Sickle cell disease and electroencephalogram hyperventilation.
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Anemia, Sickle Cell↗
Biomedical subjects
Steven G Pavlakis
Publications and source records attributed to Steven G Pavlakis.
Pediatric stroke: Opportunities and challenges in planning clinical trials.
A conference entitled "Towards the establishment of clinical trials in pediatric and newborn stroke" assembled stroke animal model researchers, pediatric stroke researchers, adult stroke trialists, and members of the Food and Drug Administration and National Institute of Neurological Disorders and Stroke to focus on the obstacles and opportunities for conducting randomized trials in pediatric stroke. The need for good prospective clinical data in newborn and pediatric stroke in regard to outcome and recurrence risk was stressed. For clinical trials, there should be a scientific rationale. Preclinical data should be as promising and as complete as possible. Adult data should be explored, both positive and negative. For medication trials, reasonable safety and bioavailability data for the agent in question should be available. Commitment of researchers, collaboration with colleagues in primary care, emergency rooms, and intensive care units, and most importantly the willingness to participate of children and their families will all be crucial. Most children with cancer in the United States are enrolled in clinical trials and have an outcome superior to the adult patient with cancer, who is less likely to be enrolled in a trial. We should strive for enrollment and outcome results in pediatric stroke similar to those found in pediatric oncology trials.
Adult↗
Lessons from adult stroke trials.
Before designing epidemiologic, genetic, or treatment trials in pediatric stroke, we should learn from adult trials which preceded. Adult trialists state that there is a need for improved animal models to mimic human disease. Dose-response curves with blinded outcome measures would improve preclinical data. Functional and histologic outcome measures would improve the animal model. In regard to human Phase 2 medication trials, safety, delivery, end points, and surrogate markers are necessary. The detection of biologic activity can be defined in Phase 2B trials. For Phase 3 trials, the experiment needs to be simple with global outcome measures as end points. New statistical designs such as futility analysis may improve and streamline trials in both adults and children. Clinical trials are a long process, and care needs to be incorporated at every step. Why is there a propensity of failed studies for acute ischemic stroke in adults? The reasons include (a) the animal model fails us, (b) the Phase 2 trials are ineffective in defining dose, and (c) the Phase 3 trials are poorly done. Because clinical trials, more often than not, fail to give positive (effective treatment) results, it seems reasonable to attempt to learn from others' past experiences before initiating pediatric stroke trials.
Adult↗
Sickle cell disease: ischemia and seizures.
Although the prevalence of seizures in children with sickle cell disease (SCD) is 10 times that of the general population, there are few prospectively collected data on mechanism. With transcranial Doppler and magnetic resonance imaging (MRI) and angiography, we evaluated 76 patients with sickle cell disease, 29 asymptomatic and 47 with neurological complications (seizures, stroke, transient ischemic attack, learning difficulty, headaches, or abnormal transcranial Doppler), who also underwent bolus-tracking perfusion MRI. The six patients with recent seizures also had electroencephalography. Group comparisons (seizure, nonseizure, and asymptomatic) indicated that abnormal transcranial Doppler was more common in the seizure (4/6; 67%) and nonseizure (26/41; 63%) groups than in the asymptomatic (10/29; 34%) group (chi2; p = 0.045), but abnormal structural MRI (chi2; p = 0.7) or magnetic resonance angiography (chi2; p = 0.2) were not. Relative decreased cerebral perfusion was found in all seizure patients and in 16 of 32 of the remaining patients with successful perfusion MRI (p = 0.03). In the seizure patients, the perfusion abnormalities in five were ipsilateral to electroencephalographic abnormalities; one had normal electroencephalogram results. These findings suggest that vasculopathy and focal hypoperfusion may be factors in the development of sickle cell disease-associated seizures.
Adolescent↗
Spinal cord infarction in meningitis: polygenic risk factors.
We report a male with spinal cord infarction and tetraplegia after Streptococcus pneumoniae meningitis. He was subsequently found to have both a Chiari I malformation and factor V Leiden mutation. A literature search was conducted to identify previously reported cases of pediatric spinal cord infarction associated with acute bacterial meningitis, anatomic brain anomalies, and hypercoagulability disorders. This article is the first report of spinal cord infarction in a child with hypercoagulability disorder and structural brain anomaly in the setting of acute bacterial meningitis. The confluence of infection, inflammation, localized pressure, and predisposition to hypercoagulability produced unique conditions resulting in infarction of the cervical spine. This report emphasizes the polygenic nature of the expression of spinal cord infarction.
Arnold-Chiari Malformation↗
Little folk strokes: current questions.
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Humans↗
Newborn brain infarction: clinical aspects and magnetic resonance imaging.
OBJECTIVE: We describe the clinical and imaging studies of 11 full-term babies with neonatal stroke. We classify the neonatal non-hemorrhagic strokes as thrombotic, embolic, or global vascular insufficiency and determine if this classification is improved by adding magnetic resonance spectroscopy (MRS) and diffusion-weighted imaging (DWI) to conventional magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). METHODS: Clinically, eight of the 11 babies presented with seizures, one with apnea, and two with lethargy. Conventional MRI and DWI were used to classify each infarct as being either borderzone or vascular distribution. The location of infarction revealed the presumed vascular pathophysiology. RESULTS: Infants were classified as having either embolic (bilateral middle cerebral artery,n=1), global ischemic (bilateral borderzone, n=2), or thrombotic infarction (unilateral middle cerebral artery, n=7; bilateral posterior cerebral arteries, n=1). DWI and MRS detected a small infarct better than conventional MRI in one patient. MRA showed abnormal intracranial arteries in three, all of who were in the thrombotic group. Even though MRS was more sensitive than conventional MRI in detecting ischemia/infarction in one patient, in another there was no detectable lactate in the stroke region found on conventional MRI. Clinical presentation was similar in global ischemia and focal infarctions, but newborn stroke was more likely to present with lateralizing focal motor seizures. Seizures were the most common presenting sign, with a paucity of other focal neurological deficits. CONCLUSION: MRI is the best approach to determine stroke pathophysiology. Brain infarction frequently presents with seizures. We speculate that the location and distribution of infarction might determine stroke timing, pathophysiology and outcome. Ongoing clinical studies will likely clarify this speculation.
Cerebral Infarction↗
Sickle cell disease: the neurological complications.
The genetic cause of sickle cell disease has been known for decades, yet the reasons for its clinical variability are not fully understood. The neurological complications result from one point mutation that causes vasculopathy of both large and small vessels. Anemia and the resultant cerebral hyperemia produce conditions of hemodynamic insufficiency. Sickled cells adhere to the endothelium, contributing to a cascade of activated inflammatory cells and clotting factors, which result in a nidus for thrombus formation. Because the cerebrovascular reserve becomes exhausted, the capacity for compensatory cerebral mechanisms is severely limited. There is evidence of small-vessel sludging, and a relative deficiency of nitric oxide in these vessels further reduces compensatory vasodilatation. Both clinical strokes and silent infarcts occur, affecting motor and cognitive function. New data suggest that, in addition to sickle cell disease, other factors, both environmental (eg, hypoxia and inflammation) and genetic (eg, mutations resulting in thrombogenesis), may contribute to a patient's stroke risk. The stroke risk is polygenic, and sickle cell disease can be considered a model for all cerebrovascular disease. This complex disease underscores the potential intellectual and practical distance between the determination of molecular genetics and effective clinical application and therapeutics.
Anemia, Sickle Cell↗