Randomized, placebo-controlled, double-blind, pilot trial to investigate safety and efficacy of Cerebrolysin in patients with aneurysmal subarachnoid hemorrhage.

ASBTRACT: BACKGROUND: There are limited neuroprotective treatment options for patients with aneurysmal subarachnoid hemorrhage (SAH). Cerebrolysin, a brain-specific proposed pleiotropic neuroprotective agent, has been suggested to improve global functional outcomes in ischemic stroke. We investigated the efficacy, safety and feasibility of administering Cerebrolysin for SAH patients. METHODS: This was a prospective, randomized, double-blind, placebo-controlled, single-center, parallel-group pilot study. Fifty patients received either daily Cerebrolysin (30 ml/day) or a placebo (saline) for 14 days (25 patients per study group). The primary endpoint was a favorable Extended Glasgow Outcome Scale (GOSE) of 5 to 8 (moderate disability to good recovery) at six-months. Secondary endpoints included the modified Ranking Scale (mRS), the Montreal Cognitive Assessment (MOCA) score, occurrence of adverse effects and the occurrence of delayed cerebral ischemia (DCI). RESULTS: No severe adverse effects or mortality attributable to Cerebrolysin were observed. No significant difference was detected in the proportion of patients with favorable six-month GOSE in either study group (odds ratio (OR): 1.49; 95% confidence interval (CI): 0.43-5.17). Secondary functional outcome measures for favorable six-month recovery i.e. a mRS of 0 to 3 (OR: 3.45; 95% CI 0.79-15.01) were comparable for both groups. Similarly, there was no difference in MOCA neurocognitive performance (p-value: 0.75) and in the incidence of DCI (OR: 0.85 95% CI: 0.28-2.59). CONCLUSIONS: Use of Cerebrolysin in addition to standard-of-care management of aneurysmal SAH is safe, well tolerated and feasible. However, the neutral results of this trial suggest that it does not improve the six-month global functional performance of patients. CLINICAL TRIAL REGISTRATION: Name of Registry: ClinicalTrials.gov Trial Registration Number: NCT01787123 . Date of Registration: 8th February 2013.

Model development and comparison of low hemorrhage-risk endoluminal patch thrombolytic treatment for ischemic stroke.

Clot dissolution drugs delivered into the systemic circulation can dissolve intracranial blood clots in 90 min with 20-50% hemorrhage rate. Immobilizing <5% of the intravenous dosage on an endoluminal patch can reduce the dissolution time to <20 min with negligible hemorrhage risk. The thrombus dissolution behavior in endoluminal patch thrombolytic treatment is modeled and compared with experimental results from a companion study. Analyses showed that the thrombus dissolution time decreases with increasing dosage, but the dissolution time reaches a dosage-independent minimum when uPA dosage on the patch is >800 IU. Model analyses showed that dissolution time in the plateau regime is controlled by diffusion. Further results showed that dissolution time could be reduced in this regime by reducing thrombus thickness. This suggests that a stented endoluminal thrombolytic >800 IU patch that compresses the thrombus to thin the clot thickness can help reduce dissolution time. This ultra-low transition dosage (i.e., 800 IU), compared to 0.6-2.4 million IU in conventional thrombolysis suggests that hemorrhage risk in endoluminal patch thrombolytic treatment is low. The low hemorrhagic-risk endoluminal patch can be considered for use in patients who are ineligible for conventional thrombolytic treatment because of high hemorrhagic treatment risk.

Characterization of thrombus stiffening in radio frequency (rf) Mechanical thrombectomy.

Intra-arterial mechanical thrombectomy (IAMT) for ischemic stroke has high recanalization rate, long treatment time window and low risk of symptomatic intracerebral haemorrhage (sICH), but thrombus fragments produced during treatment can lead to distal embolization. Fragmentation can be reduced if the thrombus is strengthened by increasing the thrombus's crosslink density. Radio frequency (rf) electric current commonly used in surgery to cut and coagulate tissue can induce crosslinking in thrombus. The increase in thrombus stiffness as a result of the increase in crosslinking from rf treatment is characterized in this study. Test results showed that the stiffness of thrombus is increased by more than 8 times after rf treatment. The dramatic increase in stiffness suggests that thrombus fragmentation and distal embolization can be reduced by applying rf during thrombectomy treatment.

In vitro examination of the pressure effect on clot dissolution with thrombolytic patch.

Bio-kinetic thrombus dissolution model has been developed to describe the thrombus dissolution behavior during endoluminal thrombolytic patch treatment to recanalize blocked vessel in ischemic strokes. The initial model ignored the effect of pulsatile pressure in the lumen. However, pulsatile pressure in the lumen may affect molecule diffusion and bio-chemical reaction rate and accelerate clot dissolution. The effect of pressure on the dissolution rate was examined in this study. The dissolution behaviors of 100-400 µm thick blood clot specimens subject to diastolic, systolic, and pulsatile pressure were characterized using Raman spectroscopy. The results showed that dissolution time was reduced by less than 2 mins and is negligible in comparison with total treatment time. The effect of pressure may be ignored and the developed bio-kinetic model may be used in surgical applications of endoluminal thrombolytic patch to estimate treatment time in ischemic stroke.

In-vitro testing of RF-enabled low force mechanical thrombectomy for ischemic stroke.

