Hartmut Vatter

Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group

Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches.

Cervical non-invasive vagus nerve stimulation (nVNS) for preventive and acute treatment of episodic and chronic migraine and migraine-associated sleep disturbance: preliminary findings from a prospective observational cohort study

BackgroundThe debilitating nature of migraine and challenges associated with treatment-refractory migraine have a profound impact on patients. With the need for alternatives to pharmacologic agents, vagus nerve stimulation has demonstrated efficacy in treatment-refractory primary headache disorders. We investigated the use of cervical non-invasive vagus nerve stimulation (nVNS) for the acute treatment and prevention of migraine attacks in treatment-refractory episodic and chronic migraine (EM and CM) and evaluated the impact of nVNS on migraine-associated sleep disturbance, disability, and depressive symptoms.MethodsTwenty patients with treatment-refractory migraine were enrolled in this 3-month, open-label, prospective observational study. Patients administered nVNS prophylactically twice daily at prespecified times and acutely as adjunctive therapy for migraine attacks. The following parameters were evaluated: pain intensity (visual analogue scale [VAS]); number of headache days per month and number of migraine attacks per month; number of acutely treated attacks; sleep quality (Pittsburgh Sleep Quality Index [PSQI]); migraine disability assessment (MIDAS); depressive symptoms (Beck Depression Inventory® [BDI]); and adverse events (AEs).ResultsOf the 20 enrolled patients, 10 patients each had been diagnosed with EM and CM. Prophylaxis with nVNS was associated with significant overall reductions in patient-perceived pain intensity; median (interquartile range) VAS scores at baseline versus 3xa0months were 8.0 (7.5, 8.0) versus 4.0 (3.5, 5.0) points (pu2009<u20090.001). Baseline versus 3-month values (meanu2009±u2009standard error of the mean) were 14.7u2009±u20090.9 versus 8.9u2009±u20090.8 (pu2009<u20090.001) for the number of headache days per month and 7.3u2009±u20090.9 versus 4.5u2009±u20090.6 (pu2009<u20090.001) for the number of attacks per month. Significant improvements were also noted in MIDAS (pu2009<u20090.001), BDI (pu2009<u20090.001), and PSQI global (pu2009<u20090.001) scores. No severe or serious AEs occurred.ConclusionIn this study, treatment with nVNS was safe and provided clinically meaningful decreases in the frequency and intensity of migraine attacks in patients with treatment-refractory migraine. Improvements in migraine-associated disability, depression, and sleep quality were also noted.

Poor-Grade Aneurysmal Subarachnoid Hemorrhage: Factors Influencing Functional Outcome—A Single-Center Series

OBJECTIVEnPatients presenting with poor-grade aneurysmal subarachnoid hemorrhage (SAH) have commonly been reported to have a poor prognosis; however, several reports suggest a favorable outcome in a subgroup of patients. We analyzed our database to identify factors determining functional outcome after poor-grade SAH.nnnMETHODSnDuring the period 2004-2014, 248 patients with poor-grade SAH were treated in our institution. Poor-grade SAH was defined as World Federation of Neurological Surgeons grades IV-V on admission. Data including patient characteristics, treatment modality, radiologic features, and functional neurologic outcome were assessed and further analyzed. Outcome was assessed according to the modified Rankin Scale after 6 months and stratified into favorable (modified Rankin Scale score 0-2) versus unfavorable (modified Rankin Scale score 3-6). A multivariate analysis was performed to identify predictors of functional outcome.nnnRESULTSnA favorable outcome was achieved in 24% of patients with poor-grade SAH. Patients with a favorable outcome were significantly younger (P = 0.005), harbored significantly smaller aneurysms (P = 0.004), and had a lower initial World Federation of Neurological Surgeons grade (P < 0.0001). An unfavorable outcome was significantly more frequent in patients with additional space-occupying hematoma compared with patients without additional space-occupying hematoma (P = 0.0009). On multivariate analysis, patient age, World Federation of Neurological Surgeons grade V, signs of cerebral herniation, aneurysm size, and presence of space-occupying hematoma were identified as significant predictors of unfavorable outcome in patients with poor-grade SAH.nnnCONCLUSIONSnA favorable outcome was achieved in 24% of severely ill patients with poor-grade SAH. Therefore, treatment of patients with poor-grade SAH should not be omitted. Careful individualized decision making is necessary for each patient.

