Advances in Mechanical Thrombectomy for Acute Ischemic Stroke Due to Large Vessel Occlusion.

Acute ischemic stroke (AIS) is a significant cause of global morbidity and mortality, with functional implications for quality of life and long-term disability. The limitations of intravenous thrombolytic therapy for the treatment of AIS, especially for emergent large vessel occlusion (ELVO), have paved the way for alternative therapies and the rapidly evolving landscape of endovascular therapy (EVT). Here, we summarize the major landmark trials that have advanced the field largely due to ongoing biomedical engineering device development that have translated into significantly improved clinical outcomes. Our review describes the clinical success of EVT, and current and future trends.

Does Increasing Packing Density Using Larger Caliber Coils Improve Angiographic Results of Embolization of Intracranial Aneurysms at 1 Year: A Randomized Trial.

BACKGROUND AND PURPOSE: The impact of increased aneurysm packing density on angiographic outcomes has not been studied in a randomized trial. We sought to determine the potential for larger caliber coils to achieve higher packing densities and to improve the angiographic results of embolization of intracranial aneurysms at 1 year. MATERIALS AND METHODS: Does Embolization with Larger Coils Lead to Better Treatment of Aneurysms (DELTA) was an investigator-initiated multicenter prospective, parallel, randomized, controlled clinical trial. Patients had 4- to 12-mm unruptured aneurysms. Treatment allocation to either 15- (experimental) or 10-caliber coils (control group) was randomized 1:1 using a Web-based platform. The primary efficacy outcome was a major recurrence or a residual aneurysm at follow-up angiography at 12 ± 2 months adjudicated by an independent core lab blinded to the treatment allocation. Secondary outcomes included indices of treatment success and standard safety outcomes. Recruitment of 564 patients was judged necessary to show a decrease in poor outcomes from 33% to 20% with 15-caliber coils. RESULTS: Funding was interrupted and the trial was stopped after 210 patients were recruited between November 2013 and June 2017. On an intent-to-treat analysis, the primary outcome was reached in 37 patients allocated to 15-caliber coils and 36 patients allocated to 10-caliber coils (OR = 0.931; 95% CI, 0.528-1.644; P = .885). Safety and other clinical outcomes were similar. The 15-caliber coil group had a higher mean packing density (37.0% versus 26.9%, P = .0001). Packing density had no effect on the primary outcome when adjusted for initial angiographic results (OR = 1.001; 95% CI, 0.981-1.022; P = .879). CONCLUSIONS: Coiling of aneurysms randomized to 15-caliber coils achieved higher packing densities compared with 10-caliber coils, but this had no impact on the angiographic outcomes at 1 year, which were primarily driven by aneurysm size and initial angiographic results.

Treatment of acute ischemic stroke: from fibrinolysis to neurointervention.

Thrombolytic therapy with intravenous recombinant tissue plasminogen activator is well established as a beneficial treatment for patients presenting with acute ischemic stroke (AIS). The odds of a favorable clinical outcome (living independently) increase as the time between stroke onset and treatment with IV thrombolysis decreases. However, many patients present with a large clot burden that seldom responds to systemic fibrinolysis. Alternative options include new and emerging endovascular therapies that have recently proven effectiveness at restoring cerebral blood flow to the ischemic brain parenchyma. This review article will briefly outline some of the key evidence for intravenous thrombolysis as well as endovascular therapy for AIS.

Ciliary neurotrophic factor protects retinal ganglion cells from axotomy-induced apoptosis via modulation of retinal glia in vivo.

Adenoviral-mediated transfer of ciliary neurotrophic factor (CNTF) to the retina rescued retinal ganglion cells (RGCs) from axotomy-induced apoptosis, presumably via activation of the high affinity CNTF receptor alpha (CNTFRalpha) expressed on RGCs. CNTF can also activate astrocytes, via its low affinity leukemia inhibitory receptor beta expressed on mature astrocytes, suggesting that CNTF may also protect injured neurons indirectly by modulating glia. Adenoviral-mediated overexpression of CNTF in normal and axotomized rat retinas was examined to determine if it could increase the expression of several glial markers previously demonstrated to have a neuroprotective function in the injured brain and retina. Using Western blotting, the expression of glial fibrillary acid protein (GFAP), glutamate/aspartate transporter-1 (GLAST-1), glutamine synthetase (GS), and connexin 43 (Cx43) was examined 7 days after intravitreal injections of Ad.CNTF or control Ad.LacZ. Compared to controls, intravitreal injection of Ad.CNTF led to significant changes in the expression of CNTFRalpha, pSTAT(3), GFAP, GLAST, GS, and Cx43 in normal and axotomized retinas. Taken together, these results suggest that the neuroprotective effects of CNTF may result from a shift of retinal glia cells to a more neuroprotective phenotype. Moreover, the modulation of astrocytes may buffer high concentrations of glutamate that have been shown to contribute to the death of RGCs after optic nerve transection.

