Reza Bavarsad Shahripour

N‐acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities

There is an expanding field of research investigating the benefits of medicines with multiple mechanisms of action across neurological disorders. N‐acetylcysteine (NAC), widely known as an antidote to acetaminophen overdose, is now emerging as treatment of vascular and nonvascular neurological disorders. NAC as a precursor to the antioxidant glutathione modulates glutamatergic, neurotrophic, and inflammatory pathways.

Real-time Validation of Transcranial Doppler Criteria in Assessing Recanalization During Intra-arterial Procedures for Acute Ischemic Stroke An International, Multicenter Study

Background and Purpose— We sought to evaluate the diagnostic accuracy of ultrasound criteria for recanalization during real-time transcranial Doppler monitoring of intra-arterial reperfusion procedures in acute ischemic stroke patients in an international, multicenter study. Methods— Consecutive acute ischemic stroke patients with proximal intracranial occlusions underwent intra-arterial reperfusion procedures with simultaneous real-time transcranial Doppler monitoring at 3 tertiary-care stroke centers. Residual flow signals at the site of angiographically confirmed occlusions were monitored at a constant transtemporal insonation angle using a standard head-frame. Recanalization was assessed simultaneously by digital subtraction angiography and ultrasound using thrombolysis in myocardial infarction and thrombolysis in brain ischemia (TIBI) criteria, respectively. Independent readers blinded to digital subtraction angiography performed validation of TIBI flow grades. The interrater reliability for assessment of TIBI grades was investigated. Results— We evaluated time-linked real-time digital subtraction angiography transcranial Doppler images from 96 diagnostic digital subtraction angiography runs during intra-arterial reperfusion procedures in 62 acute ischemic stroke patients (mean age, 59±17 years; 58% men; median baseline National Institutes of Health Stroke Scale score, 18 [interquartile range 12–21]; median time from symptom onset to intra-arterial procedure initiation, 240 minutes [interquartile range 163–308]). The interrater reliability for evaluation of TIBI grades and assessment of recanalization was good (Cohen &kgr;: 0.838 and 0.874, respectively; P<0.001). Compared with angiography, transcranial Doppler had the following accuracy parameters for detection of complete recanalization (TIBI 4 and 5 versus thrombolysis in myocardial infarction 3, flow grades): sensitivity, 88% (95% confidence interval, 72%–96%); specificity, 89% (79%–95%); positive predictive value, 81% (65%–91%); negative predictive value, 93% (84%–98%); and overall accuracy 89% (80%–94%). Conclusions— At laboratories with high-interrater reliability, TIBI criteria can accurately predict brain recanalization in real time as compared with thrombolysis in myocardial infarction angiographic scores.

The effect of NeuroAiD™ (MLC601) on cerebral blood flow velocity in subjects' post brain infarct in the middle cerebral artery territory

BACKGROUND Stroke is the third common cause of mortality and the most common cause of morbidity in adults. MLC601 (NeuroAiD™) is a treatment indicated for post stroke recovery. An increase of impaired cerebral blood flow may be an important parameter for recovery processes. The aim of this study was to investigate the effect of MLC601 on cerebral blood flow velocity as an indirect evidence of cerebral blood flow increase in post stroke subjects. METHODS This is a double-blinded, placebo controlled, randomized study of 80 subjects included within a week of stroke onset. All subjects were given either MLC601 or placebo, 4 capsules, 3 times a day for 3 months. Cerebral blood flow within the middle cerebral artery, with blood flow velocity measured by transcranial Doppler (TCD), and Barthel index was assessed at baseline and at 3 months. RESULTS The mean change in cerebral blood flow velocity in the MLC601 treatment group (15.9) was significantly increased (p=0.009) compared to the placebo group (9.6). Subjects in the treatment group also showed a significant difference in the mean rank of modified ranking scale (p<0.001) and mean change of the Barthel Index: 36 vs. 29 in the placebo group (p<0.001). CONCLUSION This is the first study suggesting that treatment with MLC601 may increase cerebral blood flow in stroke subjects. This may be mediated by an effect on stimulating microcirculation, an important process contributing to neuroplasticity in the central nervous system. This effect on cerebral blood flow may be associated with improvement in measures of functional recovery.

Vein of Galen aneurysmal malformations: critical analysis of the literature with proposal of a new classification system

Vein of Galen aneurysmal malformations are a rare and diverse group of entities with a complex anatomy, pathophysiology, and serious clinical sequelae. Due to their complexity, there is no uniform treatment paradigm. Furthermore, treatment itself entails the risk of serious complication. Offering the best treatment option is dependent on an understanding of the aberrant anatomy and pathophysiology of these entities, and tailored therapy is recommended. Herein, the authors review the current concepts related to vein of Galen aneurysmal malformations and suggest a new classification system excluding mesodiencephalic plexiform intrinsic arteriovenous malformations from this group of malformations.

