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Strokes Associated With Cocaine Use
Chapter 4
Strokes Associated With Cocaine Use P. Bhattacharya1 and P. Kucab2 1
St. Joseph Mercy Oakland, Pontiac, MI, United States, 2Detroit Medical Center, Detroit, MI, United States
SUMMARY POINTS
LIST OF ABBREVIATIONS
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ATP CEC CSF CT ET hsCRP MCP-1 MRI PRES RANTES
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Cocaine is a relatively common cause of stroke in the young population. Cocaine can result in both ischemic and hemorrhagic strokes. Clinical presentation is determined by the location of the ischemic stroke. The severity and outcome of cocaine-associated stroke are not significantly different from noncocaine-associated strokes. The best established mechanism of ischemic stroke associated with cocaine is vasospasm. Vasospasm occurs as cocaine results in an adrenergic surge, disordered calcium magnesium homeostasis and endothelin release. Other mechanisms for ischemic stroke include endothelial dysfunction, premature atherosclerosis, cardiac embolism, and vasculitis. Cocaine cessation is the mainstay of secondary prevention of stroke. Cocaine-associated strokes can safely receive intravenous tPA.
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Vasospasm is one of the most well-studied mechanisms of stroke following cocaine use. Cocaine has adrenergic properties that result in spasm of vessels. Cocaine results in increased calcium levels within blood vessel smooth muscle cells. This promotes spasm. Cocaine results in release of endothelin, which is a potent constrictor of blood vessels. Medications that relax blood vessels, such as calcium channel blockers, are used to counter the effects of blood vessel spasm.
The Neuroscience of Cocaine. DOI: http://dx.doi.org/10.1016/B978-0-12-803750-8.00004-X © 2017 Elsevier Inc. All rights reserved.
RCVS SAH sCD40L SDF-1 sICAM tPA
adenosine triphosphate circulating endothelial cells cerebrospinal fluid computed tomography endothelin high-sensitivity C reactive protein monocyte chemotactic protein-1 magnetic resonance imaging posterior reversible encephalopathy syndrome regulated on activation normal T cells expressed and secreted reversible cerebral vasoconstriction syndrome subarachnoid hemorrhage soluble CD40 ligand stromal-derived factor-1 soluble intracellular adhesion molecule tissue plasminogen activator
4.1 INTRODUCTION Cocaine is a frequently used substance of abuse. The vascular effects of cocaine increase the risk of strokes. In this chapter, we will discuss the epidemiology of strokes among cocaine users. We will describe their clinical presentation and the pathophysiological mechanisms of vascular injury leading to stroke. Finally, we will discuss the general aspects of stroke treatment and secondary prevention; and specific management issues related to strokes associated with cocaine use.
4.2 EPIDEMIOLOGY The first report of stroke related to the use of cocaine was published in 1977 (Brust & Richter, 1977). We now know that cocaine abuse is a common risk factor for cerebrovascular
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PART | I General Aspects, Features of Ill Health and Setting the Scene
events. Of the various illicit drugs that elevate ischemic stroke risk, such as opiates (Brust & Richter, 1976), amphetamines (Rothrock et al., 1988), phencyclidine (Bessen, 1982), and marijuana; the increased risk with cocaine is the most well established (Treadwell & Robinson, 2007). About 0.1% of all inpatient hospitalizations are due to a cerebrovascular event temporally related to cocaine use (Levine et al., 1990). In a hospital-based study in San Francisco, of 214 young stroke patients, 34% were using drugs. The relative risk for stroke compared with nondrug-using patients was 6.5. If cocaine was used within 6 hours of the stroke, the relative risk increased to 49.4 (Kaku & Lowenstein, 1990). A population-based study of hospitalized patients in Texas found a twofold increase in both ischemic and hemorrhagic stroke among cocaine users (Westover et al., 2007). A case control study from California among young women with stroke reported an odds ratio of 7.0 if they used cocaine and/or amphetamine (Petitti et al., 1998). In a study of 116 young stroke patients, 9.5% were associated with drug use; nearly half were cocaine users (Sloan et al., 1991). Hospital-based studies have assessed the frequency of cocaine use among stroke patients (Table 4.1). In one series, 15.6% of patients who had a urine drug screen checked upon admission were positive for cocaine metabolites (Bhattacharya et al., 2011). In another large series of 1935 stroke patients, 14.4% of intracerebral hemorrhages and 14.4% of ischemic strokes were associated with drug use (Westover et al., 2007). In the BaltimoreWashington Cooperative Young stroke study, among 18 44-year-old subjects, the use of illicit drugs was the fifth leading cause (9%) of stroke (Kittner et al., 1998). There is no racial disparity with regards to cocaine use among stroke patients (Qureshi et al., 1995). Cocaine can result in ischemic and hemorrhagic strokes. In a multicenter case series, of 28 patients, 64% had ischemic strokes. The rest of the patients were divided between intracerebral and subarachnoid hemorrhages (SAHs) (Levine et al., 1990). In another series of 54 patients over 6 years, who presented with acute
neurological deficits or headache following the use of cocaine, there were equal numbers of ischemic and hemorrhagic stroke (Daras et al., 1994). In one study of 3712 drug users, 0.4% were identified as having had a stroke, 54% of the events were ischemic stroke, 23% were SAH, and 23% were intracerebral hemorrhage (Jacobs et al., 1989). There was an increase in the use of substances (smoking, alcohol, and street drugs) from 45% in 1993 to 62% in 2005 (de los Rios et al., 2012). The proportion of patients with substance use within 24 hours prior to the stroke also increased (de los Rios et al., 2012). When patients actually have urine drug testing performed, the proportion with drugs in their system is higher than going by self-report (de los Rios et al., 2012). Therefore increasing detection of drugs among young stroke patients over time may be due to higher rates of testing or higher rates of documentation over time (de los Rios et al., 2012). In one large study, patients were more likely to be tested for cocaine if they were black or young (Silver et al., 2013). Rupture of intracranial aneurysms leading to SAH is a potentially fatal cause of stroke. In one series, about onethird of cases of aneurysmal SAH have reported recent cocaine use (Howington et al., 2003). In another large series of 1134 aneurysmal SAH patients, 142 (12.5%) had a history of recent cocaine use (Chang et al., 2013). Aneurysm rerupture rates are higher among cocaine users (Chang et al., 2013).
