Christopher J. Earley

PREGNANCY AND THE RISK OF STROKE

BACKGROUND It is widely believed that pregnancy increases the risk of stroke, but there are few data available to quantify that risk. METHODS We identified all female patients 15 through 44 years of age in central Maryland and Washington, D.C., who were discharged from any of 46 hospitals in the study area in 1988 or 1991. Two neurologists reviewed each case, using data from the womens medical records. We determined whether the women had been pregnant at the time of the stroke or up to six weeks before it occurred. For purposes of this analysis, the six-week period after pregnancy could begin with an induced or spontaneous abortion or with the delivery of a live or stillborn child. RESULTS Seventeen cerebral infarctions and 14 intracerebral hemorrhages occurred in women who were or had recently been pregnant (pregnancy-related strokes), and there were 175 cerebral infarctions and 48 intracerebral hemorrhages that were not related to pregnancy. For cerebral infarction, the relative risk during pregnancy, adjusted age and race, was 0.7 (95 percent confidence interval, 0.3 to 1.6), but it increased to 8.7 for the postpartum period (after a live birth or stillbirth) (95 percent confidence interval, 4.6 to 16.7). For intracerebral hemorrhage, the adjusted relative risk was 2.5 during pregnancy (95 percent confidence interval, 1.0 to 6.4) but 28.3 for the postpartum period (95 percent confidence interval, 13.0 to 61.4). Overall, for either type of stroke during or within six weeks after pregnancy, the adjusted relative risk was 2.4 (95 percent confidence interval, 1.6 to 3.6), and the attributable, or excess, risk was 8.1 strokes per 100,000 pregnancies (95 percent confidence interval, 6.4 to 9.7). CONCLUSIONS The risks of both cerebral infarction and intracerebral hemorrhage are increased in the six weeks after delivery but not during pregnancy itself.

Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome

Article abstract CSF and serum were obtained from 16 patients with idiopathic restless legs syndrome (RLS) and 8 age-matched healthy control subjects. Patients with RLS had lower CSF ferritin levels (1.11 ± 0.25 ng/mL versus 3.50 ± 0.55 ng/mL; p = 0.0002) and higher CSF transferrin levels (26.4 ± 5.1 mg/L versus 6.71 ± 1.6 mg/L; p = 0.018) compared with control subjects. There was no difference in serum ferritin and transferrin levels between groups. The presence of reduced ferritin and elevated transferrin levels in CSF is indicative of low brain iron in patients with idiopathic RLS.

MRI measurement of brain iron in patients with restless legs syndrome

Brain iron insufficiency in the restless legs syndrome (RLS) has been suggested by a prior CSF study. Using a special MRI measurement (R2′), the authors assessed regional brain iron concentrations in 10 subjects (five with RLS, five controls). R2′ was significantly decreased in the substantia nigra, and somewhat less significantly in the putamen, both in proportion to RLS severity. The results show the potential utility of this MRI measurement, and also indicate that brain iron insufficiency may occur in patients with RLS in some brain regions.

Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome

Objective: To assess neuropathology in individuals with restless legs syndrome (RLS). Methods: A standard neuropathologic evaluation was performed on seven brains from individuals who had been diagnosed with RLS. The substantia nigra was examined in greater detail for iron staining and with immunohistochemistry for tyrosine hydroxylase and proteins involved in iron management. Five age-matched individuals with no neurologic history served as controls. Results: There were no histopathologic abnormalities unique to the RLS brains. Tyrosine hydroxylase staining in the major dopaminergic regions appeared normal in the RLS brains. Iron staining and H-ferritin staining was markedly decreased in the RLS substantia nigra. Although H-ferritin was minimally detected in the RLS brain, L-ferritin staining was strong. However, the cells staining for L-ferritin in RLS brains were morphologically distinct from those in the control brains. Transferrin receptor staining on neuromelanin-containing cells was decreased in the RLS brains compared to normal, whereas transferrin staining in these cells was increased. Conclusions: RLS may not be rooted in pathologies associated with traditional neurodegenerative processes but may be a functional disorder resulting from impaired iron acquisition by the neuromelanin cells in RLS. The underlying mechanism may be a defect in regulation of the transferrin receptors.

Restless legs syndrome: a review of clinical and pathophysiologic features.

