Kelly D. Flemming

Sample Size Calculation for Clinical Trials Using Magnetic Resonance Imaging for the Quantitative Assessment of Carotid Atherosclerosis

PURPOSE To provide sample size calculation for the quantitative assessment of carotid atherosclerotic plaque using non-invasive magnetic resonance imaging in multi-center clinical trials. METHODS. As part of a broader double-blind randomized trial of an experimental pharmaceutical agent, 20 asymptomatic placebo-control subjects were recruited from 5 clinical sites for a multi-center study. Subjects had 4 scans in 13 weeks on GE 1.5 T scanners, using TOF, T1-/PD-/T2- and contrast-enhanced Tl-weighted images. Measurement variability was assessed by comparing quantitative data from the index carotid artery over the four time points. The wall/outer wall (W/OW) ratio was calculated as wall volume divided by outer wall volume. The percent lipid-rich/necrotic core (%LR/NC) and calcification (%Ca) were measured as a proportion of the vessel wall. For %LR/NC and %Ca, only those subjects that exhibited LR/NC or Ca components were used in the analysis. RESULTS Measurement error was 5.8% for wall volume, 3.2% for W/OW ratio, 11.1% for %LR/NC volume and 18.6% for %Ca volume. Power analysis based on these values shows that a study with 14 participants in each group could detect a 5% change in W/OW ratio, 10% change in wall volume, and 20% change in %LR/NC volume (power = 80%, p < .05). The calculated measurement errors presume any true biological changes were negligible over the 3 months that subjects received placebo. CONCLUSION In vivo MRI is capable of quantifying plaque volume and plaque composition, such as %lipid-rich/necrotic core and %calcification, in the clinical setting of a multi-center trial with low inter-scan variability. This study provides the basis for sample size calculation of future MRI trials.

Variable Presentations of Postpartum Angiopathy

Background and Purpose— Postpartum angiopathy (PPA), a rare cause of stroke in the puerperium, is heralded by severe headaches within 1–2 weeks after delivery. Angiography demonstrates segmental vasoconstriction that often resolves spontaneously. PPA is generally regarded as benign. We aimed to define clinical presentations, radiological findings, and outcomes of patients with PPA. Methods— We retrospectively reviewed patients from 3 centers with acute neurological symptoms and angiography showing vasoconstriction in the postpartum period. Patients without neuroimaging and with diagnoses of cerebral venous sinus thrombosis and aneurysmal hemorrhage were excluded. Patient characteristics, clinical symptoms, neuroimaging findings, and clinical condition at hospital discharge were collected. Results— Eighteen patients (mean age, 31 years; range, 15–41) were identified. Median gestation was 38 weeks. Twelve (67%) had a history of prior uneventful pregnancy. Neurological symptoms began on median day 5 postpartum and included headache (n=16, 89%), focal deficit (n=9, 50%), visual disturbance (n=8, 44%), encephalopathy (n=6, 33%), and seizure (n=5, 28%), often in combination. Brain imaging was abnormal in most (n=13, 72%). The most common abnormalities were intracranial hemorrhage (n=7, 39%), vasogenic edema (n=6, 35%), and infarction (n=6, 35%). Clinical outcomes were markedly variable with full recovery seen in 9 (50%), death after a fulminant course in 4 (22%), and residual deficits in 5 (28%). Conclusions— In contrast to prior reports, this group of patients with PPA had a higher proportion of nonbenign outcomes. Most patients who undergo neuroimaging have parenchymal abnormalities, which are most often stroke (hemorrhagic or ischemic) or reversible vasogenic edema.

The Natural History of Radiographically Defined Vertebrobasilar Nonsaccular Intracranial Aneurysms

Background: Vertebrobasilar nonsaccular intracranial aneurysms (VBNIA) are characterized by dilatation, elongation, and tortuosity of the vertebrobasilar system. Methods:The medical records and imaging of patients with vertebrobasilar fusiform aneurysms or dolichoectasia between 1989 and 2001 were reviewed. Prospective follow-up was obtained. Results: One hundred and fifty-nine patients were identified (74% male) with 719 patient years of follow-up. Presenting events included: hemorrhage (3%), ischemia (28%), and compression (22%). The remainder were incidental. The 1-, 5-, and 10-year risk of cerebral infarction (CI) due toVBNIA is 2.7, 11.3, and 15.9% respectively. The risk of recurrent CI is 6.7% per patient year. Median survival was 7.8 years and death was most commonly due to ischemia. Conclusions:VBNIA are more common in men and typically present in the 6–7th decade. Recurrent CI is more common than hemorrhage risk.