4.3 CLINICAL FEATURES Cocaine use can present with symptoms of cerebral ischemia, due to decrease in blood supply within an area of the brain; intracerebral hemorrhage due to rupture of a blood vessel within the brain; or SAH due to rupture of an aneurysm in a blood vessel on the surface of the brain. The onset of neurological symptoms is typically around the time of use of cocaine or within the first 3 hours after use (Treadwell & Robinson, 2007).
TABLE 4.1 Proportion of Strokes Attributed to Cocaine Use in Different Studies From Literature Study
Type of Population
Proportion Attributed to Cocaine
Bhattacharya et al. (2011)
Ischemic strokes
15.6%
Westover et al. (2007)
Ischemic strokes
14.4%
Hemorrhagic strokes
14.4%
Baltimore-Washington Cooperative Young stroke study (Kittner et al., 1998)
Young strokes
9.0%
Sloan et al. (1991)
Young strokes
9.5% had drug use; about half were cocaine
Strokes Associated With Cocaine Use Chapter | 4
Certain demographic groups have a higher incidence of cocaine-associated strokes. Cocaine-associated stroke patients were more likely to be younger and male (Bhattacharya et al., 2011). They were also more likely to be smokers, and less diabetics. Prevalence of other stroke risk-related comorbid conditions were similar between cocaine users and nonusers (Bhattacharya et al., 2011). A large proportion (73% in one study) may have no prior cardiovascular risk factors (Daras et al., 1991). The clinical features of cerebral ischemia depend on the location of the infarction. Ischemic strokes have been reported in the anterior and posterior circulations. Retinal and spinal cord infarcts are also described (Devenyi et al., 1988; Sawaya & Kaminski, 1990). The symptoms of cerebral ischemia may be transient, presenting as a transient ischemic attack. Involvement of the left hemisphere may present with right-sided paralysis and numbness, difficulty with forming speech and inability to comprehend. Strokes affecting the right hemisphere may result in left-sided paralysis and numbness and patients may not attend the paralyzed half of the body. If the stroke affects the posterior circulation, the patient may develop changes in their coordination, vision, swallowing, and speech, and may get confused, drowsy, and stuporous (Daras et al., 1991). The majority of the reports of cocaine-related stroke involve the anterior circulation. However, reports of basilar artery thrombosis following cocaine use are available (Vallee et al., 2003). About a quarter of patients monitored during their hospitalization developed some form of arrhythmia (Bhattacharya et al., 2011), such as sinus bradycardia or tachycardia, sick sinus syndrome, atrial and ventricular premature contractions, supraventricular tachycardia, atrial flutter, and fibrillation (Bhattacharya et al., 2011).
Compared with patients without cocaine in their urine, those who were cocaine positive have similar severity, mechanisms, and outcomes (as measured by the discharge destination) (Bhattacharya et al., 2011; Silver et al., 2013) (see Fig. 4.1). Intracranial hemorrhages secondary to cocaine use can be intracerebral, SAH, or intraventricular in location (Kibayashi et al., 1995; Nolte et al., 1996). The presentation is not different from intracerebral hemorrhage due to other causes such as hypertension. Typical cases have acute onset of headache, paralysis, speech problems and depending on the size of the hemorrhage, there may be alteration of consciousness. A CT scan of the head will distinguish whether the paralysis is due to cerebral ischemia or an intracerebral hemorrhage. The classic presentation of SAH is a thunderclap headache described as the worst headache in the patient’s life. For a significant proportion of patients, the bleeding is so severe that death may occur even before arrival at the hospital. The clinical course of SAH can be complicated by vasospasm within the first few days of illness, resulting in delayed cerebral ischemia, which can be potentially disabling. The presentation on admission with aneurysmal SAH is similar to those without cocaine with regards to severity of clinical features. In-hospital mortality was significantly higher among those with cocaine use (26% vs 17%) (Chang et al., 2013). In an adjusted analysis, cocaine use was an independent predictor of mortality (2.9 times the odds compared to nonusers). The only other predictors in this study were age and severity of clinical presentation. In a series of 150 patients with SAH, the authors found a fivefold increased risk of high-grade SAH among cocaineassociated SAHs compared to those that were not associated with cocaine (Howington et al., 2003). In another
FIGURE 4.1 Comparison of modified Rankin scores (mRS) among cocaine users and nonusers at discharge from hospital (Bhattacharya, Taraman et al., 2011). There were no significant differences. Distribution of mRS among cocaine (n 5 41) and noncocaine (n 5 221) related strokes.
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PART | I General Aspects, Features of Ill Health and Setting the Scene
series, patients with SAH may have an increased prevalence of vasospasm with recent cocaine exposure (Conway & Tamargo, 2001). On cardiac evaluations, there is an increased risk of regional wall motion abnormalities in patients with SAH who have used cocaine. This might explain some of the poorer outcome among patients with cocaine and SAH (Kothavale et al., 2006).
4.4 PATHOPHYSIOLOGY There are a number of mechanisms through which cocaine results in cerebral ischemia (Table 4.2). Some mechanisms have extensive research, whereas other mechanisms are based on isolated case reports.
