Advances in the Diagnosis and Treatment of Pediatric Arterial Ischemic Stroke.

Though rare, stroke in infants and children is an important cause of mortality and chronic morbidity in the pediatric population. Neuroimaging advances and implementation of pediatric stroke care protocols have led to the ability to rapidly diagnose stroke and in many cases determine the stroke etiology. Though data on efficacy of hyperacute therapies, such as intravenous thrombolysis and mechanical thrombectomy, in pediatric stroke are limited, feasibility and safety data are mounting and support careful consideration of these treatments for childhood stroke. Recent therapeutic advances allow for targeted stroke prevention efforts in high-risk conditions, such as moyamoya, sickle cell disease, cardiac disease, and genetic disorders. Despite these exciting advances, important knowledge gaps persist, including optimal dosing and type of thrombolytic agents, inclusion criteria for mechanical thrombectomy, the role of immunomodulatory therapies for focal cerebral arteriopathy, optimal long-term antithrombotic strategies, the role of patent foramen ovale closure in pediatric stroke, and optimal rehabilitation strategies after stroke of the developing brain.

3-Aminobenzamide protects against cerebral artery injury and inflammation in rats with intracranial aneurysms.

This study aimed to investigate the treatment effects and molecular mechanism of 3-aminobenzamide (3-AB) on intracranial aneurysms (IA). The IA model was established in male Sprague-Dawley (SD) rats and sham group was set up without ligation. The rats were intraperitoneally injected with normal saline in sham and model control groups and 10 mg/kg, 20 mg/kg and 40 mg/kg 3-AB for low, middle and high 3-AB groups for 3 months, respectively. The rates in and blood pressures of caudal artery were measured and anterior cerebral artery and olfactory artery were stained with hematoxylin and eosin (HE) for morphology observation. Besides, the effects of 3-AB on inflammatory cells, macrophages, neutrophils and T cells, were evaluated using immunohistochemistry. Gene expressions of TNF-α, MMP-9, MMP-2, iNOS, TLR4, PARP-1 and p65 were measured using qRT-PCR and the protein levels of TLR4, PARP-1 and p-p65 were evaluated using western blotting. Blood pressures of rats in 3-AB treatment groups were decreased in a dose-dependent manner. The damage of cerebral artery wall was alleviated and the inflammatory cells (macrophages, neutrophils and T cells) were reduced to some extent in 3-AB high-dose groups. The gene expression of TNF-α, MMP-9, MMP-2, iNOS, TLR4, PARP-1 and p65, as well as the protein expression of TLR4, PARP-1 and p-p65 in 3-AB treatment groups were decreased in a dose-dependent manner (P < 0.01).3-AB exhibited therapeutic effects on IA through inhibiting the secretions of inflammatory cytokines and MMPs.

Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke.

Activation of the NOD-like receptor protein (NLRP3)-inflammasome has been postulated to mediate inflammatory responses to brain damage during ischemic/reperfusion (I/R) injury. We therefore hypothesized that MCC950, a selective NLRP3-inflammasome inhibitor provides protection in mouse model of transient middle cerebral artery occlusion (tMCAO). Focal cerebral ischemia was induced by 60 min tMCAO followed by intraperitoneal administration of MCC950 (50 mg/kg) or saline at 1 h and 3 h post-occlusion. After 24 h of I/R, mice were tested for neurological outcome and were sacrificed for the analysis of infarct size and estimating NLRP3-inflammasome and apoptotic markers as well. Spectrophotometric method was used to determine hemoglobin (Hb) content as a marker of intracerebral hemorrhage. MCC950-treated mice showed a substantial reduction in infarction, edema and Hb content compared to saline controls in parallel with improved neurological deficits. MCC950 reduced expression of NLRP3-inflammasome cleavage products Caspase-1 and interlukin-1ß (IL-1ß) in penumbral region. These protective effects of MCC950 were associated with decreased TNF-α levels as well as poly (ADP-ribose) polymerase (PARP) and Caspase-3 cleavage and paralleled less phosphrylated NFκBp65 and IκBα levels. Taken together, these data indicate that inhibition of NLRP3-inflammasome with MCC950 has therapeutic potential in ischemic stroke models. Further investigations into the therapeutic efficacy and protocols are needed to confirm whether MCC950 treatment could be a promising candidate for clinical trials.