Population-Based Study of Symptomatic Internal Carotid Artery Occlusion: Incidence and Long-Term Follow-Up

Background and Purpose— Internal carotid artery (ICA) occlusion is an important cause of transient ischemic attack (TIA) and cerebral infarction. There are no previous population-based natural history studies evaluating outcome after symptomatic ICA occlusion (SICAO). Methods— We performed a retrospective, population-based study of SICAO. All Olmsted County (Minnesota) residents with possible SICAO from 1986 to 2000 were identified by cross-referencing appropriate clinical and imaging codes. Inclusion criteria were cerebral infarction or TIA in a carotid distribution and imaging documentation of ipsilateral ICA occlusion <3 months after the index event. Kaplan–Meier estimates were used to calculate the risk of cerebral infarction, myocardial infarction, and death after SICAO. Results— Seventy-five patients qualified. Annual SICAO incidence was 6 per 100 000 persons (age and gender adjusted to the 2000 US white population). Risk of cerebral infarction during follow-up was 8% at 30 days, 10% at 1 year, and 14% at 5 years. Five of 11 cerebral infarctions occurred within the first week after diagnosis of occlusion. Risk of myocardial infarction was 0% at 30 days, 8% at 1 year, and 24% at 5 years. Risk of death was 7%, 13%, and 29%, respectively. Conclusions— There may be 15 000 to 20 000 incident cases of SICAO in the United States annually. Risk of cerebral infarction after SICAO is initially high and then stabilizes, whereas risk of myocardial infarction is initially low but gradually increases. Better strategies are needed to reduce early stroke recurrence in this setting.

Prospective hemorrhage risk of intracerebral cavernous malformations

Objective: Our goal was to describe the prospective risk and timing of symptomatic hemorrhage in a large cohort of followed patients with intracerebral cavernous malformations (ICMs). Methods: All patients between 1989 and 1999 with the radiographic diagnosis of intracerebral cavernous malformation were identified retrospectively. The records and radiographic data were reviewed, and follow-up after diagnosis was obtained. An incidence rate was used to calculate annual risk of symptomatic hemorrhage. Predictive factors for outcomes used univariate and multivariable analysis with p < 0.05. Results: A total of 292 patients were identified (47.3%male) with 2,035 patient years of follow-up. Seventy-four patients presented with hemorrhage, 108 with symptoms not related to hemorrhage (seizure or focal deficit), and 110 as asymptomatic. The overall annual rate of hemorrhage in those presenting initially with hemorrhage, with symptoms not related to hemorrhage, or as an incidental finding was 6.19%, 2.18%, and 0.33%, respectively. Patients who presented initially with symptomatic hemorrhage (hazard ratio 5.14; 95% confidence interval [CI] 2.54–10.4; p < 0.001) were at higher risk for future hemorrhage, and hemorrhage risk decreased with time. Male gender (hazard ratio 2.36; 95% CI 1.14–4.89; p = 0.02), and multiplicity of ICMs (hazard ratio 2.65; 95% CI 1.30–5.43; p = 0.01) also increased the risk of hemorrhage. The median time from first to second hemorrhage was 8 months. Conclusions: This study provides an estimate of prospective annual symptomatic hemorrhage risk in patients with ICMs stratified by initial presenting symptom. Prior hemorrhage, male gender, and multiplicity of ICMs may predict future hemorrhage. Hemorrhage risk decreases with time in those initially presenting with hemorrhage.

Brainstem cavernous malformations: anatomical, clinical, and surgical considerations

Symptomatic brainstem cavernous malformations carry a high risk of permanent neurological deficit related to recurrent hemorrhage, which justifies aggressive management. Detailed knowledge of the microscopic and surface anatomy is important for understanding the clinical presentation, predicting possible surgical complications, and formulating an adequate surgical plan. In this article the authors review and illustrate the surgical and microscopic anatomy of the brainstem, provide anatomoclinical correlations, and illustrate a few clinical cases of cavernous malformations in the most common brainstem areas.

The Preoperative Cerebrovascular Consultation: Common Cerebrovascular Questions Before General or Cardiac Surgery

All types of health care providers may be called on to evaluate the risk of ischemic stroke related to an upcoming surgical procedure, particularly in patients with established cerebrovascular disease. We outline possible mechanisms contributing to perioperative stroke, summarize available data on the stroke risk associated with selected surgeries, and highlight recognized risk factors. We then provide recommended answers to some of the questions commonly encountered at the preoperative cerebrovascular consultation: What is the appropriate time interval between a stroke and elective surgery? What is the perioperative stroke risk for patients with established carotid or vertebrobasilar large artery stenosis, and what are the cardiac implications of detecting a cerebrovascular large artery stenosis? Should patients with a large artery stenosis undergo prophylactic revascularization procedures before undergoing general surgery? What treatment is appropriate for patients with both coronary artery and carotid or vertebrobasilar large artery stenosis? What is the appropriate perioperative management of antiplatelet and anticoagulant medications with respect to stroke risk?