4.4.1 Vasospasm Several lines of evidence demonstrate vasospasm as a mechanism following cocaine use. Chronic intracisternal injection of cocaine produced angiographic vasoconstriction of the rabbit basilar artery, which could be reversed if cocaine was coinfused with an endothelin A and B receptor antagonist: PD145065 (Fandino et al., 2003). Infusions of cocaine resulted in spasm of the basilar artery in a proportion of the rabbits (Wang et al., 1990). An autopsy study on a patient’s brain after a cocaineassociated stroke demonstrated narrowing of intradural blood vessels without inflammation (Konzen et al., 1995). There are various proposed mechanisms of vasospasm secondary to cocaine.
TABLE 4.2 Mechanisms of Ischemic Stroke Among Patients Using Cocaine Vasospasm G Proadrenergic effects of cocaine G Disorder of calcium magnesium homeostasis G Elevation of endothelin levels Platelet activation Endothelial dysfunction Premature atherogenesis Apoptosis of cerebral vascular smooth muscle cells Vasculitis Cardiac embolism G Thromboembolism G Infective endocarditis Hypercoagulability Autoregulatory failure G Posterior reversible encephalopathy syndrome (PRES) G Reversible cerebral vasoconstriction syndrome (RCVS) Embolization of injected contaminants
1. The proadrenergic mechanism: Cocaine exerts sympathomimetic effects by preventing the uptake of norepinephrine, serotonin, and dopamine at presynaptic nerve terminals. This leads to vasoconstriction. Destruction of adrenergic nerve endings in cats, using 6-hydroxydopamine reversed the cocaine-mediated constriction (Madden et al., 1995). Yet administration of phentolamine, an alpha-1 and -2 adrenergic antagonist did not reverse cocaine-mediated vasoconstriction, suggesting additional mechanisms. Also, other drugs that inhibit norepinephrine uptake, such as tricyclic antidepressants, are not associated with cerebrovascular accidents (Havranek et al., 1996). 2. Disorder of calcium magnesium homeostasis: Pretreatment with diltiazem, a calcium channel blocker, will block cocaine-mediated vasospasm (Isner & Chokshi, 1989). Magnesium is a naturally occurring calcium antagonist. It gates the release of intracellular calcium in vascular smooth muscle cells, and promotes relaxation, contrary to calcium which promotes vascular smooth muscle contraction and thereby vasoconstriction. In situ studies on the rat brain show that perfusion of the cerebral microcirculation with CSF depleted in extracellular magnesium results in rapid and progressive spasm followed by rupture of venules and capillaries. This results in formation of focal hemorrhages and brain edema (Altura & Gupta, 1992). Various experiments have studied the effects of cocaine exposure on magnesium homeostasis. Exposure of cultured canine cerebral vascular smooth muscle cells to cocaine decreases the intracellular magnesium within seconds. This contributes to intracellular calcium increase (Zhang et al., 1996). Wistar rats injected intravenously with cocaine showed a dramatic decrease in the magnesium levels down to over 50% within about 10 minutes of injection (Altura & Gupta, 1992). There was a decrease in intracellular pH and ATP production indicating intracellular acidosis and energy failure (Altura & Gupta, 1992). When cocaine was applied to canine cerebral vascular smooth muscle cells, there was a significant increase in the intracellular calcium levels, released from the sarcoplasmic reticulum (Zhang et al., 1996). Smooth muscle cells from cerebral arteries in male mongrel dogs were superfused with progressively increasing concentrations of cocaine. Intracellular calcium levels rose significantly even with the smallest concentration of cocaine, within the first minute (Zhang et al., 1996), and continued to rise up to 5 minutes. When the cells were washed with cocaine free solution, the calcium levels reduced, but did not return to baseline levels up to 30 minutes after exposure (Zhang et al., 1996).
Strokes Associated With Cocaine Use Chapter | 4
3. Endothelin-based mechanisms: Endothelin (ET), a potent vasoconstrictor, is increased following cocaine use. First, in cultures of pig, bovine, and human endothelial cells, application of cocaine increased ET-1 release (Hendricks-Munoz et al., 1996; WilbertLampen et al., 1998). Second, cocaine-abusing mothers have elevated plasma levels of ET-1 (Samuels et al., 1993). Third, cocaine-intoxicated patients show elevated plasma and urine levels of ET-1 (Fandino et al., 2003). Suffusion of rabbit basilar artery with cocaine resulted in progressive vasoconstriction that plateaued for 2 hours after stopping suffusion (Yoon et al., 2007). When the artery was suffused with PD145065, an endothelin A and B receptor antagonist, the constriction reversed, and the artery dilated to a caliber greater than baseline, before cocaine suffusion (Yoon et al., 2007). In another human study, chronic cocaine users had elevated ET-1 levels. After 4 weeks of abstention, the levels came back to normal, at par with controls (Saez et al., 2011). Levels of other endothelial markers such as SDF-1 (stromal-derived factor-1), sICAM (soluble intracellular adhesion molecule), and hsCRP (high-sensitivity C reactive protein) were elevated initially and reverted to control levels after 4 weeks of abstention (Saez et al., 2011). The endothelin release following cocaine use is mediated by endothelial sigma receptors that are activated by cocaine. Activated sigma receptors release ET-1 causing vasoconstriction. Sigma receptor antagonists will prevent ET-1 release (Wilbert-Lampen et al., 1998).
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2011). Moreover, patients with longer duration of exposure and higher intake of cocaine had higher levels of sCD40L, suggesting a higher degree of activation with prolonged exposure.