Caffeoyl Triterpenoid Esters as Potential Anti-ischemic Stroke Agents from Celastrus orbiculatus.

Three new triterpenoids, celastrusins A-C (1-3), together with 3-O-caffeoyl-α-amyrin (4) were isolated from the root bark of Celastrus orbiculatus. Their structures were identified by spectroscopic analysis, X-ray crystallography using Cu Kα radiation, and the comparison of both observed and reported spectroscopic data. An in vitro bioassay revealed that the caffeoyl triterpenoid esters 1, 3, and 4 possess neuroprotective effects against oxygen-glucose deprivation (OGD) induced SH-SY5Y cell damage. Further animal studies indicated that compound 1 significantly reduced brain infarction after transient middle cerebral artery occlusion (MCAO) in rats using a 10 mg/kg (i.v.) dose.

Endovascular revascularization results in IMS III: intracranial ICA and M1 occlusions.

BACKGROUND: Interventional Management of Stroke III did not show that combining IV recombinant tissue plasminogen activator (rt-PA) with endovascular therapies (EVTs) is better than IV rt-PA alone. OBJECTIVE: To report efficacy and safety results for EVT of intracranial internal carotid artery (ICA) and middle cerebral artery trunk (M1) occlusion. METHODS: Five revascularization methods for persistent occlusions after IV rt-PA treatment were evaluated for prespecified primary and secondary endpoints, after accounting for differences in key baselines variables using propensity scores. Revascularization was scored using the arterial occlusive lesion (AOL) and the modified Thrombolysis in Cerebral Ischemia (mTICI) scores. RESULTS: EVT of 200 subjects with intracranial ICA or M1 occlusion resulted in 81.5% AOL 2-3 recanalization, in addition to 76% mTICI 2-3 and 42.5% mTICI 2b-3 reperfusion. Adverse events included symptomatic intracranial hemorrhage (SICH) (8.0%), vessel perforations (1.5%), and new emboli (14.9%). EVT techniques used were standard microcatheter n=51; EKOS n=14; Merci n=77; Penumbra n=39; Solitaire n=4; multiple n=15. Good clinical outcome was associated with both TICI 2-3 and TICI 2b-3 reperfusion. Neither modified Rankin scale (mRS) 0-2 (28.5%), nor 90-day mortality (28.5%), nor asymptomatic ICH (36.0%) differed among revascularization methods after propensity score adjustment for subjects with intracranial ICA or M1 occlusion. CONCLUSIONS: Good clinical outcome was associated with good reperfusion for ICA and M1 occlusion. No significant differences in efficacy or safety among revascularization methods were demonstrated after adjustment. Lack of high-quality reperfusion, adverse events, and prolonged time to treatment contributed to lower-than-expected mRS 0-2 outcomes and study futility compared with IV rt-PA. TRIAL REGISTRATION NUMBER: NCT00359424.

Preceding intravenous thrombolysis facilitates endovascular mechanical recanalization in large intracranial artery occlusion.