Risk of Ischemic Stroke in Patients With Symptomatic Vertebrobasilar Stenosis Undergoing Surgical Procedures

Background and Purpose— There is little information to provide an estimate for stroke risk in patients with established stenosis or occlusion in the basilar or intracranial vertebral arteries undergoing surgical procedures. The objective of this study was to determine the ischemic stroke risk in this specific patient population. Methods— A medical records linkage system retrospectively identified patients with a diagnosis of symptomatic vertebrobasilar stenosis or occlusion matched with surgical procedures. Patients were selected if they had stenosis or occlusion of the basilar or intracranial vertebral arteries identified on vascular imaging before undergoing surgical procedures under general anesthesia. Clinical and radiographic features were reviewed, along with the nature of the surgeries and details of the perioperative management. Records were reviewed for the diagnosis of stroke occurring within 1 month of surgery. Results— Thirty-eight patients with a history of symptomatic vertebrobasilar ischemia underwent 50 operations under general anesthesia, and 3 had ischemic strokes in the vertebrobasilar territory immediately after surgery, a per-procedure rate of 6.0% (95% confidence interval, 1.2 to 16.6) All 3 had episodes of prolonged hypotension (systolic blood pressure <100 mm Hg for >10 minutes) during surgery. Conclusions— The risk of perioperative stroke in patients with vertebrobasilar stenosis undergoing surgery under general anesthesia is 6.0%, which is notably higher than the risk for patients with other patterns of cerebrovascular disease.

Clinical Worsening in Reversible Cerebral Vasoconstriction Syndrome

IMPORTANCE Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches and evidence of vasoconstriction with subsequent resolution. The clinical course of RCVS is traditionally considered monophasic and benign. However, recurrent episodes of focal neurological symptoms have been described after initial presentation. OBJECTIVE To define the frequency, timing, and consequences of clinical worsening in patients with diagnosis of RCVS. DESIGN, SETTING, AND PARTICIPANTS Retrospective observational study of consecutive patients with RCVS at 2 referral institutions for neurological disease. MAIN OUTCOME AND MEASURE Clinical worsening after diagnosis of RCVS. We defined clinical worsening as new permanent or transient neurological deficits (compared with presenting signs and symptoms) or new onset of seizures. We performed a logistic regression analysis to assess associations between patient characteristics and clinical worsening. Functional outcome was assessed at 1 to 3 months using the modified Rankin score. RESULTS We identified 59 patients (median age, 47 years; interquartile range, 32-54 years) with RCVS. Twenty patients (34%) experienced clinical worsening after a median of 2.5 days (range, several hours to 14 days). Eight of the 20 patients who worsened had permanent deficits, including 4 who died. We did not find an association between age, sex, smoking, migraine, acute or chronic hypertension, peripartum state, or use of serotonergic drugs with clinical worsening. Clinical worsening was associated with radiological infarction (P = .001) and worse functional outcome (P < .004). Functional outcome was favorable (modified Rankin score 0-2) in 51 patients (86.4%). CONCLUSIONS AND RELEVANCE Clinical worsening after diagnosis is common in patients with RCVS. Thus, RCVS is self-limited but not strictly monophasic. Most patients have a very favorable outcome, but clinical worsening may result in permanent deficits.

Fulminant postpartum cerebral vasoconstriction syndrome.

OBJECTIVE To raise awareness of the potentially adverse consequences of postpartum cerebral vasoconstriction, which is typically considered benign and self-limiting, by describing 4 fulminantly fatal cases. DESIGN Retrospective case series. SETTING Tertiary referral center. PATIENTS Four postpartum women aged 15 to 33 years developed acute neurologic deficits 1 to 8 days after uncomplicated deliveries. One had a history of migraine headaches and 2 had histories of spontaneous abortion. Two of the patients had uneventful pregnancies and 2 had preeclampsia, 1 of whom had acute hepatic failure. Presenting symptoms included severe headache (n=3), focal deficit (n=1), seizure (n=1), and encephalopathy (n=1). Initial brain imaging results demonstrated cortical ischemia and global edema in 2 patients, lobar hemorrhage in 1, and normal findings in 1. All had rapid clinical deterioration from hours to days with multiterritorial infarctions and global brain edema on imaging. All had angiographic findings of diffuse, severe, segmental multifocal arterial narrowings. INTERVENTIONS Aggressive treatment was attempted with most patients including intravenous magnesium sulfate, corticosteroids, calcium channel blockers, balloon angioplasty, vasopressors, and osmotic agents. Two patients underwent serial angiography, with results showing severe, recurrent proximal vasoconstriction involving all major intracranial vessels. RESULTS All patients had fulminant, accelerating courses leading to their deaths within 8 to 24 days after delivery. CONCLUSIONS Postpartum vasoconstriction can be fatal, with rapid progression of vasoconstriction, ischemia, and brain edema. Clinicians need to be aware of the potential consequences of this condition. Postpartum women with acute neurologic symptoms require prompt investigation with noninvasive cerebrovascular imaging and close monitoring for possible secondary deterioration.