4.4.3 Endothelial Dysfunction From Chronic Cocaine Use Chronic cocaine users had significantly lower rises in the forearm blood flow in response to infusions of nitroprusside and acetylcholine using forearm plethysmography. Intracoronary infusion of acetylcholine in these subjects showed vasoconstriction of the coronaries instead of the normal response of dilatation. Following intranasal cocaine administration, coronary vasoconstriction is greater in diseased segments. This suggests that there may be focal areas of endothelial dysfunction with loss of nitric oxide due to cocaine (Flores et al., 1990). These experiments indicate impairment of endothelium-dependent vasorelaxation following cocaine (Havranek et al., 1996). Dysfunctional endothelium is prothrombotic. Repeated cocaine use has toxic effects on the endothelial cells, resulting in repeated cycles of cell loss followed by proliferation; which makes the endothelium unable to respond to G protein-mediated releasing agents for nitric oxide (Havranek et al., 1996). Secondly, the ratio of thromboxane B2 to prostaglandin F1alpha is increased after cocaine (Eichhorn et al., 1992). This altered ratio creates a thrombotic state.
4.4.2 Cocaine-Induced Platelet Activation
4.4.4 Premature Atherogenesis Among Chronic Cocaine Users
Platelet-rich thrombi were first discovered in coronary vessels in myocardial infarction following cocaine use (Kolodgie et al., 1991). Pathology studies of thrombectomy specimens in acute cocaine-associated stroke showed a bland thrombus, which suggests platelet dysfunction (Konzen et al., 1995). Fourteen healthy cocaine-naı¨ve volunteers received cocaine intranasally and saline placebo. Following cocaine inhalation, bleeding time decreased and there was an increase in platelet microaggregates. Levels of platelet factor 4 and beta thromboglobulin were also increased. Thus acute cocaine exposure results in platelet activation (Heesch et al., 2000). Baseline blood and samples after 4 weeks of abstinence were evaluated in 23 chronic cocaine abusers admitted to a rehabilitation facility (Pereira et al., 2011). There were higher monocyte platelet aggregates than controls, which reduced to control levels after 4 weeks of abstinence. Similarly, levels of soluble CD40 ligand (sCD40L), a marker of activated platelets, were elevated initially and reduced to control levels (Pereira et al.,
In blood samples from 23 chronic cocaine users, RANTES (regulated on activation normal T cells expressed and secreted) was elevated; a chemokine that recruits leukocytes into areas of inflammation in the endothelium, leading to premature atherosclerosis (Pereira et al., 2011). Further, chronically activated platelets release elastase that causes degradation of arterial elastic tissue, a precursor to atherogenesis (Heesch et al., 2000). In chronic cocaine abusers, levels of circulating endothelial cells (CEC) were markedly elevated. After 4 weeks of abstention, the levels had reduced but were still significantly elevated compared to controls. CECs are a marker of endothelial injury. The persistent elevation of CECs after the short period of abstention suggests that the effects on vascular endothelial injury are more sustained in chronic cocaine users. Such endothelial injury initiates atherosclerosis, often in the absence of traditional cardiovascular risk factors. In this study, the levels of MCP-1 (monocyte chemotactic protein-1), an endothelial marker,
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PART | I General Aspects, Features of Ill Health and Setting the Scene
were significantly elevated among chronic cocaine users and did not return to normal after 4 weeks of cocaine abstention. MCP-1 is responsible for mononuclear infiltration; another important step in atherogenesis (Saez et al., 2011). SDF-1 works to attract endothelial progenitor cells to enable endothelial repair following injury. The return of SDF-1 to normal in the face of persistently elevated CECs and MCP-1 suggest that the body’s repair response to endothelial injury following cocaine use is inadequate (Saez et al., 2011).
4.4.5 Cocaine-Induced Apoptosis of Cerebral Vascular Smooth Muscle Cells Smooth muscle cells from the basilar arteries of dogs were treated with cocaine in increasing concentrations. Morphological features of apoptosis such as nuclear fragmentation and condensation of chromatin were examined (Su et al., 2003). Cells cultured with cocaine had a higher death rate than controls. The percentage of apoptotic cells was also increased in cocaine-treated samples, and the proportion of these cells varied depending on the dose of cocaine and the time of exposure (Su et al., 2003). Cocaine-mediated apoptosis is believed to be set off by the rapid rise in intracellular calcium that occurs within minutes of cocaine exposure. The pathway from the onset of apoptosis to the occurrence of vascular thrombosis is also unclear. However, it is thought to contribute to the rupture of plaques (Su et al., 2003).
Cocaine can induce a cardiomyopathy and an intracavitary thrombus (Petty et al., 1990). Finally, strokes can occur from septic emboli from infective endocarditis in intravenous drug users (Brown et al., 1992).
4.4.8 Other Mechanisms 1. Cocaine can induce a hypercoagulability related to a depletion of antithrombin III and protein C (Isner & Chokshi, 1989). 2. The adrenergic surge induced by cocaine can result in a hypertensive crisis. This can cause an alteration of cerebral autoregulation (Treadwell & Robinson, 2007): reversible cerebral vasoconstriction syndrome (RCVS) or posterior reversible encephalopathy syndrome (PRES), both of which can result in ischemic stroke. 3. Impurities such as talc or sugar in street cocaine when injected intravenously, may embolize to the cerebrovascular system (Brown et al., 1992). Use of adulterants such as procainamide, quinidine, and antihistamine may also have toxic effects (Treadwell & Robinson, 2007). 4. Cocaine is implicated in causing a moyamoya-like vasculopathy resulting in bilateral strokes (Schwartz & Scott, 1998).
