Fenwick T. Nichols

Prevention of a First Stroke by Transfusions in Children with Sickle Cell Anemia and Abnormal Results on Transcranial Doppler Ultrasonography

BACKGROUND Blood transfusions prevent recurrent stroke in children with sickle cell anemia, but the value of transfusions in preventing a first stroke is unknown. We used transcranial Doppler ultrasonography to identify children with sickle cell anemia who were at high risk for stroke and then randomly assigned them to receive standard care or transfusions to prevent a first stroke. METHODS To enter the study, children with sickle cell anemia and no history of stroke had to have undergone two transcranial Doppler studies that showed that the time-averaged mean blood-flow velocity in the internal carotid or middle cerebral artery was 200 cm per second or higher. The patients were randomly assigned to receive standard care or transfusions to reduce the hemoglobin S concentration to less than 30 percent of the total hemoglobin concentration. The incidence of stroke (cerebral infarction or intracranial hemorrhage) was compared between the two groups. RESULTS A total of 130 children (mean [+/-SD] age, 8.3+/-3.3 years) were enrolled; 63 were randomly assigned to receive transfusions and 67 to receive standard care. At base line, the transfusion group had a slightly lower mean hemoglobin concentration (7.2 vs. 7.6 g per deciliter, P=0.001) and hematocrit (20.4 vs. 21.7 percent, P=0.002). Ten patients dropped out of the transfusion group, and two patients crossed over from the standard-care group to the transfusion group. There were 10 cerebral infarctions and 1 intracerebral hematoma in the standard-care group, as compared with 1 infarction in the transfusion group -- a 92 percent difference in the risk of stroke (P<0.001). This result led to the early termination of the trial. CONCLUSIONS Transfusion greatly reduces the risk of a first stroke in children with sickle cell anemia who have abnormal results on transcranial Doppler ultrasonography.

The use of transcranial ultrasonography to predict stroke in sickle cell disease

BACKGROUND Stroke, especially cerebral infarction, is a major cause of morbidity and mortality in children with sickle cell disease. Primary prevention of stroke by transfusion therapy may be feasible if there is a way to identify the patients at greatest risk. Transcranial Doppler ultrasonography can measure flow velocity in the large intracranial arteries. The narrowing of these arteries, which leads to cerebral infarction, is characterized by an increased velocity of flow. METHODS Using transcranial Doppler ultrasonography, we prospectively measured the velocity of cerebral blood flow in children and young adults being followed because of sickle cell disease. The results were classified as either normal or abnormal on the basis of the highest velocity of flow in the middle cerebral artery. Abnormal velocity was defined as a flow greater than or equal to 170 cm per second, a definition determined by post hoc analysis to maximize the predictive success of the test. The end point was a clinically apparent first cerebral infarction. RESULTS Two hundred eighty-three transcranial ultrasound examinations were performed in 190 patients with sickle cell disease (age at entry, 3 to 18 years). After an average follow-up of 29 months, cerebral infarction was diagnosed in seven patients. In 23 patients the results of the ultrasound examinations were abnormal, and in 167 patients they were normal. The clinical and hematologic characteristics of the two groups were similar, but six of the seven strokes occurred among the 23 patients with abnormal ultrasound results (P less than 0.00001 by Fishers exact test). In this group, the relative risk of stroke was 44 (95 percent confidence interval, 5.5 to 346). CONCLUSIONS Transcranial ultrasonography can identify the children with sickle cell disease who are at highest risk for cerebral infarction. Periodic ultrasound examinations and the selective use of transfusion therapy could make the primary prevention of stroke an achievable goal.

Unilateral cerebral inactivation produces differential left/right heart rate responses

We studied heart rate following unilateral hemispheric inactivation by intracarotid amobarbital in 25 patients undergoing preoperative evaluation for epilepsy surgery. Heart rate increased after left hemisphere inactivation, but decreased following right hemisphere inactivation. The results are consistent with differential left/right cerebral hemispheric effects on autonomic function, and appear related to functional and anatomic asymmetries in both the central and peripheral nervous systems.

