Mario Kofler

Spreading depolarizations in patients with spontaneous intracerebral hemorrhage: Association with perihematomal edema progression.

Pathophysiologic mechanisms of secondary brain injury after intracerebral hemorrhage and in particular mechanisms of perihematomal-edema progression remain incompletely understood. Recently, the role of spreading depolarizations in secondary brain injury was established in ischemic stroke, subarachnoid hemorrhage and traumatic brain injury patients. Its role in intracerebral hemorrhage patients and in particular the association with perihematomal-edema is not known. A total of 27 comatose intracerebral hemorrhage patients in whom hematoma evacuation and subdural electrocorticography was performed were studied prospectively. Hematoma evacuation and subdural strip electrode placement was performed within the first 24 h in 18 patients (67%). Electrocorticography recordings started 3 h after surgery (IQR, 3–5 h) and lasted 157 h (median) per patient and 4876 h in all 27 patients. In 18 patients (67%), a total of 650 spreading depolarizations were observed. Spreading depolarizations were more common in the initial days with a peak incidence on day 2. Median electrocorticography depression time was longer than previously reported (14.7 min, IQR, 9–22 min). Postoperative perihematomal-edema progression (85% of patients) was significantly associated with occurrence of isolated and clustered spreading depolarizations. Monitoring of spreading depolarizations may help to better understand pathophysiologic mechanisms of secondary insults after intracerebral hemorrhage. Whether they may serve as target in the treatment of intracerebral hemorrhage deserves further research.

Neuroinflammation is Associated with Brain Extracellular TAU-Protein Release after Spontaneous Subarachnoid Hemorrhage

INTRODUCTION Animal data suggest an association between neuroinflammation and secondary brain injury including axonal injury after aneurysmal subarachnoid hemorrhage (aSAH). We sought to study the association between brain extracellular interleukin (IL)-6 and TAU-protein levels as a surrogate marker for neuroinflammation and axonal injury in patients with poor grade aSAH. METHODS Prospectively collected data from 26 consecutive poor-grade aSAH patients with multimodal neuromonitoring including cerebral microdialysis (CMD) were retrospectively analyzed. IL-6 and TAU-protein levels were analyzed using ELISA from a single CMD-sample every 24 hours and correlated with brain metabolic and hemodynamic parameters. Patients were dichotomized to highgrade (N=10) or low-grade (N=16) neuroinflammation according to their median CMD-IL-6 levels. Data were analyzed using generalized estimating equations to account for multiple within-subject measurements. RESULTS Perilesional probe location (P=0.02) and aSAH related intracerebral hemorrhage (aICH) volume (P=0.003) at admission were associated with high-grade neuroinflammation. Brain extracellular TAU-protein levels (P=0.001), metabolic distress and delayed cerebral infarction (DCI; P=0.001) were linked to high-grade neuroinflammation. Relative or absolute phosphor-TAU levels were not correlated with CMD-IL-6 levels. High-grade neuroinflammation was a predictor for worse outcome three months after ictus, independently from probe location, initial Hunt&Hess grade and age (P=0.01). CONCLUSION Neuroinflammation after aSAH is associated with intraparenchymal bleeding, deranged cerebral metabolism and TAU-protein release. The impact of potential anti-inflammatory treatment strategies on secondary brain injury after aSAH has to be investigated in future studies.

Enteral nutrition increases interstitial brain glucose levels in poor-grade subarachnoid hemorrhage patients:

Low brain tissue glucose levels after acute brain injury are associated with poor outcome. Whether enteral nutrition (EN) reliably increases cerebral glucose levels remains unclear. In this retrospective analysis of prospectively collected observational data, we investigate the effect of EN on brain metabolism in 17 poor-grade subarachnoid hemorrhage (SAH) patients undergoing cerebral microdialysis (CMD) monitoring. CMD-values were obtained hourly. A nutritional intervention was defined as the clinical routine administration of EN without supplemental parenteral nutrition. Sixty-three interventions were analyzed. The mean amount of EN per intervention was 472.4 ± 10.7 kcal. CMD-glucose levels significantly increased from 1.59 ± 0.13 mmol/l at baseline to a maximum of 2.03 ± 0.2 mmol/l after 5 h (p < 0.001), independently of insulin-treatment, baseline serum glucose, baseline brain metabolic distress (CMD-lactate-to-pyruvate-ratio (LPR) > 40) and the microdialysis probe location. The increase in CMD-glucose was directly dependent on the magnitude of increase of serum glucose levels (p = 0.007). No change in CMD-lactate, CMD-pyruvate, CMD-LPR, or CMD-glutamate (p > 0.4) was observed. Routine EN also increased CMD-glucose even if baseline concentrations were critically low ( < 0.7 mmol/l, neuroglucopenia; p < 0.001). These results may have treatment implications regarding glucose management of poor-grade aneurysmal SAH patients.