Concentric enhancement of the middle cerebral artery, demonstrated on MRI studies in the setting of cocaine use, suggests vasculitis as a possible mechanism; although the speculation is mainly due to extrapolation of similar enhancement noted in other vasculitis, such as giant cell arteritis or cerebral vasculitis (Han et al., 2008). Biopsyproven vasculitis with cocaine use is a rare event but case reports are described (Krendel et al., 1990; Levine et al., 1990; Fredericks et al., 1991; Merkel et al., 1995; Morrow & McQuillen, 1993).
There has not been much systematic research into the mechanisms by which cocaine results in intracerebral or SAH. Presumably, the adrenergic surge that follows cocaine use results in rupture of microscopic Charcot Bouchard aneurysms in small blood vessels in the depths of the brain resulting in intracerebral hemorrhage (Brown et al., 1992). Alternatively, ischemic infarction may result in hemorrhagic conversion within ischemic areas (Brown et al., 1992). Finally, septic emboli from infective endocarditis can result in mycotic aneurysm resulting in intracerebral hemorrhage (Esse et al., 2011). For SAH, the acute elevation of blood pressure that occurs minutes within ingestion of cocaine results in rupture of a preexisting vascular lesion (Brown et al., 1992). Reversible cerebral vasoconstriction, a recently described arteriopathy, can occur with cocaine and result in SAH.
4.4.7 Cardiac Embolism
4.5 TREATMENT
Cocaine results in cardiac embolism through many mechanisms. Cocaine-associated strokes are often associated with cardiac arrhythmias, that can result in formation of intracavitary thrombi. Cocaine can result in cardiac ischemia, which can result in partial or global ventricular wall abnormality, which can potentiate the development of a cardiac thrombus (Alqahtani et al., 2015). Similarly, cocaine can result in myocardial infarction, which can be complicated by thromboembolism (Brown et al., 1992).
Treatment of ischemic stroke following cocaine use is not much different from the routine treatment of ischemic stroke. Within the first 4.5 hours after the onset of symptoms, patients should be considered for administration of thrombolytics in order to limit disability in the long term. The concern with giving tPA is that cocaine use may be associated with surges in blood pressure which may increase the risk of intracerebral hemorrhage (MartinSchild et al., 2009). In a large series of cocaine-associated
4.4.6 Vasculitis
Strokes Associated With Cocaine Use Chapter | 4
ischemic strokes, 33.3% received tPA. There were no hemorrhages. This is in spite of the fact that chronic cocaine users had an increased rate of preexisting intracranial small vessel disease (Martin-Schild et al., 2009). Patients with cocaine-associated strokes tended to get tPA if they had more severe strokes. The rate of home discharge or discharge to an inpatient rehabilitation unit was the same. The rate of favorable functional outcome at discharge was also similar to those not getting tPA (MartinSchild et al., 2009). Patients with cocaine-associated strokes who got tPA did not show large surges of blood pressure during close monitoring as anticipated (MartinSchild et al., 2009). The biggest intervention for secondary prevention is the cessation of cocaine abuse. Getting patients the appropriate help and referral to deaddiction centers is paramount. As with other ischemic strokes, whether or not the underlying blood vessels are abnormal, antiplatelet agents such as aspirin are mandatory. As noted in the pathophysiology section, platelet activation occurs during the acute phase of cocaine ingestion. This is the basis for the use of antiplatelet agents following ischemic stroke following cocaine use. Control of underlying vascular risk factors, such as hypertension and diabetes, is the next important intervention. For the treatment of hypertension, there may be some basis to choose calcium channel blockers. However this is based on experimental models rather than on realworld clinical data. As we understand the pathophysiology of cocaine-related strokes better, specific treatment strategies may evolve.
MINI-DICTIONARY OF TERMS G
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Ischemic stroke: The most common type of stroke that occurs due to blockage of blood supply to a part of the brain due to either narrowing of the blood vessel caliber or obstruction of the blood vessel by a blood clot. Intracerebral hemorrhage: Bleeding into the substance of the brain resulting in loss of function corresponding to that part of the brain. It is more disabling than ischemic stroke and can be fatal. Subarachnoid hemorrhage: Bleeding that occurs into the space surrounding the brain, usually from an aneurysm in one of the main blood vessels supplying the brain. Endothelium: Inner lining of the blood vessels that is very sensitive to stimuli that can cause dilatation or constriction of blood vessels as well as initiate plaque formation within vessels. Apoptosis: The process of programmed cell death that normally occurs as a genetically regulated process, but can be provoked by exposures to different stimuli.
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Vasculitis: Inflammation of the wall of the blood vessel that results in blockages of blood vessels, causing stroke. tPA (tissue plasminogen activator): This is a widely used medication to treat ischemic stroke within 4.5 hours of the start of symptoms. It works by dissolving the blood clot that blocks the blood vessel in a stroke.