Stroke Prevention Trial in Sickle Cell Anemia

Stroke occurs in 7-8% of children with Sickle Cell Disease (Hb SS) and is a major cause of morbidity. Rates of recurrence have been reduced from 46-90% to less than 10% through chronic blood transfusions. Prevention of first stroke, however, would be preferable because even one stroke can cause irreversible brain injury. Transcranial Doppler (TCD) ultrasound can detect arterial blood flow rates associated with subsequent stroke risk. By combining TCD screening and a potentially effective treatment, first stroke may be prevented. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) is the first stroke prevention trial in Hb SS and the first randomized, controlled use of transfusion in Hb SS. This multi-center trial is designed to test whether reducing sickle hemoglobin to 30% or less with periodic blood transfusions will reduce first-time stroke by at least 70% compared to standard care. Primary endpoints will be clinically evident symptoms of cerebral infarction with consistent findings on Magnetic Resonance Imaging and Angiography (MRI/MRA) or symptomatic intracranial hemorrhage. Secondary endpoints will be asymptomatic brain lesions detected by MRI in brain areas not involved in primary endpoints. The design calls for a 6-month start-up interval, 18 months of TCD screening and randomization, and observation for stroke from entry through month 54. Key features of the trial are standardized TCD and MRI/MRA protocols interpreted blindly, and blinded adjudication of endpoints. The sample size (60 per treatment group) is based on prospective data relating TCD velocity to risk of stroke. A time-averaged mean velocity of > or = 200 cm/sec is associated with a 46% risk of cerebral infarction over 39 months. The sample size is sufficient to detect 70% reduction in the primary endpoint at 90% power. This trial will determine if transfusion is effective in the primary prevention of stroke. Secondary aims may further the understanding of the effects of transfusion on the brain and guide future research into cerebrovascular disease in Hb SS.

Remote Evaluation of Acute Ischemic Stroke Reliability of National Institutes of Health Stroke Scale via Telestroke

Background and Purpose— Despite Food and Drug Administration approval of tissue-type plasminogen activator for stroke, obstacles in the US healthcare system prevent its widespread use. The Remote Evaluation for Acute Ischemic Stroke (REACH) program was developed to address these issues in rural settings. A key component of stroke assessment in the REACH system is the National Institutes of Health Stroke Scale (NIHSS) evaluation. We sought to determine whether, using the REACH system, NIHSS values of bedside and remote evaluators would correspond. Methods— Twenty patients were recruited. On obtaining consent, a neurologist performed a bedside NIHSS evaluation on each patient. Within 1 hour, using any broadband-connected workstation—either office or home personal computer and a landline phone to speak with the patient—a second neurologist remotely evaluated the patient through the REACH system. Paired t tests and Pearson correlation coefficients were used to examine NIHSS reliability performed bedside and remotely. Results— NIHSS ranged from 1 to 24. Correlations between bedside and remote locations (r =0.9552, P =0.0001) were very strong, and t tests indicate that the means were not different. Conclusions— The NIHSS can be reliably performed over the REACH system. This supports our endeavor to bring stroke expertise to rural community hospitals.

REACH Clinical Feasibility of a Rural Telestroke Network

Background and Purpose— Development of stroke networks is critical to bringing guideline-driven stroke care to rural, underserved areas. Methods— A Web-based telestroke tool, REACH, was developed to provide a foundation for a rural stroke network that delivered acute stroke consults 24 hours per day 7 days per week to 8 rural community hospitals in Georgia. Results— There were 194 acute stroke consults delivered. Thirty patients were treated with tissue plasminogen activator (tPA). The mean National Institutes of Health Stroke Score (NIHSS) was 15.4, and the median NIHSS was 12.5. The mean onset to treatment time (OTT) was 122 minutes. The OTT dropped from 143 minutes in the first 10 patients treated to 111 minutes in last 20 patients. Of the 30 patients treated with tPA, 23% (7) were treated in ≤90 minutes and 60% (18) were treated within 2 hours. There were no symptomatic intracerebral hemorrhages. Conclusions— The REACH telestroke system permits the rapid and safe use of tPA in rural community hospitals. Over time, the system became more efficient and OTT decreased.

Pathophysiology and treatment of stroke in sickle-cell disease: present and future

Sickle-cell anaemia is the most common cause of stroke in children, and stroke is one of the most devastating complications of sickle-cell disease. Overt strokes are typically due to large-artery vasculopathy affecting the intracranial internal carotid arteries and proximal middle cerebral arteries, whereas silent strokes typically occur in the territory of penetrating arteries. The sickled red blood cell can contribute to the pathogenesis of stroke via abnormal adherence to the vascular endothelium and by haemolysis, which results in endothelial cell activation, a hypercoaguable state, and alterations in vasomotor tone. Red-blood-cell transfusion, the most common preventive measure for stroke in sickle-cell disease, is associated with iron overload in chronic disease. Therefore, interventions directed towards the potential mechanisms that promote vasculopathy and occlusion in sickle-cell anaemia should be investigated. Here we review the epidemiology, clinical spectrum, and pathophysiology of stroke in sickle-cell disease to identify potential therapeutic targets.

