIONS: Patients with SAH were in a hypercoagulable state at admission and remained so 24 hours after SAH. Increased clot firmness could be caused by increased platelet function, because platelet maximum clot elasticity was increased despite normal fibrinogen and coagulation factor XIII levels.

[Screening for intracranial aneurysms].

This review states the reasons for considering screening for intracranial aneurysms in Denmark: if patients have two first-degree relatives with intracranial aneurysms, are 30-70 years old, do not have competing disorders, which could significantly shorten life expectancy, and subsequently in patients with autosomal dominant kidney disease and a family history of subarachnoid haemorrhage. MR angiography should be the imaging study of choice, unless contraindicated. Generally, the ethical consequences ought to be considered before carrying out screening.

Using automated electrode localization to guide stimulation management in DBS.

Deep Brain Stimulation requires extensive postoperative testing of stimulation parameters to achieve optimal outcomes. Testing is typically not guided by neuroanatomical information on electrode contact locations. To address this, we present an automated reconstruction of electrode locations relative to the treatment target, the subthalamic nucleus, comparing different targeting methods: atlas-, manual-, or tractography-based subthalamic nucleus segmentation. We found that most electrode contacts chosen to deliver stimulation were closest or second closest to the atlas-based subthalamic nucleus target. We suggest that information on each electrode contact's location, which can be obtained using atlas-based methods, might guide clinicians during postoperative stimulation testing.

Post-operative deep brain stimulation assessment: Automatic data integration and report generation.

BACKGROUND: The gold standard for post-operative deep brain stimulation (DBS) parameter tuning is a monopolar review of all stimulation contacts, a strategy being challenged by recent developments of more complex electrode leads. OBJECTIVE: Providing a method to guide clinicians on DBS assessment and parameter tuning by automatically integrating patient individual data. METHODS: We present a fully automatic method for visualization of individual deep brain structures in relation to a DBS lead by combining precise electrode recovery from post-operative imaging with individual estimates of deep brain morphology utilizing a 7T-MRI deep brain atlas. RESULTS: The method was evaluated on 20 STN DBS cases. It demonstrated robust automatic creation of 3D-enabled PDF reports visualizing electrode to brain structure relations and proved valuable in detecting miss placed electrodes. DISCUSSION: Automatic DBS assessment is feasible and can conveniently provide clinicians with relevant information on DBS contact positions in relation to important anatomical structures.

Non-aneurysmal subarachnoid hemorrhage: When is a second angiography indicated?

Purpose Repeat imaging in patients with non-aneurysmal subarachnoid hemorrhage (NASAH) remains controversial. We aim to report our experience with NASAH with different hemorrhage patterns, and to investigate the need for further diagnostic workup to determine the underlying cause of hemorrhage. Method We conducted a retrospective analysis of all spontaneous SAH with an initial negative computed tomography (CT) with angiography (CTA) and/or digital subtraction angiography (DSA) from October 2011 through May 2017. According to the bleeding pattern on the admission CT scan, NASAH was divided into two subgroups: (1) perimesencephalic SAH (PMSAH) and (2) non-perimesencephalic SAH (nPMSAH). Radiological data included the admission CT, CTA, DSA, and magnetic resonance imaging (MRI) with angiography (MRA). Results Seventy-four patients met the inclusion criteria. Thirty-nine (52.7%) patients had PMSAH on the initial CT scan, and 35 (47.3%) had nPMSAH. All underwent CTA and/or DSA revealing no vascular abnormalities. Forty-seven (63.5%) patients underwent subsequent diagnostic workup. DSA was performed in all patients at least once. No abnormalities were found on the repeat DSA or other radiological follow-up studies except in one (1.4%) patient with nPMSAH, in whom a follow-up DSA revealed a small saccular anterior choroidal artery aneurysm, considered to be the source of hemorrhage. Conclusion A repeat DSA may not be needed in case of PMSAH, if the initial negative DSA is technically adequate with absence of hematoma and vasospasm. In contrast, a follow-up DSA should be mandatory for confirming or excluding vascular pathology in case of nPMSAH in order to prevent rebleeding.