The choroid plexus: a comprehensive review of its history, anatomy, function, histology, embryology, and surgical considerations

IntroductionThe role of the choroid plexus in cerebrospinal fluid production has been identified for more than a century. Over the years, more intensive studies of this structure has lead to a better understanding of the functions, including brain immunity, protection, absorption, and many others. Here, we review the macro- and microanatomical structure of the choroid plexus in addition to its function and embryology.MethodThe literature was searched for articles and textbooks for data related to the history, anatomy, physiology, histology, embryology, potential functions, and surgical implications of the choroid plexus. All were gathered and summarized comprehensively.ConclusionWe summarize the literature regarding the choroid plexus and its surgical implications.

Safety of Intravenous Thrombolysis among Stroke Patients Taking New Oral Anticoagulants—Case Series and Systematic Review of Reported Cases

BACKGROUND Current guidelines do not recommend the administration of intravenous tissue plasminogen activator (IV-tPA) to patients with acute ischemic stroke (AIS) who take new oral anticoagulants (NOACs). We present a multicenter case series of IV-tPA use while the patients are on NOACs, as well as a systematic review of the literature. METHODS We reviewed the medical records of consecutive patients on NOACs who received IV-tPA for symptoms of AIS at four participating stroke centers in the United States and Europe. Safety endpoints were post-thrombolysis symptomatic intracranial hemorrhage (sICH) or other serious systemic bleeding. RESULTS Between October 2010 and October 2014, 6 patients received IV-tPA for possible AIS while taking dabigatran. None of the patients had sICH or any other hemorrhagic complication. Literature review resulted in a total of 26 patients receiving IV-tPA while on NOACs (dabigatran: 15, rivaroxaban: 10, apixaban: 1). Among them, two patients experienced sICH and died. None of the patients experienced major extracranial hemorrhage; however, minor and asymptomatic hemorrhagic complications were described in 7 patients. Pooled analysis indicates an sICH rate of 6.45% (95% CI by the adjusted Wald method: .8-21.7%). The mean interval between the last dose of NOAC and IV thrombolysis was 12 ± 7.8 [4-28.3] hours. CONCLUSIONS Although the safety of IV-tPA cannot be definitively confirmed in a small series, consideration of stroke severity and management of hemorrhage risk with general precautions with post-tPA management protocols can justify treatment in the absence of coagulopathy.

Systemic Inflammatory Response Syndrome in Tissue-Type Plasminogen Activator–Treated Patients is Associated With Worse Short-term Functional Outcome

Background and Purpose— Systemic inflammatory response syndrome (SIRS) is a generalized inflammatory state. The primary goal of the study was to determine whether differences exist in outcomes in SIRS and non-SIRS intravenous tissue-type plasminogen activator–treated patients. Methods— Consecutive patients were retrospectively reviewed for the evidence of SIRS during their admission. SIRS was defined as the presence of ≥2 of the following: body temperature <36°C or >38°C, heart rate >90, respiratory rate >20, and white blood cells <4000/mm or >12 000 mm, or >10% bands. Patients diagnosed with infection (via positive culture) were excluded. Results— Of the 241 patients, 44 had evidence of SIRS (18%). Adjusting for pre–tissue-type plasminogen activator National Institutes of Health Stroke Scale, age, and race, SIRS remained a predictor of poor functional outcome at discharge (odds ratio [OR], 2.58; 95% confidence interval [CI], 1.16–5.73; P=0.0197). Conclusions— In our sample of tissue-type plasminogen activator–treated (tPA) patients, ~1 in 5 patients developed SIRS. Furthermore, we found the presence of SIRS to be associated with poor short-term functional outcomes and prolonged length of stay.

Intravenous thrombolysis for acute ischemic stroke occurring during hospitalization for transient ischemic attack