Cranioplasty and Ventriculoperitoneal Shunt Placement after Decompressive Craniectomy: Staged Surgery Is Associated with Fewer Postoperative Complications.

OBJECTIVEnDecompressive craniectomy (DC) requires later cranioplasty (CP) in survivors. However, if additional ventriculoperitoneal shunt (VPS) placement due to shunt-dependent hydrocephalus is necessary, the optimal timing of both procedures still remains controversial. We therefore analyzed our computerized database concerning the optimal timing of CP and VPS regarding postoperative complications.nnnMETHODSnFrom 2009-2014, 41 cranioplasty procedures with simultaneous or staged VPS placement were performed at the authors institution. Patients were stratified into two groups according to the time from CP to VPS (simultaneous and staged). Patient characteristics, timing of CP and VPS, as well as procedure-related complications, were assessed and analyzed.nnnRESULTSnOverall CP and VPS were performed simultaneously in 41% and in staged fashion in 59% of the patients. The overall complication rate was 27%. Patients who underwent simultaneous CP and VPS suffered significantly more often from complications compared with patients who underwent staged CP and VPS procedures (47% vs. 12%; P = 0.03). Patients with simultaneous CP and VPS had a significantly higher rate of infectious postoperative complications compared with patients with staged procedures (P = 0.003). On multivariate analysis, simultaneous CP and VPS procedure was the only significant predictor of postoperative complication after CP and VPS (P = 0.03).nnnCONCLUSIONnWe provide detailed data on surgical timing and complications for cranioplasty and ventriculoperitoneal shunt placement after DC. The present data suggest that patients who undergo staged CP and VPS procedures might benefit from a lower complication rate. This might influence future surgical decision making regarding optimal timing of CP and VPS placement.

Occipital nerve block prior to occipital nerve stimulation for refractory chronic migraine and chronic cluster headache: Myth or prediction?:

Background Occipital nerve stimulation (ONS) results in beneficial outcomes, with marked pain relief, in otherwise intractable chronic migraine (CM) and chronic cluster headache (CCH). Some studies have reported that a positive response to occipital nerve block (ONB) administered prior to ONS predicts a positive response to ONS. However, other studies concerned with proper patient selection claimed no predictive value for ONB. The aim of this study was to re-evaluate the usefulness and predictive value of ONB prior to ONS. Methods Literature searches on the predictive value of ONB were performed in MEDLINE and PubMed. Patient data were extracted and a pooled analysis was performed. Results The literature review revealed 133 patients with CM and seven patients with CCH who received preoperative ONB. To date, a randomized controlled study examining the relationship between ONB and ONS has not been conducted in patients with CM. Conclusions Current literature suggests that ONB does not sufficiently predict ONS responsiveness in patients with refractory CM and CCH; this important issue requires further investigation.

Laser interstitial thermotherapy (LiTT) in epilepsy surgery

Besides other innovative stereotactic procedures (radiofrequency thermocoagulation, focused ultrasound, gamma knife) laser interstitial thermotherapy (LiTT) provides minimally invasive destruction of pathological soft tissues which could be especially relevant for epilepsy surgeries involving adult and pediatric patients. Unlike standard resections, no craniotomy is required; just a tiny borehole trepanation is sufficient. Damage to cortical areas when accessing deep lesions can be minimized or completely avoided, and treating epileptogenic foci near eloquent or even vital brain areas becomes possible. Here, we briefly describe the history and rationale of laser neurosurgery as well as the technical key features of the two currently available systems for magnetic resonance-guided LiTT (Visualase®, NeuroBlate®; CE marks pending for both). We also discuss the published clinical experience with LiTT in the field of epilepsy surgery (approximately 200 cases) with regard to complications, LiTT-induced, long-term brain structural alterations, seizure outcome, preliminary neuropsychological findings and first estimates of treatment costs. Overall, the seizure outcome appears to be slightly worse than for resective surgery. Due to insufficient research methods (e.g. non-established measures, lack of a control condition), the expected neuropsychological superiority over resective surgery has not been unambiguously demonstrated thus far. Also, the cost-benefit ratio requires further critical evaluation. Clinical, multi-center and adequately controlled outcome studies of high quality should also accompany the imminent introduction of LiTT into the field of epilepsy surgery and therewith permit critical scientific evaluation and rational, individual, clinical decisions.