REFERENCES Alqahtani, S. A., Burger, K., et al. (2015). Cocaine-induced acute fatal basilar artery thrombosis: Report of a case and review of the literature. American Journal of Case Reports, 16, 393 397. Altura, B. M., & Gupta, R. K. (1992). Cocaine induces intracellular free Mg deficits, ischemia and stroke as observed by in-vivo 31P-NMR of the brain. Biochimica et Biophysica Acta, 1111(2), 271 274. Bessen, H. A. (1982). Intracranial hemorrhage associated with phencyclidine abuse. JAMA, 248(5), 585 586. Bhattacharya, P., Taraman, S., et al. (2011). Clinical profiles, complications, and disability in cocaine-related ischemic stroke. The Journal of Stroke & Cerebrovascular Diseases, 20(5), 443 449. Brown, E., Prager, J., et al. (1992). CNS complications of cocaine abuse: Prevalence, pathophysiology, and neuroradiology. American Journal of Roentgenology, 159(1), 137 147. Brust, J. C., & Richter, R. W. (1976). Stroke associated with addiction to heroin. The Journal of Neurology, Neurosurgery, and Psychiatry, 39 (2), 194 199. Brust, J. C., & Richter, R. W. (1977). Stroke associated with cocaine abuse--? New York State Journal of Medicine, 77(9), 1473 1475. Chang, T. R., Kowalski, R. G., et al. (2013). Impact of acute cocaine use on aneurysmal subarachnoid hemorrhage. Stroke, 44(7), 1825 1829. Conway, J. E., & Tamargo, R. J. (2001). Cocaine use is an independent risk factor for cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Stroke, 32(10), 2338 2343. Daras, M., Tuchman, A. J., et al. (1991). Central nervous system infarction related to cocaine abuse. Stroke, 22(10), 1320 1325. Daras, M., Tuchman, A. J., et al. (1994). Neurovascular complications of cocaine. Acta Neurologica Scandinavica, 90(2), 124 129. de los Rios, F., Kleindorfer, D. O., et al. (2012). Trends in substance abuse preceding stroke among young adults: A population-based study. Stroke, 43(12), 3179 3183. Devenyi, P., Schneiderman, J. F., et al. (1988). Cocaine-induced central retinal artery occlusion. CMAJ, 138(2), 129 130. Eichhorn, E. J., Demian, S. E., et al. (1992). Cocaine-induced alterations in prostaglandin production in rabbit aorta. The Journal of the American College of Cardiology, 19(3), 696 703. Esse, K., Fossati-Bellani, M., et al. (2011). Epidemic of illicit drug use, mechanisms of action/addiction and stroke as a health hazard. Brain and Behavior, 1(1), 44 54. Fandino, J., Sherman, J. D., et al. (2003). Cocaine-induced endothelin-1dependent spasm in rabbit basilar artery in vivo. Journal of Cardiovascular Pharmacology, 41(2), 158 161. Flores, E. D., Lange, R. A., et al. (1990). Effect of cocaine on coronary artery dimensions in atherosclerotic coronary artery disease: Enhanced vasoconstriction at sites of significant stenoses. The Journal of the American College of Cardiology, 16(1), 74 79.
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Fredericks, R. K., Lefkowitz, D. S., et al. (1991). Cerebral vasculitis associated with cocaine abuse. Stroke, 22(11), 1437 1439. Han, J. S., Mandell, D. M., et al. (2008). BOLD-MRI cerebrovascular reactivity findings in cocaine-induced cerebral vasculitis. Nature Clinical Practice Neurology, 4(11), 628 632. Havranek, E. P., Nademanee, K., et al. (1996). Endothelium-dependent vasorelaxation is impaired in cocaine arteriopathy. The Journal of the American College of Cardiology, 28(5), 1168 1174. Heesch, C. M., Wilhelm, C. R., et al. (2000). Cocaine activates platelets and increases the formation of circulating platelet containing microaggregates in humans. Heart, 83(6), 688 695. Hendricks-Munoz, K. D., Gerrets, R. P., et al. (1996). Cocainestimulated endothelin-1 release is decreased by angiotensinconverting enzyme inhibitors in cultured endothelial cells. Cardiovascular Research, 31(1), 117 123. Howington, J. U., Kutz, S. C., et al. (2003). Cocaine use as a predictor of outcome in aneurysmal subarachnoid hemorrhage. Journal of Neurosurgery, 99(2), 271 275. Isner, J. M., & Chokshi, S. K. (1989). Cocaine and vasospasm. The New England Journal of Medicine, 321(23), 1604 1606. Jacobs, I. G., Roszler, M. H., et al. (1989). Cocaine abuse: Neurovascular complications. Radiology, 170(1 Pt 1), 223 227. Kaku, D. A., & Lowenstein, D. H. (1990). Emergence of recreational drug abuse as a major risk factor for stroke in young adults. Annals of Internal Medicine, 113(11), 821 827. Kibayashi, K., Mastri, A. R., et al. (1995). Cocaine induced intracerebral hemorrhage: Analysis of predisposing factors and mechanisms causing hemorrhagic strokes. Human Pathology, 26(6), 659 663. Kittner, S. J., Stern, B. J., et al. (1998). Cerebral infarction in young adults: The Baltimore-Washington Cooperative Young Stroke Study. Neurology, 50(4), 890 894. Kolodgie, F. D., Virmani, R., et al. (1991). Increase in atherosclerosis and adventitial mast cells in cocaine abusers: An alternative mechanism of cocaine-associated coronary vasospasm and thrombosis. The Journal of the American College of Cardiology, 17(7), 1553 1560. Konzen, J. P., Levine, S. R., et al. (1995). Vasospasm and thrombus formation as possible mechanisms of stroke related to alkaloidal cocaine. Stroke, 26(6), 1114 1118. Kothavale, A., Banki, N. M., et al. (2006). Predictors of left ventricular regional wall motion abnormalities after subarachnoid hemorrhage. Neurocritical Care, 4(3), 199 205. Krendel, D. A., Ditter, S. M., et al. (1990). Biopsy-proven cerebral vasculitis associated with cocaine abuse. Neurology, 40(7), 1092 1094. Levine, S. R., Brust, J. C., et al. (1990). Cerebrovascular complications of the use of the “crack” form of alkaloidal cocaine. The New England Journal of Medicine, 323(11), 699 704. Madden, J. A., Konkol, R. J., et al. (1995). Cocaine and benzoylecgonine constrict cerebral arteries by different mechanisms. Life Science, 56 (9), 679 686. Martin-Schild, S., Albright, K. C., et al. (2009). Intravenous tissue plasminogen activator in patients with cocaine-associated acute ischemic stroke. Stroke, 40(11), 3635 3637. Merkel, P. A., Koroshetz, W. J., et al. (1995). Cocaine-associated cerebral vasculitis. Seminars in Arthritis and Rheumatism, 25(3), 172 183. Morrow, P. L., & McQuillen, J. B. (1993). Cerebral vasculitis associated with cocaine abuse. Journal of Forensic Science, 38(3), 732 738.