Summary Restlesslegs syndrome (RLS), although long ignored and still much underdiagnosed,disrupts the life and sleep considerably of those who have it. Recent clinicaland basic research provides for better definition and pathophysiologicunderstanding of the disorder. The body of knowledge about this disorder hasbeen expanding rapidly during the past decade and it has altered our conceptsof this disorder. This review of RLS covers history, diagnosis, morbidity ofsleep disturbance, relation to periodic limb movements in both sleep andwaking, secondary causes, severity assessment methods, phenotypes for possiblegenetic patterns, epidemiology, pathophysiology, and medical treatmentconsiderations. The emphasis on pathophysiology includes consideration ofcentral nervous system localization, neurotransmitter and other systemsinvolved, and the role of iron metabolism. Studies to date support theauthors’ recently advanced iron–dopamine model ofRLS.

Increased Carotid Artery Intimal-Medial Thickness in Asymptomatic Older Subjects With Exercise-Induced Myocardial Ischemia

BACKGROUND Previous studies have shown an association between symptomatic coronary artery disease (CAD) and increased intimal-medial thickness of the common carotid artery (CCA IMT), a purported index of atherosclerosis. This study determines whether CCA IMT is increased in asymptomatic older subjects with an ischemic ST-segment response to treadmill exercise. METHODS AND RESULTS CCA IMT was measured by B-mode ultrasound in community-dwelling volunteers from the Baltimore Longitudinal Study of Aging, including 397 healthy subjects (age, 58.5+/-15.8 years) with normal ECG responses to maximum treadmill exercise, 72 asymptomatic subjects (age, 66.1+/-13.4 years) with exercise-induced horizontal or downsloping ST-segment depression >/=1 mm, and 38 subjects (age, 77. 4+/-7.8 years) with clinically manifest CAD as diagnosed by medical history and resting ECG. Forty-three subjects with abnormal exercise ECGs also underwent exercise thallium scintigraphy. Exercise-induced ST-segment depression was associated with increased IMT (P<0.0001) independent of age and manifest CAD. After adjustment for age, IMT values progressively increased from healthy subjects to asymptomatic subjects with positive exercise ECG alone to those with concordant positive ECG and thallium scintigraphic findings who had virtually identical IMT to subjects with manifest CAD. Each 0.1-mm increase in IMT was associated with a 1.91-fold (95% CI, 1.46 to 2.50; P<0.0001) increased risk for concordant positive exercise tests or manifest CAD, independent of other significant predictors of CAD. CONCLUSIONS CCA IMT is increased in older subjects with asymptomatic myocardial ischemia as evidenced by exercise ECG alone or in combination with thallium scan. Carotid ultrasound may help to identify asymptomatic individuals with CAD.

Cerebral infarction in young adults The Baltimore-Washington Cooperative Young Stroke Study

Background: Few reports on stroke in young adults have included cases from all community and referral hospitals in a defined geographic region. Methods: At 46 hospitals in Baltimore City, 5 central Maryland counties, and Washington, DC, the chart of every patient 15 to 44 years of age with a primary or secondary diagnosis of possible cerebral arterial infarction during 1988 and 1991 was abstracted. Probable and possible etiologies were assigned following written guidelines. Results: Of 428 first strokes, 212 (49.5%) were assigned at least one probable cause, 80 (18.7%) had no probable cause but at least one possible cause, and 136 (31.8%) had no identified probable or possible cause. Of the 212 with at least one probable cause, the distribution of etiologies was cardiac embolism(31.1%), hematologic and other (19.8%), small vessel (lacunar) disease(19.8%), nonatherosclerotic vasculopathy (11.3%), illicit drug use (9.4%), oral contraceptive use (5.2%), large artery atherosclerotic disease (3.8%), and migraine (1.4%). There were an additional 69 recurrent stroke patients. Conclusions: In this hospital-based registry within a region characterized by racial/ethnic diversity, cardiac embolism, hematologic and other causes, and lacunar stroke were the most common etiologies of cerebral infarction in young adults. Nearly a third of both first and recurrent strokes had no identified cause.

The role of iron in restless legs syndrome.