Mechanical thrombectomy for ischemic stroke has high recanalization rate, long treatment time window and low hemorrhage risk. However, the clot engagement approach of caging the clot against the vessel wall can cause vessel stenosis and stroke recurrence. A device with reduced radial stenting force that reduces vessel wall friction would minimize stenosis and damage. The use of localized Radio Frequency (RF) to enable clot engagement and retrieval with minimal stenting force is explored in this study. New mechanical thrombectomy devices enabled with RF (Patent No.: US 62/172,043) were built and tested on human blood clots in vessels ex vivo. Test results showed that the RF-mechanical thrombectomy successfully and reproducibly captured and retrieved the clots without relying on stent caging of the clot against the vessel wall. Further work will be conducted on animals to compare vessel wall damage between conventional and RF-mechanical thrombectomy.

Feasibility examination of isolated zonal thrombolysis using Raman spectroscopy.

Intravenous thrombolysis for the treatment of ischemic stroke requires long treatment time and high drug dosage which increases the risk of hemorrhage. Localized zonal dosage of urokinase between 100 - 500 International Units (IU), i.e., less than 5% of typical systemic dosage (60,000 - 120,000 IU) at the thrombus can shorten the treatment time to less than 30 minutes while reducing the risk of hemorrhage. The effect of zonal-delivered urokinase on the molecular changes in a 100 µm thick by 20 mm diameter blood clot was quantified using Raman spectroscopy. In situ Raman spectra showed that the fibrin concentration in the clot decreased with time. The results verified that a zonal-delivered urokinase can dissolve the clot and reduce the treatment time. Further trials on animals will be conducted to examine the potential of zonal-delivery to accelerate clot dissolution for ischemic stroke while minimizing the risk of hemorrhage.

Characterization of pressure reduction in coil-filled aneurysm under flow of human blood with and without anti-coagulant.

Filling aneurysms with embolization coils is a widely used part of the treatment to stop intracranial aneurysm from rupturing. However, the effect of coiling on aneurysmal pressure has not been established. In this study, the effect of intra-aneurysmal coiling on pressure reduction was characterized. Coil deployment in the aneurysm will disturb flow and may induce aneurysmal coagulation. These effects were experimentally examined in this study using silicone rubber saccular aneurysm models. Changes in aneurysmal blood pressure under pulsatile flow were characterized. With coils in the aneurysm, results showed that flow reduction of anti-coagulated blood in the aneurysm did not reduce aneurysmal pressure. Significant pressure reduction was observed only when the blood's coagulation ability is restored to normal. These results suggest that blood coagulation is pivotal to pressure reduction and concomitant with rupture risk reduction in treatments of aneurysm with coils.

Angioplasty and stenting for intracranial atherosclerotic stenosis: position statement of the Hong Kong Society of Interventional and Therapeutic Neuroradiology.

As a means of preventing secondary ischaemic stroke, angioplasty and stenting are considered potentially beneficial for patients with severe intracranial atherosclerotic stenosis. However, the role of stenting has been challenged since the publication of the first randomised controlled trial on Stenting versus Aggressive Medical Management for Preventing Recurrent stroke in Intracranial arterial Stenosis (SAMMPRIS). This indicated that aggressive medical management was superior to stenting using Wingspan to prevent recurrent stroke, because stenting has a high peri-procedural stroke and death rate. In this paper, we review the management of intracranial atherosclerosis, revisit the skepticism on stenting, and state our position on the topic in the form of recommendations. These are based on the prevalence of the disease in Hong Kong, the high risk of recurrent stroke despite medical therapy in the presence of haemodynamic intracranial stenosis without sufficient collaterals, an analysis of the weak points of SAMMPRIS, and results of clinical studies in Hong Kong.

Pipeline embolisation device for wide-necked internal carotid artery aneurysms in a hospital in Hong Kong: preliminary experience.

OBJECTIVE. To review our hospital's experience with the pipeline embolisation device to reconstruct wide-necked intracranial aneurysms. DESIGN. Descriptive case series. SETTING. A regional neurosurgical centre in Hong Kong. PATIENTS. Patients presented with wide-necked intracranial internal carotid artery aneurysms who underwent pipeline embolisation device reconstruction between October 2008 and June 2009. RESULTS. There were 13 wide-necked internal carotid artery aneurysms (in nine patients) treated by pipeline embolisation device reconstruction. Eleven aneurysms were de-novo; two were recurrent. The complete occlusion rate was 66% (8/13) at the first angiographic follow-up and 69% (9/13) at the second follow-up. One patient developed in-stent stenosis and in another there was distal migration of the stent. There was no added neurological deficit in any patient. CONCLUSION. In our series, the clinical results from using the pipeline embolisation device for the treatment of non-ruptured internal carotid artery aneurysms appeared encouraging. However, larger studies with longer follow-up duration are warranted to assess the complications and durability of the device for reconstructing internal carotid artery aneurysms.

Extrusion of the peritoneal catheter of a VP shunt system through a gastrostomy wound.

BACKGROUND: A variety of complications can occur following ventriculoperitoneal shunt. We report a case of extrusion of the catheter tip through the old scar of the percutaneous endoscopic gastrostomy (PEG) wound. CASE DESCRIPTION: A 70-year-old male suffered from an intracerebral hemorrhage and then developed hydrocephalus. He required a ventriculoperitoneal shunt. This patient required a PEG for gastroenteric feeding. The PEG was removed 4 years after the insertion because of infection. The tip of the distal shunt tube extruded through the scar of the PEG wound 2 years later. CONCLUSION: The catheter end of VP shunt can extrude through the weak point of an old PEG scar. This kind of complication should be brought to mind while performing abdominal surgery in patients with VP shunts.