Nolte, K. B., Brass, L. M., et al. (1996). Intracranial hemorrhage associated with cocaine abuse: A prospective autopsy study. Neurology, 46(5), 1291 1296. Pereira, J., Saez, C. G., et al. (2011). Platelet activation in chronic cocaine users: Effect of short term abstinence. Platelets, 22(8), 596 601. Petitti, D. B., Sidney, S., et al. (1998). Stroke and cocaine or amphetamine use. Epidemiology, 9(6), 596 600. Petty, G. W., Brust, J. C., et al. (1990). Embolic stroke after smoking “crack” cocaine. Stroke, 21(11), 1632 1635. Qureshi, A. I., Safdar, K., et al. (1995). Stroke in young black patients. Risk factors, subtypes, and prognosis. Stroke, 26(11), 1995 1998. Rothrock, J. F., Rubenstein, R., et al. (1988). Ischemic stroke associated with methamphetamine inhalation. Neurology, 38(4), 589 592. Saez, C. G., Olivares, P., et al. (2011). Increased number of circulating endothelial cells and plasma markers of endothelial damage in chronic cocaine users. Thrombosis Research, 128(4), e18 e23. Samuels, P., Steinfeld, J. D., et al. (1993). Plasma concentration of endothelin-1 in women with cocaine-associated pregnancy complications. American Journal of Obstetrics & Gynecology, 168(2), 528 533. Sawaya, G. R., & Kaminski, M. J. (1990). Spinal cord infarction after cocaine use. The Southern Medical Journal, 83(5), 601 602. Schwartz, M. S., & Scott, R. M. (1998). Moyamoya syndrome associated with cocaine abuse. Case report. Neurosurgical Focus, 5(5), e7. Silver, B., Miller, D., et al. (2013). Urine toxicology screening in an urban stroke and TIA population. Neurology, 80(18), 1702 1709. Sloan, M. A., Kittner, S. J., et al. (1991). Occurrence of stroke associated with use/abuse of drugs. Neurology, 41(9), 1358 1364. Su, J., Li, J., et al. (2003). Cocaine induces apoptosis in cerebral vascular muscle cells: Potential roles in strokes and brain damage. The European Journal of Pharmacology, 482(1 3), 61 66. Treadwell, S. D., & Robinson, T. G. (2007). Cocaine use and stroke. Postgraduate Medical Journal, 83(980), 389 394. Vallee, J. N., Crozier, S., et al. (2003). Acute basilar artery occlusion treated by thromboaspiration in a cocaine and ecstasy abuser. Neurology, 61(6), 839 841. Wang, A. M., Suojanen, J. N., et al. (1990). Cocaine- and methamphetamine-induced acute cerebral vasospasm: An angiographic study in rabbits. American Society of Neuroradiology, 11(6), 1141 1146. Westover, A. N., McBride, S., et al. (2007). Stroke in young adults who abuse amphetamines or cocaine: A population-based study of hospitalized patients. Archives of General Psychiatry, 64(4), 495 502. Wilbert-Lampen, U., Seliger, C., et al. (1998). Cocaine increases the endothelial release of immunoreactive endothelin and its concentrations in human plasma and urine: Reversal by coincubation with sigma-receptor antagonists. Circulation, 98(5), 385 390. Yoon, S. H., Zuccarello, M., et al. (2007). Acute cocaine induces endothelin-1-dependent constriction of rabbit basilar artery. Endothelium, 14(3), 137 139. Zhang, A., Cheng, T. P., et al. (1996). Acute cocaine results in rapid rises in intracellular free calcium concentration in canine cerebral vascular smooth muscle cells: Possible relation to etiology of stroke. Neuroscience Letters, 215(1), 57 59.
Strokes Associated With Cocaine Use P. Bhattacharya1 and P. Kucab2 1
St. Joseph Mercy Oakland, Pontiac, MI, United States, 2Detroit Medical Center, Detroit, MI, United States
SUMMARY POINTS
LIST OF ABBREVIATIONS
G
ATP CEC CSF CT ET hsCRP MCP-1 MRI PRES RANTES
G
G
G
G
G
Cocaine is a relatively common cause of stroke in the young population. Cocaine can result in both ischemic and hemorrhagic strokes. Clinical presentation is determined by the location of the ischemic stroke. The severity and outcome of cocaine-associated stroke are not significantly different from noncocaine-associated strokes. The best established mechanism of ischemic stroke associated with cocaine is vasospasm. Vasospasm occurs as cocaine results in an adrenergic surge, disordered calcium magnesium homeostasis and endothelin release. Other mechanisms for ischemic stroke include endothelial dysfunction, premature atherosclerosis, cardiac embolism, and vasculitis. Cocaine cessation is the mainstay of secondary prevention of stroke. Cocaine-associated strokes can safely receive intravenous tPA.
KEY FACTS G
G
G
G
G
Vasospasm is one of the most well-studied mechanisms of stroke following cocaine use. Cocaine has adrenergic properties that result in spasm of vessels. Cocaine results in increased calcium levels within blood vessel smooth muscle cells. This promotes spasm. Cocaine results in release of endothelin, which is a potent constrictor of blood vessels. Medications that relax blood vessels, such as calcium channel blockers, are used to counter the effects of blood vessel spasm.