BACKGROUND AND AIMS: Acute occlusions of the large intracranial arteries are relatively resistant to intravenous thrombolysis. Therefore, multimodal approaches combining intravenous thrombolysis with endovascular mechanical recanalization are increasingly being applied. In this setting, intravenous thrombolysis may facilitate subsequent mechanical thrombectomy. To test this hypothesis, we analyzed the influence of intravenous thrombolysis on net intervention time in subsequent endovascular mechanical recanalization. METHODS: In this retrospective single-center analysis, we compared net intervention time with and without preceding intravenous thrombolysis in patients treated by endovascular mechanical recanalization between 01/2003 and 06/2010. The net intervention time was defined as the interval between the onset of endovascular thrombus manipulation and successful vessel recanalization. RESULTS: We identified 65 eligible patients, 35 of whom were treated by intravenous thrombolysis before mechanical therapy. Recanalization was achieved in 26 patients with (74%) and 23 patients without preceding intravenous thrombolysis (77%). In the case of successful recanalization, the net intervention time was significantly shorter in patients with preceding intravenous thrombolysis (24·8 ± 22·8 vs. 44·2 ± 40·5 min; P<0·05). This difference remained significant after restricting the analysis to the patients treated by the Penumbra Stroke System(©) (n=32). After three-months, patients with preceding intravenous thrombolysis were more likely to be functionally independent (modified Rankin Scale≤2) than those without (P<0·05). CONCLUSIONS: Our findings suggest that preceding intravenous thrombolysis may reduce the intervention time in patients treated by endovascular mechanical recanalization. However, due to the retrospective design of our study, these findings have to be interpreted with caution and need confirmation in a larger patient population.

Prevalence and risk factors for aspirin and clopidogrel resistance in patients with coronary artery disease or ischemic cerebrovascular disease.

The objective of this study was to identify possible risk factors associated with a lack of response to aspirin and clopidogrel treatments in patients with coronary or cerebral ischemic artery disease. A point-of-care analyzer, VerifyNow (Accumetrics, San Diego, CA), was used to measure adenosine-5-diphosphate and platelet P2YI2 receptor blockage to investigate the responses of a group of 197 patients to aspirin and/ or clopidogrel therapies (aspirin therapy, 178; clopidogrel therapy, 139; both drugs, 144). Of these 197 patients, 135 (68.5%) had coronary artery disease and 72 (31.5%) had ischemic cerebrovascular disease. Aspirin resistance was defined as an ARU (aspirin reaction units) > or =550, and clopidogrel resistance was defined as platelet inhibition <20%. Twenty-five of 178 aspirin users (14.0%) were resistant to aspirin, and 54 of 139 (38.8%) clopidogrel users were resistant to clopidogrel. The data indicate that low hemoglobin (Hb) level in aspirin users and high systolic and diastolic blood pressures in clopidogrel users are significantly related to treatment resistance (p < 0.05). The latter finding is possibly due to the greater adhesiveness and increased aggregability of platelets in hypertensive patients.

Unusual neuroradiological findings in systemic lupus erythematosus.

A 47-year-old woman affected by systemic lupus erythematosus (SLE) presented with headache, fever, splenomegaly and edema of the lower extremities. CT showed diffuse low density in the cerebral white matter and marked splenomegaly in the abdomen. T2-weighted MR images showed diffuse high intensity lesions in the white matter. After immunosuppressive therapy with prednisolone, there was marked improvement in the cranial CT and MR appearances. The underlying pathological process was probably edema secondary to a lupus microangiopathy. SLE can be complicated by a widespread abnormality of the white matter with marked radiological changes but few neurological signs. In the present case, only an episodic mild hemiparesis for 3 weeks without seizure and psychiatric disturbance was found neurologically during the whole clinical course.

[Isolated angiitis of the central nervous system with high immune complex titer, first presenting as intracranial hemorrhage during cesarean section].

A case of isolated angiitis of the central nervous system (IACNS) which first presented as intracranial hemorrhage during cesarean section was reported. The patient was a 27-year-old female who showed severe headache during cesarean section. CT scan disclosed hematoma in the right parieto-occipital area. Carotid and vertebral angiograms demonstrated striking areas of stenosis and irregularity of all intracranial arteries. There was no abnormality in the branches of the external carotid arteries. Systemic angiograms showed no evidence of systemic vasculitis. Biopsy of the temporal artery showed no abnormal findings. Titer of immune complex was elevated. Angiitis showed no improvement with corticosteroid alone, but improved markedly with corticosteroid plus cyclophosphamide. Elevated titer of immune complex became normal. Treatment with a combination of corticosteroid and cyclophosphamide is recommended in IACN.

Hemorrhagic stroke due to cerebral vasculitis and the role of immunosuppressive therapy.