The impressive relief from restless legs syndrome (RLS) symptoms provided by levodopa treatment indicates RLS is caused by a dopaminergic abnormality. But similar and more lasting relief also occurs for iron treatment in some patients. Thus there are two major putative causes for RLS: CNS dopaminergic abnormality and CNS iron insufficiency. This article presents the data documenting that both peripheral and CNS iron insufficiency occur with RLS symptoms. Brain iron insufficiency is supported by independently replicated cerebrospinal fluid and brain imaging studies for patients without iron deficiency (ID) anemia. Autopsy studies and intravenous iron treatment further link brain iron insufficiency to RLS. The brain iron insufficiency in patients with RLS is now well established. In this article the data are reviewed that support the following postulates combining dopaminergic and iron causes of RLS: (1) All conditions that compromise iron availability will increase the risk of RLS leading to a higher than expected prevalence of RLS in these conditions. (2) Some patients with RLS have marginal CNS iron status that can become insufficient when deprived of normal access to adequate peripheral iron or may be insufficient even with normal access to adequate peripheral iron. (3) The change or reduced CNS iron status produces RLS symptoms largely through its effects on the dopaminergic system and the corollary to 3. (4) Dopaminergic system abnormalities producing RLS symptoms will be included in those produced by brain ID. Study of the iron model of RLS offers hope for developing new treatment approaches and perhaps methods to prevent or cure the disorder.

Stroke in children and sickle-cell disease Baltimore-Washington Cooperative Young Stroke Study

Background/Purpose: The Baltimore-Washington Cooperative Young Stroke Study is the largest biracial urban-suburban population-based study to examine the etiology of strokes in children. Methods: We identified all children aged 1 to 14 years discharged from all 46 hospitals in central Maryland and Washington, DC with a diagnosis of ischemic stroke and intracerebral hemorrhage in the years 1988 and 1991. Each medical record was reviewed by two neurologists for appropriateness of the diagnosis of stroke and for information on the patients history, clinical presentation, pertinent investigations, hospital stay, and outcome at time of discharge. Results: Eighteen children with ischemic infarction and 17 with intracerebral hemorrhage were identified. The most common cause of ischemic stroke was sickle-cell disease (39%), followed by vasculopathic (33%) and indeterminate(28%) causes. Causes of intracerebral hemorrhages were arteriovenous malformation (29%), hematologic (23%), vasculopathy (18%), surgical complication (12%), coagulopathy (6%), and indeterminate (12%). The overall incidence for childhood stroke was 1.29 per 100,000 per year, with ischemic stroke occurring at a rate of 0.58 per 100,000 and intracerebral hemorrhage occurring at a rate of 0.71 per 100,000. The incidence of stroke among children with sickle-cell disease was estimated to be 0.28% or 285 per 100,000 per year. Conclusion: Sickle-cell disease plays a disproportionately high role in childhood stroke when a biracial population is surveyed.

Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome.

Restless leg syndrome (RLS) is a sensorimotor disorder. Clinical studies have implicated the dopaminergic system in RLS, while others have suggested that it is associated with insufficient levels of brain iron. To date, alterations in brain iron status have been demonstrated but, despite suggestions from the clinical literature, there have been no consistent findings documenting a dopaminergic abnormality in RLS brain tissue. In this study, the substantia nigra and putamen were obtained at autopsy from individuals with primary RLS and a neurologically normal control group. A quantitative profile of the dopaminergic system was obtained. Additional assays were performed on a catecholaminergic cell line and animal models of iron deficiency. RLS tissue, compared with controls, showed a significant decrease in D2R in the putamen that correlated with severity of the RLS. RLS also showed significant increases in tyrosine hydroxylase (TH) in the substantia nigra, compared with the controls, but not in the putamen. Both TH and phosphorylated (active) TH were significantly increased in both the substantia nigra and putamen. There were no significant differences in either the putamen or nigra for dopamine receptor 1, dopamine transporters or for VMAT. Significant increases in TH and phosphorylated TH were also seen in both the animal and cell models of iron insufficiency similar to that from the RLS autopsy data. For the first time, a clear indication of dopamine pathology in RLS is revealed in this autopsy study. The results suggest cellular regulation of dopamine production that closely matches the data from cellular and animal iron insufficiency models. The results are consistent with the hypothesis that a primary iron insufficiency produces a dopaminergic abnormality characterized as an overly activated dopaminergic system as part of the RLS pathology.