Expression of the 40 kDa catecholamine regulated protein in the normal and injured rat retina.

Catecholamine regulated protein 40 (CRP40) has been shown to be expressed in the central nervous system (CNS) of several mammalian species where it may function in a similar manner to members of the heat shock protein (HSP) family. Immunohistochemical and immunoblotting techniques were utilized to investigate whether CRP40 is expressed in normal rat retinas. In addition, changes in CRP40 expression were studied following optic nerve transection. The immunohistochemical results showed that CRP40 is expressed in the normal rat retina. The protein was found to be highly expressed in the ganglion cell layer (GCL), the inner nuclear layer (INL) and the outer plexiform layer (OPL). In addition, a low level of CRP40 was found in the inner plexiform layer (IPL), and in the inner segment layer (ISL). No expression was found in the outer nuclear layer (ONL) of normal rat retina. The immunoblotting results show that CRP40 expression decreased in a time-dependent fashion after the optic nerve transection. This decrease indicates that the expression of CRP40 is dependent on the neuron's normal physiological state and that it plays an important function in physiological and pathological conditions in the retina.

Contribution of the commissure of Probst to binaural evoked responses in the rat's inferior colliculus: interaural time differences.

Binaural evoked responses were recorded with glass micropipettes from the central nucleus of the rat's inferior colliculus (ICC) before and after transection of the commissure of Probst (CP) with a microsurgical knife. The peak-to-peak amplitude of the averaged evoked response was measured for binaural clicks with interaural time differences (ITDs) between -1.0 and +30.0 ms (positive values reflecting ipsilateral-leading-contralateral click pairs). Before transection, the amplitude of the evoked response decreased as the ITD was shifted in favor of larger ipsilateral lead times. After transection of the CP, acoustic stimulation of the ipsilateral ear was much less effective in reducing evoked response amplitude. Responses to both short (+/-1.0 ms) and long (1.0-30.0 ms) ITD intervals were affected. After recordings were made, both anterograde and retrograde tract tracing methods were used to verify that the CP was completely transected and that all crossed projections from the dorsal nucleus of the lateral lemniscus (DNLL) to ICC were destroyed. The surgery completely eliminated the retrograde transport of fluorogold from the ICC to the opposite DNLL and blocked the anterograde transport of biotinylated dextran to contralateral DNLL and ICC. The physiological consequences of CP transection are attributed to the complete destruction of decussating, inhibitory (GABAergic) efferent projections from the DNLL.

Kainic acid lesions of the superior olivary complex: effects on sound localization by the albino rat.

The ability of rats to localize sounds in space was determined before and after kainic acid lesions of the superior olivary complex (SOC). Animals were tested with a 45-ms noise burst delivered from loudspeakers on the right or left of midline. Anatomical data showed that the lesions destroyed neurons in SOC while preserving fibers of passage in the trapezoid body and other decussating pathways of the auditory brainstem. Animals with either unilateral or bilateral SOC lesions were impaired in their ability to localize a single noise burst postoperatively. Deficits were also found after unilateral lesions restricted primarily to the lateral superior olive. SOC lesions resulted in an elevation in minimum audible angles for sound localization.

Projections from the superior olive and lateral lemniscus to tonotopic regions of the rat's inferior colliculus.