A Case of Tranexamic Acid as Adjunctive Treatment for Chronic Subdural Hematoma with Multiple Recurrences.

BACKGROUND Chronic subdural hematoma (CSDH) is a common neurosurgical condition that is treated using a cranial burr hole evacuation procedure, but recurrence is common. The use of anticoagulant therapy can increase the risk of developing a recurrent subdural hematoma. We present a challenging case of a patient on long-term anticoagulant therapy following previous aortic and aortic valve surgery who had CSDH with multiple recurrences and was ultimately treated with tranexamic acid as an adjunct to surgery. CASE REPORT A male patient in his mid-sixties presented with a headache and bilateral CSDH. Apart from a mechanical heart valve, he was otherwise healthy. A standard burr hole evacuation was performed, but the left hematoma and symptoms recurred after three months, and he presented with additional symptoms of aphasia and right-hand weakness. He had an additional three procedures followed by recurrences over a period of six weeks. Following his fifth and final surgical procedure, he was given postoperative intravenous tranexamic acid 10 mg/kg four times during the first 24 hours with dalteparin sodium 9,500 international units (IU) twice daily. His symptoms resolved, and after nine months he had no residual hematoma, and no thromboembolic complications occurred. CONCLUSIONS This case has demonstrated that tranexamic acid can be used as an adjunctive treatment to surgery when dealing with recurring CSDH, even in patients who require concomitant anticoagulant therapy. Although clinical trials are underway to evaluate tranexamic acid as a medical treatment for CSDH, this case report may support further studies that include patients with risk factors for thromboembolic disease.

Differentiated effects of deep brain stimulation and medication on somatosensory processing in Parkinson's disease.

OBJECTIVES: Deep brain stimulation (DBS) and dopaminergic medication effectively alleviate the motor symptoms in Parkinson's disease (PD) patients, but their effects on the sensory symptoms of PD are still not well understood. To explore early somatosensory processing in PD, we recorded magnetoencephalography (MEG) from thirteen DBS-treated PD patients and ten healthy controls during median nerve stimulation. METHODS: PD patients were measured during DBS-treated, untreated and dopaminergic-medicated states. We focused on early cortical somatosensory processing as indexed by N20m, induced gamma augmentation (31-45Hz and 55-100Hz) and induced beta suppression (13-30Hz). PD patients' motor symptoms were assessed by UPDRS-III. RESULTS: Using Bayesian statistics, we found positive evidence for differentiated effects of treatments on the induced gamma augmentation (31-45Hz) with highest gamma in the dopaminergic-medicated state and lowest in the DBS-treated and untreated states. In contrast, UPDRS-III scores showed beneficial effects of both DBS and dopaminergic medication on the patients' motor symptoms. Furthermore, treatments did not affect the amplitude of N20m. CONCLUSIONS: Our results suggest differentiated effects of DBS and dopaminergic medication on cortical somatosensory processing in PD patients despite consistent ameliorating effects of both treatments on PD motor symptoms. SIGNIFICANCE: The differentiated effect suggests differences in the effect mechanisms of the two treatments.

Quantitative sensory testing and structural assessment of sensory nerve fibres in amyotrophic lateral sclerosis.

OBJECTIVE: In this prospective study, involvement of sensory nerve fibres in ALS patients was assessed using functional and structural measures in the form of quantitative sensory testing (QST) and skin and nerve biopsies. METHODS: Thirty-two ALS patients and 32 healthy subjects were evaluated with a QST battery comprising thresholds of mechanical detection, mechanical pain, vibration detection, cold detection, warm detection, heat pain, and pinprick sensation. Skin biopsies were evaluated in 31 ALS patients by intraepidermal nerve fibre density (IENFD) and axonal swelling ratios, and growth-associated protein 43 (GAP-43) antibody staining. Sural nerve biopsies were evaluated using teased fibre analysis in eight patients. RESULTS: Mean values for QST parameters and IENFD in ALS patients were within normal range. However, the patients had increased axonal swelling ratios and GAP-43 antibody staining was negative in all patients. CONCLUSIONS: Although QST and IENFD were affected in only a small subset of ALS patients, the axonal swellings observed in all patients indicate that the affection is more frequent, and suggests that IENFD count may not be sufficient. The negative GAP-43 staining suggested an insufficiency of regeneration in small sensory nerve fibres.