Brain temperature but not core temperature increases during spreading depolarizations in patients with spontaneous intracerebral hemorrhage

Spreading depolarizations (SDs) are highly active metabolic events, commonly occur in patients with intracerebral hemorrhage (ICH) and may be triggered by fever. We investigated the dynamics of brain-temperature (Tbrain) and core-temperature (Tcore) relative to the occurrence of SDs. Twenty consecutive comatose ICH patients with multimodal electrocorticograpy (ECoG) and Tbrain monitoring of the perihematomal area were prospectively enrolled. Clusters of SDs were defined as ≥2 SDs/h. Generalized estimating equations were used for statistical calculations. Data are presented as median and interquartile range. During 3097 h (173 h [81–223]/patient) of ECoG monitoring, 342 SDs were analyzed of which 51 (15%) occurred in clusters. Baseline Tcore and Tbrain was 37.3℃ (36.9–37.8) and 37.4℃ (36.7–37.9), respectively. Tbrain but not Tcore significantly increased 25 min preceding the onset of SDs by 0.2℃ (0.1–0.2; p < 0.001) and returned to baseline 35 min following SDs. During clusters, Tbrain increased to a higher level (+0.4℃ [0.1–0.4]; p = 0.006) when compared to single SDs. A higher probability (OR = 36.9; CI = 36.8–37.1; p < 0.001) of developing SDs was observed during episodes of Tbrain ≥ 38.0℃ (23% probability), than during Tbrain ≤ 36.6℃ (9% probability). Spreading depolarizations – and in particular clusters of SDs – may increase brain temperature following ICH.

Clinical Use of Cerebral Microdialysis in Patients with Aneurysmal Subarachnoid Hemorrhage—State of the Art

Objective To review the published literature on the clinical application of cerebral microdialysis (CMD) in aneurysmal subarachnoid hemorrhage (SAH) patients and to summarize the evidence relating cerebral metabolism to pathophysiology, secondary brain injury, and outcome. Methods Study selection: Two reviewers identified all manuscripts reporting on the clinical use of CMD in aneurysmal SAH patients from MEDLINE. All identified studies were grouped according to their focus on brain metabolic changes during the early and subacute phase after SAH, their association with mechanisms of secondary brain injury and outcome. Results The review demonstrated: (1) limited literature is available in the very early phase before the aneurysm is secured. (2) Brain metabolic changes related to early and delayed secondary injury mechanisms may be used in addition to other neuromonitoring parameters in the critical care management of SAH patients. (3) CMD markers of ischemia may detect delayed cerebral ischemia early (up to 16 h before onset), underlining the importance of trend analysis. (4) Various CMD-derived parameters may be associated with patient outcome at 3–12 months, including CMD-lactate-to-pyruvate-ratio, CMD-glucose, and CMD-glutamate. Conclusion The clinical use of CMD is an emerging area in the literature of aneurysmal SAH patients. Larger prospective multi-center studies on interventions based on CMD findings are needed.

Brain Extracellular Interleukin-6 Levels Decrease Following Antipyretic Therapy with Diclofenac in Patients with Spontaneous Subarachnoid Hemorrhage

In patients with aneurysmal subarachnoid hemorrhage (aSAH), increased brain extracellular interleukin (IL)-6 levels measured by cerebral microdialysis (CMD) were associated with disease severity, early brain injury, delayed cerebral infarction, and axonal injury. In this study, we analyzed brain extracellular IL-6 levels of aSAH patients following parenteral diclofenac. Twenty-four mechanically ventilated poor-grade aSAH patients were included. Changes in cerebral metabolism, brain/body temperature, and CMD-IL-6 levels following intravenous diclofenac infusion (DCF; 75 mg diluted in 100 cc normal saline) were retrospectively analyzed from prospectively collected bedside data (at 1 hour before DCF = baseline; and at 2, 4, and 8 hours after DCF). Statistical analysis was performed using generalized estimating equations. Seventy-two events in 24 aSAH patients were analyzed. Median age was 60 years (interquartile range [IQR]: 52-67), admission Hunt & Hess grade was 4 (IQR: 3-5), and modified Fisher grade (mFisher) was 4 (IQR: 3-4). Higher CMD-IL-6 levels at baseline were linked to fever, higher mFisher, delayed cerebral infarction, and metabolic distress (p < 0.05). CMD-IL-6 levels at baseline were 281.4 pg/mL (IQR: 47-1866) and significantly (p < 0.001; Wald-X2 = 106) decreased at 2 hours to 86.3 pg/mL (IQR: 7-1946), at 4 hours to 40.9 pg/mL (IQR: 4-1237), and at 8 hours to 53.5 pg/mL (IQR: 5-1085), independent of probe location or day after bleeding. Parenteral diclofenac may attenuate brain extracellular proinflammatory response in poor-grade aSAH patients.