Cerebral vasculitis may occur in isolation or in conjunction with a systemic illness. Although a relatively infrequent cause of intracerebral or subarachnoid hemorrhage, it should be considered in a setting of relevant systemic symptoms, an unexplained progressive neurologic disorder, or in a patient lacking risk factors for hemorrhagic stroke. Diagnosis may be difficult because the results of most studies may be normal or nonspecific. Because treatment is effective in many of the cerebral vasculitides, vigorous pursuit of the diagnosis is warranted.

Temporal arteritis presenting as an extrapyramidal disorder.

A case of temporal arteritis presenting with extrapyramidal symptoms (tremor, rigidity and extrapyramidal hypertonus) unresponsive to conventional treatment is here described. The onset of headache and laboratory abnormalities suggestive of temporal arteritis prompted a temporal artery biopsy which confirmed the diagnosis; the administration of corticosteroids led to the resolution of all symptoms.

Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease. Effects of pyridoxine and folic acid treatment.

Severe homocysteinemia due to genetic defects either of pyridoxal 5-phosphate (PLP)-dependent cystathionine beta-synthase (CBS) or of enzymes in vitamin B12 and folate metabolism is associated with very early-onset vascular disease. Therefore, we studied homocysteine metabolism in 72 patients presenting before the age of 55 years with occlusive arterial disease of cerebral, carotid, or aorto-iliac vessels. Twenty patients (28%) had basal homocysteinemia; and 26 patients (36%) had abnormal increases of plasma homocysteine after peroral methionine loading, which exceeded the highest value for 46 comparable controls and was within the range for 20 obligate heterozygotes for homocystinuria due to CBS deficiency. Basal plasma homocysteine content was strongly and negatively correlated to vitamin B12 and folate concentrations. Plasma PLP was depressed in most patients but there was no correlation between PLP and homocysteine values. In 20 patients, treatment with pyridoxine hydrochloride (240 mg/day) and folic acid (10 mg/day) reduced fasting homocysteine after 4 weeks by a mean of 53%, and methionine response by a mean of 39%. These data show that a substantial proportion of patients with early-onset vascular disease have impaired homocysteine metabolism, which may contribute to vascular disease, and that the impaired metabolism can be improved easily and without side effects.

Local intraarterial fibrinolysis in the carotid territory.

A series comprising 12 patients who had intraarterial local fibrinolysis in the carotid territory is reported. A classification is proposed that divides the different types of occlusions into three groups on the basis of angiographic location. Group 1 (two cases) comprises occlusion of the extra- and/or intracranial carotid artery with patency of the circle of Willis and the lenticulostriate arteries. In this group, there is no brain infarction, the CT findings are normal, and the clinical signs are mainly hemodynamic and intermittent. Fibrinolysis may be performed late and rather safely and completed by surgery or angioplasty of the neck vessel stenosis responsible for the occlusion. Group 2 (five cases) comprises occlusions of the cortical arteries without involvement of the lenticulostriate arteries. The mechanism of the occlusion can be hemodynamic or embolic. Group 3 (five cases) comprises occlusions of intracerebral arteries involving the lenticulostriate arteries. In groups 2 and 3 with brain infarction, fibrinolysis will only be able to restore viability of the area of cerebral tissue surrounding the infarction (penumbra). The time factor is particularly critical in group 3 because lenticulostriate arteries are terminal vessels whose revascularization may induce hemorrhages with increasing frequency as the occlusion time is prolonged. The time factor is less critical in group 2 because collaterals make the ischemia less severe in the infarcted area and the vital and functional consequences of hemorrhage are not as serious as in group 3 because of the location. In this series, all the symptomatic complications of hemorrhage (two cases) occurred in group 3, in patients treated later than 6 hr after clinical onset. Given the time delay inherent in performing CT and angiography and in making the medical decision, it is considered dangerous to undertake fibrinolytic therapy in group 3, unless it can be started before 4 or 5 hr after clinical onset.

Localized isolated angiitis of the central nervous system associated with primary intracerebral lymphoma.