Minocycline to Improve Neurologic Outcome in Stroke (MINOS): A dose-finding study

Background and Purpose— Minocycline is a promising anti-inflammatory and protease inhibitor that is effective in multiple preclinical stroke models. We conducted an early phase trial of intravenous minocycline in acute ischemic stroke. Methods— Following an open-label, dose-escalation design, minocycline was administered intravenously within 6 hours of stroke symptom onset in preset dose tiers of 3, 4.5, 6, or 10 mg/kg daily over 72 hours. Minocycline concentrations for pharmacokinetic analysis were measured in a subset of patients. Subjects were followed for 90 days. Results— Sixty patients were enrolled, 41 at the highest dose tier of 10 mg/kg. Overall age (65±13.7 years), race (83% white), and sex (47% female) were consistent across the doses. The mean baseline National Institutes of Health Stroke Scale score was 8.5±5.8 and 60% received tissue plasminogen activator. Minocycline infusion was well tolerated with only 1 dose limiting toxicity at the 10-mg/kg dose. No severe hemorrhages occurred in tissue plasminogen activator-treated patients. Pharmacokinetic analysis (n=22) revealed a half-life of approximately 24 hours and linearity of parameters over doses. Conclusions— Minocycline is safe and well tolerated up to doses of 10 mg/kg intravenously alone and in combination with tissue plasminogen activator. The half-life of minocycline is approximately 24 hours, allowing every 24-hour dosing. Minocycline may be an ideal agent to use with tissue plasminogen activator.

Transcranial Doppler correlation with cerebral angiography in sickle cell disease.

Background and Purpose Cerebral infarction in sickle cell disease is associated with arterial narrowing or occlusions of intracranial arteries. Primary stroke prevention would be feasible if a noninvasive screening test could be developed to detect intracranial disease in patients before symptoms develop. Methods To determine the sensitivity and specificity of transcranial Doppler in detecting significant (≥50% lumen diameter reduction) intracranial arterial lesions, we compared transcranial Doppler and cerebral angiography in a primarily young, symptomatic group of 33 patients (18 males and 15 females) with sickle cell disease. Results From a total of 34 examinations, transcranial Doppler detected significant abnormalities in 26 of 29 (sensitivity 90%, specificity 100%). Five were normal by both techniques. The transorbital examination detected abnormalities in two patients whose studies were otherwise unremarkable. Conclusions Transcranial Doppler is sensitive and specific for the detection of arterial vasculopathy of sickle cell disease. Screening should include a transorbital examination of the distal internal carotid artery as well as examination using the transtemporal approach.

Remote Evaluation of Acute Ischemic Stroke in Rural Community Hospitals in Georgia

Background and Purpose— Despite Food and Drug Administration approval of tissue-type plasminogen activator (tPA) for stroke, obstacles in the US health care system prevent widespread use. The Remote Evaluation for Acute Ischemic Stroke (REACH) program was developed to address these obstacles in rural settings. We have previously shown the reliability of the REACH system in performing a valid National Institutes of Health Stroke Scale (NIHSS) evaluation at the Medical College of Georgia (MCG). We now report on the performance of the system since its deployment in 5 rural hospitals in east Georgia. Methods— The rural emergency department (ED) staff can activate a Code REACH protocol 24 hours per day, 7 days per week by calling the Emergency Communications Center (ECC, an in-house dispatch center) at MCG, who pages the on-call consultant. The consultant calls back the ECC and is connected to the waiting ED. Simultaneously, using any broadband-connected workstation, the consultant logs in to the REACH system, allowing performance of an NIHSS evaluation, review of the computerized tomography (CT) images transmitted by the local radiology staff, and then the consultant can speak to the patient and family to verify time of onset. Results— The REACH system has evaluated 75 patients from March 2003 to April 2004, and 12 have received tPA, all without intracranial hemorrhage complications. NIHSS scores ranged from 0 to 30, with a mean of 14.3 (SD= 8.7, median 11.5). The mean onset to door time was 70.9 minutes (SD= 70.8, median 50), the mean door to consult time was 45.1 minutes (SD= 39.8, median 34), and the mean door to NIHSS completion was 62.9 minutes (SD= 50.8, median 51). The mean onset to needle time was 135.33 minutes (SD= 51.45, median 134.5). Conclusion— The REACH system enables remote stroke physicians to direct the local ED staff to administer tPA in rural settings where thrombolytics were not previously used. REACH may be used as a rapid consult tool to provide the same quality of stroke care to patients in rural hospitals as is given in tertiary stroke centers. This supports our endeavor to bring stroke expertise to rural community hospitals.