The projections to physiologically defined tonotopic regions of the central nucleus of the inferior colliculus (ICC) from the adult rat's superior olivary complex (SOC) and lateral lemniscus were investigated using retrograde tract tracing methods. Iontophoretic injections of the retrograde tracers, Fluoro-Gold (FG) or horseradish peroxidase (HRP), were made into the ICC through a glass micropipette, which also served as a recording electrode to determine the frequency response at the injection site. Injections were made into frequency-specific regions based on the best responses of neurons to contralaterally presented tones between 2 25 kHz. In the dorsal nucleus of the lateral lemniscus (DNLL) neurons were labeled both ipsilaterally and contralaterally to the injection site with a larger proportion projecting to the contralateral side. The distribution of labeled cells was concentric, with high frequencies represented along the outer margin and low frequencies represented centrally within DNLL. The lateral superior olive (LSO) was labeled bilaterally, with high frequencies represented medially and low frequencies laterally along the nuclear axis. The projection from the medial superior olive (MSO) was ipsilateral, with high frequencies represented ventrally and low frequencies dorsally. The projection from the superior paraolivary nucleus (SPN) was also largely ipsilateral, with high frequencies represented medially and low frequencies laterally. The intermediate and ventral nuclei of the lateral lemniscus (INLL and VNLL) were also labeled ipsilaterally and exhibited a distribution of tracer that depended on the frequency of the injection site: the low frequency projection was banded but the high frequency projection was more evenly distributed.

Sound localization after kainic acid lesions of the dorsal nucleus of the lateral lemniscus in the albino rat.

The ability of rats to localize sounds in space was determined before and after kainic acid lesions of the dorsal nucleus of the lateral lemniscus (DNLL). The rats were trained to approach a 45-ms noise burst delivered from loudspeakers on the right or left of midline. Lesions were made by local injection of kainic acid into the DNLL. Rats with unilateral lesions of DNLL were impaired in their postoperative ability to localize a single noise burst. Rats with bilateral lesions also had deficits in postoperative performance, but the severity of the impairment was not substantially greater than that expected from a unilateral lesion. The mean pre- and postoperative minimum audible angles were 14.8 degrees and 40.4 degrees for rats with complete unilateral lesions and 13.5 degrees and 36.0 degrees for rats with bilateral lesions.

Sound localization after transection of the commissure of Probst in the albino rat.

1. The ability of rats to localize sounds in space was determined before and after cutting of the commissure of Probst. The commissure of Probst was transected at its midline decussation with a microknife inserted into the brain according to stereotaxic coordinates. Six animals were tested after extensive lesions that destroyed all of the commissure of Probst fibers. An additional animal was tested after a smaller lesion that destroyed most of the commissure of Probst but left some fibers intact. Three control animals were tested before and after surgical intervention that did not involve the commissure of Probst. 2. The animals were tested in a semicircular apparatus with loudspeakers located on the right or left of midline. They were trained to make a response toward the left or right in the direction of the active loudspeaker. Correct reponses were rewarded by delivery of a small quantity of water from spouts located at +30 and -30 degrees azimuth. Tests of sound localization were conducted with a single broadband noise burst, 45 ms in duration, presented at the beginning of each trial. The position of the active loudspeakers was varied from trial to trial and performance at different speaker angles was calculated to determine psychometric curves. Minimum audible angles were estimated by interpolation from a performance level of 75% correct. 3. After postoperative testing was completed, the effectiveness of the lesions was confirmed by cell counts to determine the extent of retrograde degeneration in the dorsal nucleus of the lateral lemniscus (DNLL). These data showed that most of the contralaterally projecting neurons in DNLL underwent retrograde degeneration and the number of neurons was reduced by 60-65%. Ninety to 95% of the contralaterally projecting neurons in the DNLL disappeared within 7 wk after transection of the commissure of Probst. 4. The condition of damaged commissural fibers was further confirmed by tract tracing methods. A unilateral Fluoro-Gold injection was made into the inferior colliculus and the auditory brain stem was examined for retrograde label. No labeled neurons were seen in the contralateral DNLL in cases with complete transection of the commissure of Probst. In addition, the distribution of Fluoro-Gold labeling in other brain stem auditory structures was similar to that seen in normal animals. This result confirmed that the transection of the commissure of Probst was successful and that projections to other auditory structures remained intact. 5. Transection of the commissure of Probst produced marked deficits in midline sound localization. Although sound localization was still possible, there was a degradation in the ability of rats to localize sounds in the horizontal plane. The mean minimum audible angle was elevated 22.1 degrees after destruction of the commissure of Probst compared with a shift of only 2.0 degrees in control animals.