Isolated angiitis of the central nervous system (IACNS) is a form of granulomatous vasculitis that is confined to the nervous system. A patient with localized IACNS affecting the left internal carotid and posterior cerebral artery adjacent to a primary intracerebral lymphoma of the midbrain along with associated granulomatous inflammation of the dura, leptomeninges, and ependyma of the aqueduct of Sylvius is described. His course was complicated by many neurologic complications before his death. Prednisone and cyclophosphamide were unable to control his disease. More aggressive therapy may be indicated for patients with lymphoproliferative lesions and associated central nervous system (CNS) vasculitis who fail to respond to conventional therapy.

[Intraarterial urokinase infusion therapy for the acute intracranial major artery occlusion].

Recently percutaneous transluminal coronary recanalization therapy (PTCR) with urokinase infusion has became one of popular technique for coronary arterial occlusion. This paper reported clinical experience of intraarterial urokinase infusion therapy for acute or superacute stroke patients. The procedure was followed by angiographical study which revealed the major intracerebral arterial occlusion in three cases. Case 1: A 74-year-old female had sudden onset of clouding of consciousness with complete left hemiplegia. The patient was in our urological ward because of treatment for her right ureter tumor, as the patient was immediately subjected to angiographical study and complete occlusion of the trunk of the right middle cerebral artery was revealed four hours after onset. Successively 240,000 IU of urokinase solution was injected through the arterial catheter after angiographical study. This procedure repeated two times with 10 minute intervals. So total amount of 720,000 IU of urokinase was given by intraarterial injection. Immediately after the last urokinase injection the patient started to recover her consciousness and weakness. Simultaneous angiogram demonstrated partial recanalization of the proximal branches of the middle cerebral artery. The following day, she had complete recovery from her neurological deficits although she had transient hemorrhagic tendency. The final angiogram showed no existence of obstructed cerebral arteries as well as no low density areas in computed tomographic images. Case 2: A 73-year-old female, with the left internal carotid occlusion at the site of C1-2 portion, was instituted infusion therapy of similar procedure with total amount of 960,000 IU oi urokinase ten to twenty hours after onset. However, no rewarding was obtained.(ABSTRACT TRUNCATED AT 250 WORDS)

[Role of gamma cineangiography in the evaluation of chronic cerebral arteriopathies]. / Place de la gamma-ciné-angiographie dans l'évaluation des artériopathies cérébrales chroniques.

Gamma scintigraphy plays an important role in the topographic diagnosis of focalized cerebrovascular insufficiency. Furthermore, sequential imaging allows a comparative study of arterial distribution while studying the "transit time" of the radioactive tracer. In this work, the authors attempted to quantify transit time in patients with chronic cerebrovascular insufficiency while comparing the radioactivity in the hemispheres with that of the various arterial territories. The study of the arca and slope of the various arterial territories. The study of the area and slope of the tracer profile indirectly gives information about the cerebro-correlation between cerebrovascular resistance and the clinical state, there was, however, an interesting relation during vasodilator treatment (ifenprodil tartrate) in which promising clinical results were preceded by an increase in the arterial inflow component of the radioactivity curve.

Experimental treatment of cerebral vascular spasm secondary to subarachnoid hemorrhage.

Cerebral artery spasm following subarachnoid hemorrhage (SAH) is a major cause of morbidity and mortality. Treatment or prevention methods are most desirable. Using the basilar artery of the rabbit, cerebral arterial spasm was induced with an injection of 4 ml of autologous blood via cisternal puncture in six treated, four pre-treated and six control animals. Vertebral angiography was performed before and at ten, twenty, thirty and sixty minutes after the injection of blood was carried out, and the presence of spasm and its cause were followed in these animals. Pre-treated and treated subjects received 2 mg/kg of diltiazem (a calcium antagonist) either before and after the injection of blood, respectively. Analysis of vessel diameters by computer assisted densitometry showed that the treated group had a significant reduction of basilar artery spasm when compared to the control group, while in the pre-treated group, spasm was prevented.