Posterior Reversible Encephalopathy Syndrome as an Overlooked Complication of Induced Hypertension for Cerebral Vasospasm Systematic Review and Illustrative Case

Background and Purpose— Delayed cerebral ischemia associated with cerebral vasospasm is a common cause of secondary neurological decline after aneurysmal subarachnoid hemorrhage (SAH). Triple-H therapy, induced hypertension, hypervolemia, and hemodilution, is often used to treat cerebral vasospasm. However, hypertensive treatment may carry significant medical morbidity, including cardiopulmonary, renal, and intracranial complications. Posterior reversible encephalopathy syndrome (PRES) is a reversible intracranial complication that has rarely been reported in the setting of induced hypertension. Methods— We present an illustrative case of PRES in a patient with induced hypertension for SAH-related cerebral vasospasm and performed a systematic review. Furthermore, the electronic database MEDLINE was searched for additional data in published studies of PRES after induced hypertension. Results— Overall, 7 case reports presenting 10 patients who developed PRES secondary to induced hypertension were found. Eighty-two percent of the patients were women. In all cases, the clinical symptoms were attributed to cerebral vasospasm before the diagnosis of PRES. The time from onset of induced hypertension to the development of PRES was 7.8±3.8 days. After the diagnosis of PRES and careful taper down of the blood pressure, the neurological symptoms resolved almost completely within a few days in all patients. Conclusions— PRES in the setting of SAH is an overlooked complication of hypertensive therapy for the treatment of vasospasm. However, the diagnosis of this phenomenon is crucial given the necessity to reverse hypertensive therapy, which is contrary to the usual management of patients with vasospasm.

The earlier the better? Bevacizumab in the treatment of recurrent MGMT-non-methylated glioblastoma

PurposeThe adequate second-line therapy of patients with glioblastoma (GBM) is a matter of ongoing debate. This particularly applies to patients with a non-methylated MGMT promotor who are known to have a poor response to alkylating chemotherapy. In some countries, antiangiogenic therapy with BEV is applied as second-line therapy, and in others nitrosourea therapy is second-line choice. It is an open question whether the delay of BEV to third-line therapy has a negative impact on survival.MethodsA total of 61 adult patients (median age 56.9xa0years) with MGMT-non-methylated relapsed GBM treated with BEV (nxa0=xa045) or nitrosourea (nxa0=xa016) as second-line therapy were analyzed retrospectively and compared regarding progression-free survival (PFS) and overall survival (OS).ResultsPatients treated with second-line BEV had longer median PFS (107xa0days, 95xa0% CI 80.7–133.2xa0days) than patients with second-line nitrosourea (52xa0days, 95xa0% CI 36.3–67.7xa0days, Pxa0=xa00.011, logrank test). However, there was no significant difference in overall survival (BEV median 170xa0days, 95xa0% CI 87.2–252.8xa0days; nitrosourea median 256xa0days, 95xa0% CI 159.9–352.0xa0days, Pxa0=xa00.468). PFS was similar after BEV third-line therapy (median 117xa0days, 95xa0% CI 23.6–210.4xa0days) as compared to second-line BEV therapy (median 107xa0days, 95xa0% CI 80.7–133.3xa0days, Pxa0=xa00.584).ConclusionOur findings suggest that early treatment with BEV in patients with MGMT-non-methylated relapsed GBM is associated with a better PFS, but not with superior OS, possibly implicating that the early, i.e., second-line, use of BEV is not mandatory and BEV treatment may safely be delayed to third-line therapy in this subgroup of patients.