Probabilistic versus deterministic tractography for delineation of the cortico-subthalamic hyperdirect pathway in patients with Parkinson disease selected for deep brain stimulation.

OBJECTIVE Diffusion-weighted MRI (DWI) and tractography allows noninvasive mapping of the structural connections of the brain, and may provide important information for neurosurgical planning. The hyperdirect pathway, connecting the subthalamic nucleus (STN) with the motor cortex, is assumed to play a key role in mediating the effects of deep brain stimulation (DBS), which is an effective but poorly understood treatment for Parkinson disease. This study aimed to apply recent methodological advances in DWI acquisition and analysis to the delineation of the hyperdirect pathway in patients with Parkinson disease selected for surgery. METHODS High spatial and angular resolution DWI data were acquired preoperatively from 5 patients with Parkinson disease undergoing DBS. The authors compared the delineated hyperdirect pathways and associated STN target maps generated by 2 different tractography methods: a tensor-based deterministic method, typically available in clinical settings, and an advanced probabilistic method based on constrained spherical deconvolution. In addition, 10 high-resolution data sets with the same scanning parameters were acquired from a healthy control participant to assess the robustness of the tractography results. RESULTS Both tractography approaches identified connections between the ipsilateral motor cortex and the STN. However, the 2 methods provided substantially different target regions in the STN, with the target center of gravity differing by > 1.4 mm on average. The probabilistic method (based on constrained spherical deconvolution) plausibly reconstructed a continuous set of connections from the motor cortex, terminating in the dorsolateral region of the STN. In contrast, the tensor-based method reconstructed a comparatively sparser and more variable subset of connections. Furthermore, across the control scans, the probabilistic method identified considerably more consistent targeting regions within the STN compared with the deterministic tensor-based method, which demonstrated a 1.9-2.4 times higher variation. CONCLUSIONS These data provide a strong impetus for the use of a robust probabilistic tractography framework based on constrained spherical deconvolution, or similar advanced DWI models, in clinical settings. The inherent limitations and demonstrated inaccuracy of the tensor-based method leave it questionable for use in high-precision stereotactic DBS surgery. The authors have also described a straightforward method for importing tractography-derived information into any clinical neuronavigation system, based on the generation of track-density images.

Increasing infection rate in multiple implanted pulse generator changes in movement disorder patients treated with deep brain stimulation.

BACKGROUND: Deep brain stimulation has been performed at the Department of Neurosurgery, Aarhus University Hospital (AUH), for 16 years. The risk of infection related to implantable pulse generator (IPG) replacement constitutes a weakness in the long-term DBS treatment. OBJECT: The aim of this study is to investigate the association between risk of infection and number of IPG replacements. METHODS: All patients who underwent IPG replacement at the AUH from June 1996 until September 2012 were included in the study, and their medical records were systematically reviewed. The data was analyzed using Fisher's exact test on contingency tables. RESULTS: 220 procedures of IPG replacement were completed on 105 patients who suffered from various movement disorders. Up to 5 IPG changes were registered in a single patient. Thirteen patients incurred infection requiring surgical intervention. Testing for risk of infection associated with number of IPG changes, this study found significantly different infection rates (p = 0.0052). In the groups with 3 and 4 IPG changes, infection rates reached over 20%. CONCLUSION: This study found significantly different rates of infection related to the number of IPG changes. Further investigation and resources should be directed towards improving the lifespan of IPGs.

Defining the intercommissural plane and stereotactic coordinates for the Basal Ganglia in the Göttingen minipig brain.