Background There are limited data regarding the use of intravenous thrombolysis in patients who experienced acute ischemic symptoms during their hospitalization for prior transient ischemic attack. Aim We sought to prospectively evaluate the safety and efficacy of intravenous thrombolysis for the treatment of acute ischemic stroke occurring during hospitalization for transient ischemic attack in an international, multicenter study. Methods Consecutive patients with acute ischemic stroke that occurred during hospitalization for prior transient ischemic attack were treated with intravenous thrombolysis in five tertiary-care stroke centers. Early arterial recanalization was determined by transcranial Doppler at the end of recombinant tissue plasminogen activator infusion using previously validated criteria. Symptomatic intracranial hemorrhage complicating intravenous thrombolysis was evaluated using the National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study definition. Functional independence at three-months was defined as Modified Rankin Scale score of 0–2. Results Systemic recombinant tissue plasminogen activator infusion (median onset-to-treatment time 70 mins, interquartile range 50–150) was given in 25 consecutive patients (mean age 66 ± 10 years) who developed acute ischemic stroke symptoms (median National Institutes of Health Stroke Scale score 10 points; interquartile range 8–14) during hospitalization for prior transient ischemic attack (median ABCD2 score 5 points; median time-to-symptom recurrence 24 h, interquartile range 24–48). No symptomatic intracranial hemorrhage (0%; 95% confidence interval 0–12%) was documented. Early complete recanalization occurred in 64% of patients (95% confidence interval 44–80%), and 84% (95% confidence interval 65–94%) achieved three-month functional independence. The rate of three-month functional independence was higher in patients treated with intravenous tissue plasminogen activator within 90 mins from symptom onset compared with those with onset-to-treatment time>90 mins (81% vs. 33%; P = 0·031). Conclusions Intravenous thrombolysis for symptoms of acute ischemic stroke occurring after hospitalization for transient ischemic attack appears to be safe. These pilot data support resetting the clock if new symptoms recur shortly after transient ischemic attack.

Cerebral Microbleeds and Risk of Intracerebral Hemorrhage Post Intravenous Thrombolysis

BACKGROUND Stroke patients who have cerebral micro bleeds (CMBs) could be potentially at a greater risk for symptomatic intracerebral hemorrhage (sICH) than those patients without CMBs. The aim of our study was to investigate whether the presence and burden of CMBs are associated with post IVT sICH. METHODS In this multicenter study, consecutive patients treated with intravenous tissue plasminogen activator were prospectively identified and analyzed. Patients without magnetic resonance imaging (MRI) within 24 hours of treatment were excluded. CMBs were defined as round or oval, hypointense lesions with associated blooming on T2*-weighted MRI up to 10 mm in diameter. Outcome measures included the occurrence of sICH or death. RESULTS Of 672 patients with IVT (mean age 62 ± 14 years, 52% men, median admission NIHSS: 7 points), 103 patients had CMBs on T2*-MRI. Ten patients had more than 10, whereas the remaining 93 patients had 1-10 CMBs on T2*-MRI. The rates of sICH did not differ between patients with and patients without 1-10 CMBs (5.8% versus 3.5%; P = .27). However, sICH occurred more frequently (P = .0009) in patients with > 10 CMBs (30%, 95% confidence interval [CI] by the adjusted Wald method: 10%-61%). After adjusting for potential confounders, the presence of >10 CMBs on T2*-MRI was independently (P = .0004) associated with a higher likelihood for sICH (odds ratio [OR]:13.4, 95%CI:3.2-55.9). CONCLUSIONS Our findings indicate an increased risk of sICH after IVT when more than 10 CMBs are present.

Predictors of Systemic Inflammatory Response Syndrome in Ischemic Stroke Undergoing Systemic Thrombolysis with Intravenous Tissue Plasminogen Activator

BACKGROUND Systemic inflammatory response syndrome (SIRS) is an inflammatory process associated with poor outcomes in acute ischemic stroke (AIS) patients. However, no study to date has investigated predictors of SIRS in AIS patients treated with intravenous (IV) tissue plasminogen activator (tPA). METHODS Consecutive patients were retrospectively reviewed for evidence of SIRS during their acute hospitalization. SIRS was defined as the presence of 2 or more of the following: (1) body temperature less than 36°C or greater than 38°C, (2) heart rate greater than 90, (3) respiratory rate greater than 20, or (4) white blood cell count less than 4000/mm or greater than 12,000/mm or more than 10% bands for more than 24 hours. Those diagnosed with an infection were excluded. A scoring system was created to predict SIRS based on patient characteristics available at the time of admission. Logistic regression was used to evaluate potential predictors of SIRS using a sensitivity cutoff of ≥65% or area under the curve of .6 or more. RESULTS Of 212 patients, 44 had evidence of SIRS (21%). Patients with SIRS were more likely to be black (61% versus 54%; P = .011), have lower median total cholesterol at baseline (143 versus 167 mg/dL; P = .0207), and have history of previous stroke (51% versus 35%; P = .0810). Ranging from 0 to 6, the SIRS prediction score consists of African American (2 points), history of hypertension (1 point), history of previous stroke (1 point), and admission total cholesterol less than 200 (2 points). Patients with an SIRS score of 4 or more were 3 times as likely to develop SIRS when compared with patients with a score of ≤3 (odds ratio = 2.815, 95% confidence interval 1.43-5.56, P = .0029). CONCLUSIONS In our sample of IV tPA-treated AIS patients, clinical and laboratory characteristics available on presentation were able to identify patients likely to develop SIRS during their acute hospitalization. Validation is required in other populations. If validated, this score could assist providers in predicting who will develop SIRS after treatment with IV tPA.