Early thrombosis prophylaxis with enoxaparin is not associated with hematoma expansion in patients with spontaneous intracerebral hemorrhage

Early pharmacological deep vein thrombosis (DVT) prophylaxis is recommended by guidelines, but rarely started within 48 h. We aimed to analyze the effect of early (within 48 h) versus late (>48 h) DVT prophylaxis on hematoma expansion (HE) and outcome in patients with spontaneous intracerebral hemorrhage (ICH).

Erratum to: Acyclovir resistance in herpes simplex virus type I encephalitis: a case report

We apologize for the mistake which slipped through all careful reading and re-reading: it must, correctly, read throughout the entire paper ... foscarnet i.v. 60 mg per kg bodyweight (b.w.), t.i.d. It is correct that 40 mg/kg b.w. is the recommended daily dose (Chilukuri and Rosen 2011), but in view of the dramatic clinical and neuro-imaging course we opted for an increased dose carefully monitoring for side effects.

Response to the letter to the editor by Andreas Sauerbrei on “Acyclovir resistance in herpes simplex type I encephalitis, a case report”

Sir, We gratefully acknowledge the thoughtful comments given by Andreas Sauerbrei to our publication on a case with Acyclovir resistant HSV I encephalitis (Bergmann et al. 2017). We fully agree that acyclovir has already been shown to be highly efficacious in HSV I encephalitis as shown in the Swedish prospective randomized trial by Sköldenberg et al. (1984) and that clinical resistance to acyclovir still is highly uncommon in immunocompetent patients. We rather extensively discussed this aspect in the introduction of our case report; we also agree that it is difficult to prove such an acyclovir resistance. We based the clinical assumption of acyclovir resistance upon the fact that the patient had been treated by intensified acyclovir (750 mg qid, i.e., 3000 mg per day) for a period of 9 days without clinical, laboratory (CSF) and neuro-radiological improvement, whereas after the initiation of intravenous foscarnet—in the rather high dosage of 60 mg per kg bodyweight (b.w.), t.i.d.—both neurologic, laboratory (CSF), and neuro-radiologic findings improved substantially. It is correct that 40 mg/kg b.w. is the recommended daily dose (Chilukuri and Rosen 2003), but in view of the dramatic clinical and neuro-imaging course, we opted for an increased dose carefully monitoring for side-effects. Besides this, the assumption of acyclovir resistance was further enhanced by the detection of a mutation of thymidin kinase gene at position A156V which is involved in the majority of cases of acyclovir resistance. The fact that the following reference to this (Andrei and Snoeck 2013. Herpes simplex virus drug-resistance: new muta t ions and ins ights . Curr Opin Infec t Dis . 2013;26:551–560) has been given in our paper might have escaped the writer of the letter. The clinicians’ foremost aim must be best possible diagnostic, therapeutic, and overall management of every patient with a potentially lethal disease. Our patient‘s rapidly progressing course of HSV I encephalitis with clinical, neuro-radiological, and laboratory deterioration over almost 10 days prompted us to consider acyclovir resistance, which was confirmed by the genotypic sequencing done in the Institute of Virology at the Medical University Vienna, as acknowledged at the end of our manuscript. In view of the many uncertainties in this field of viral resistance testing and in view of the clear reversal of the clinical, neuro-radiological, and laboratory course of disease, we very cautiously formulated our concluding sentence: B...., we do not yet know whether increasing the dose of acyclovir during the genotypic sequencing or the initiation of foscarnet led to improvement of our patient’s medical condition.^

Longitudinal profile of iron accumulation in good‐grade subarachnoid hemorrhage

MRI parameters of iron concentration (R2*, transverse relaxation rate), microstructural integrity (mean diffusivity and fractional anisotropy), as well as gray and white matter volumes were analyzed in patients with subarachnoid hemorrhage (SAH) and uncomplicated clinical course to detect the evolution of brain tissue changes 3 weeks and 12 months after ictus.