The intercommissural line joining the anterior and posterior commissures defines stereotactic coordinate systems used in functional neurosurgical procedures. Such coordinate systems are generally accepted in humans and nonhuman primate experimental settings and provide high stereotactic precision and reproducibility. The ethical concern surrounding the use of nonhuman primates has motivated and helped popularize the use of the Göttingen minipig as an alternative experimental model for experimental functional neurosurgery. We investigated the position and variability of the intercommissural line in the minipig brain using in vivo MRI. From these data, standard coordinates for the minipig basal ganglia were estimated. We found the variability of the intercommissural line to be small in the Göttingen minipig and the variability of the basal ganglia structures to the mid-commissural point to be minor.

MRI protocol for in vivo visualization of the Göttingen minipig brain improves targeting in experimental functional neurosurgery.

BACKGROUND: The Göttingen minipig is increasingly used as an animal model in experimental neuroscience as a much needed alternative to non-human primates. Accurate spatial targeting in this species in vivo is challenging, and most clinically available magnetic resonance imaging (MRI) protocols do not provide sufficient spatial resolution for this purpose. Thus, the aim of this study was to develop an in vivo pre-operative MRI protocol allowing direct visualization of individual nuclei of major interest in the minipig brain. MATERIALS AND METHODS: Three Göttingen minipigs underwent MRI using an inversion-recovery fast spin-echo sequence that was optimized with regards to the following parameters: inversion time, relaxation time, echo time and spatial and temporal resolution, giving a scan duration acceptable for the tight schedule usually employed in a neurosurgical procedure. The most optimal pulse sequence was applied in 8 Göttingen minipigs and the anatomical structures were identified. RESULTS AND CONCLUSION: High-resolution images with excellent contrast were acquired, presenting negligible geometric distortions. Minor flow artifacts from the large neck vessels generated the most prominent artifact. Determination of coordinates necessary in experimental neurosurgery in the Göttingen minipig was considerably improved with this MRI protocol.

Improved asymmetry of gait in Parkinson's disease with DBS: gait and postural instability in Parkinson's disease treated with bilateral deep brain stimulation in the subthalamic nucleus.

Postural instability is a sign of progression of Parkinson's disease (PD) and often resistant to levodopa treatment. To explore the effect of bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) on postural stability and gait, full body gait analyses were performed without medication, OFF and ON DBS in eight PD patients and 12 healthy age-matched controls. DBS setting was changed at least 3 hours before gait analysis. To describe asymmetry most and least affected sides (MAS and LAS) were rated with the Unified Parkinson's Disease Rating Scale, motor part and quantitative gait analysis with the Vicon 612 gait analysis system. Stride length and gait velocity but not cadence improved ON DBS. The distances between the heel markers and center of mass (COM) were asymmetric and reduced OFF DBS. STN DBS increased the distances significantly and reduced asymmetry. The improvement in heel to COM distance was larger on the MAS compared with the LAS. OFF DBS knee momentum asymmetry was inversed so that LAS was more impaired than MAS. ON DBS asymmetry improved. PD patients OFF DBS place the heel too close to COM. The most affected body side has the most impaired swing and the result is a smaller knee moment on the opposite and least affected body side and an asymmetric gait pattern with disturbed balance OFF STN DBS. The asymmetry OFF DBS improved ON DBS. We suggest that DBS facilitates symmetric gait and thereby improves balance during gait.

Deep brain stimulation electrode anchoring using BioGlue((R)), a protective electrode covering, and a titanium microplate.

The authors present an easily applicable deep brain stimulation (DBS) electrode anchoring technique for use in human and experimental animals. The anchoring technique combines the use of fibrin glue, a two-component surgical adhesive (BioGlue), a protective electrode covering, and a titanium microplate. The BioGlue (CryoLife International, Inc., Kennesaw, GA, USA) hinders unwanted electrode movement during the electrode fixation step and seals the burr hole, while the protective electrode covering protects the electrode under the titanium microplate which keeps the electrode in a permanent position. The described technique further has the advantage of being cosmetically acceptable to the human patient, and furthermore it perfectly adapts to the smaller and irregular-shaped skull in experimental animals. The described technique has clinically been used to implant DBS-electrodes in the subthalamic nucleus for Parkinson disease and is the preferred DBS-electrode anchoring technique for our experimental DBS-studies in the Göttingen minipig.