Surgical Treatment of Spinal Dural Arteriovenous Fistula: Management and Long-Term Outcome in a Single-Center Series.

OBJECTIVEnTo perform a retrospective chart review of surgically treated patients with spinal dural arteriovenous fistula (SDAVF), a rare disease but the most common vascular malformation of the spine, focusing on clinical characteristics and functional outcome during long-term follow-up.nnnMETHODSnBetween June 1990 and April 2012, 29 patients with SDAVFs were treated surgically in a single institution. Patient characteristics, time from onset of symptoms to treatment, radiologic features, treatment-related complications, and functional outcome were analyzed. Outcome was assessed according to the Aminoff-Logue scale during follow-up. Results of magnetic resonance imaging scans performed during long-term follow-up were correlated with functional outcome.nnnRESULTSnThere were 3 female (10%) and 26 male (90%) patients with SDAVFs treated surgically. Mean age was 61 years ± 11. Location of the fistula was at the thoracic level in 20 patients (69%), at the lumbar level in 8 patients (28%), and at the sacral level in 1 patient (3%). Mean postoperative Aminoff-Logue scale scores regarding gait and micturition improved after treatment compared with preoperatively (P = 0.02; P = 0.03). After surgical treatment, 22 patients (76%) achieved improvement in neurologic symptoms. In 6 patients (21%), neurologic status was the same as preoperatively. In 1 patient (3%), neurologic status worsened. Medullary signal alteration of diagnostic magnetic resonance imaging scans did not correlate with functional outcome (P = 0.2). Mean follow-up time was 63 months ± 55. All SDAVFs were treated in a single session without recurrence during the long-term follow-up period.nnnCONCLUSIONSnSurgical treatment of SDAVFs is safe and effective and leads to an improvement of neurologic symptoms in most patients. Surgical treatment of SDAVFs also provides long-term stability.

Low-dose radiosurgery or hypofractionated stereotactic radiotherapy as treatment option in refractory epilepsy due to epileptogenic lesions in eloquent areas – Preliminary report of feasibility and safety

PURPOSEnThe eradication of epileptogenic lesions (e.g. focal cortical dysplasia) can be used for treatment of drug-resistant focal epilepsy, but in highly eloquent cortex areas it can also lead to a permanent neurological deficit. In such cases the neuromodulation effect of low-dose high-precision irradiation of circumscribed lesions may represent an alternative therapy.nnnMETHODnA total of 10 patients with eloquent localized lesions causing pharmacoresistant focal epilepsy were prospectively identified. After informed consent, six patients agreed and were treated with risk adapted low-dose radiosurgery (SRS) or hypofractionated stereotactic radiotherapy (hfSRT). Comprehensive data concerning treatment modalities and outcome after short-term follow up (mean=16.3 months) were prospectively collected and evaluated.nnnRESULTSnFrom the six patients, two patients were treated with hfSRT (marginal dose 36 Gy) and four with SRS (marginal dose 13 Gy). Clinical target volume (CTV) ranged from 0.70 ccm to 4.32 ccm. The short-term follow-up ranged from 6 to 27 months. There were no side effects or neurological deficits after treatment. At last available follow-up two patients were seizure-free, one of them being off antiepileptic drugs. The seizure frequency improved in one and remained unchanged in three patients.nnnCONCLUSIONnTreatment of eloquent localized epileptogenic lesions by SRS and hfSRT showed no adverse events and an acceptable seizure outcome in this small prospective patient series. The relatively short-term follow-up comprises one of the studys drawbacks and therefore a longer follow-up should be awaited in order to evaluate the neuromodulation effect of the treatment. These preliminary results may however justify the initiation of a larger prospective trial investigating whether focused low-dose stereotactic irradiation could be an option for lesions in eloquent brain areas.