The Neuroscience of Cocaine. DOI: http://dx.doi.org/10.1016/B978-0-12-803750-8.00004-X © 2017 Elsevier Inc. All rights reserved.
RCVS SAH sCD40L SDF-1 sICAM tPA
adenosine triphosphate circulating endothelial cells cerebrospinal fluid computed tomography endothelin high-sensitivity C reactive protein monocyte chemotactic protein-1 magnetic resonance imaging posterior reversible encephalopathy syndrome regulated on activation normal T cells expressed and secreted reversible cerebral vasoconstriction syndrome subarachnoid hemorrhage soluble CD40 ligand stromal-derived factor-1 soluble intracellular adhesion molecule tissue plasminogen activator
4.1 INTRODUCTION Cocaine is a frequently used substance of abuse. The vascular effects of cocaine increase the risk of strokes. In this chapter, we will discuss the epidemiology of strokes among cocaine users. We will describe their clinical presentation and the pathophysiological mechanisms of vascular injury leading to stroke. Finally, we will discuss the general aspects of stroke treatment and secondary prevention; and specific management issues related to strokes associated with cocaine use.
4.2 EPIDEMIOLOGY The first report of stroke related to the use of cocaine was published in 1977 (Brust & Richter, 1977). We now know that cocaine abuse is a common risk factor for cerebrovascular
31
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PART | I General Aspects, Features of Ill Health and Setting the Scene
events. Of the various illicit drugs that elevate ischemic stroke risk, such as opiates (Brust & Richter, 1976), amphetamines (Rothrock et al., 1988), phencyclidine (Bessen, 1982), and marijuana; the increased risk with cocaine is the most well established (Treadwell & Robinson, 2007). About 0.1% of all inpatient hospitalizations are due to a cerebrovascular event temporally related to cocaine use (Levine et al., 1990). In a hospital-based study in San Francisco, of 214 young stroke patients, 34% were using drugs. The relative risk for stroke compared with nondrug-using patients was 6.5. If cocaine was used within 6 hours of the stroke, the relative risk increased to 49.4 (Kaku & Lowenstein, 1990). A population-based study of hospitalized patients in Texas found a twofold increase in both ischemic and hemorrhagic stroke among cocaine users (Westover et al., 2007). A case control study from California among young women with stroke reported an odds ratio of 7.0 if they used cocaine and/or amphetamine (Petitti et al., 1998). In a study of 116 young stroke patients, 9.5% were associated with drug use; nearly half were cocaine users (Sloan et al., 1991). Hospital-based studies have assessed the frequency of cocaine use among stroke patients (Table 4.1). In one series, 15.6% of patients who had a urine drug screen checked upon admission were positive for cocaine metabolites (Bhattacharya et al., 2011). In another large series of 1935 stroke patients, 14.4% of intracerebral hemorrhages and 14.4% of ischemic strokes were associated with drug use (Westover et al., 2007). In the BaltimoreWashington Cooperative Young stroke study, among 18 44-year-old subjects, the use of illicit drugs was the fifth leading cause (9%) of stroke (Kittner et al., 1998). There is no racial disparity with regards to cocaine use among stroke patients (Qureshi et al., 1995). Cocaine can result in ischemic and hemorrhagic strokes. In a multicenter case series, of 28 patients, 64% had ischemic strokes. The rest of the patients were divided between intracerebral and subarachnoid hemorrhages (SAHs) (Levine et al., 1990). In another series of 54 patients over 6 years, who presented with acute
neurological deficits or headache following the use of cocaine, there were equal numbers of ischemic and hemorrhagic stroke (Daras et al., 1994). In one study of 3712 drug users, 0.4% were identified as having had a stroke, 54% of the events were ischemic stroke, 23% were SAH, and 23% were intracerebral hemorrhage (Jacobs et al., 1989). There was an increase in the use of substances (smoking, alcohol, and street drugs) from 45% in 1993 to 62% in 2005 (de los Rios et al., 2012). The proportion of patients with substance use within 24 hours prior to the stroke also increased (de los Rios et al., 2012). When patients actually have urine drug testing performed, the proportion with drugs in their system is higher than going by self-report (de los Rios et al., 2012). Therefore increasing detection of drugs among young stroke patients over time may be due to higher rates of testing or higher rates of documentation over time (de los Rios et al., 2012). In one large study, patients were more likely to be tested for cocaine if they were black or young (Silver et al., 2013). Rupture of intracranial aneurysms leading to SAH is a potentially fatal cause of stroke. In one series, about onethird of cases of aneurysmal SAH have reported recent cocaine use (Howington et al., 2003). In another large series of 1134 aneurysmal SAH patients, 142 (12.5%) had a history of recent cocaine use (Chang et al., 2013). Aneurysm rerupture rates are higher among cocaine users (Chang et al., 2013).
4.3 CLINICAL FEATURES Cocaine use can present with symptoms of cerebral ischemia, due to decrease in blood supply within an area of the brain; intracerebral hemorrhage due to rupture of a blood vessel within the brain; or SAH due to rupture of an aneurysm in a blood vessel on the surface of the brain. The onset of neurological symptoms is typically around the time of use of cocaine or within the first 3 hours after use (Treadwell & Robinson, 2007).
TABLE 4.1 Proportion of Strokes Attributed to Cocaine Use in Different Studies From Literature Study
Type of Population
Proportion Attributed to Cocaine
Bhattacharya et al. (2011)
Ischemic strokes
15.6%
Westover et al. (2007)
Ischemic strokes
14.4%
Hemorrhagic strokes
14.4%
Baltimore-Washington Cooperative Young stroke study (Kittner et al., 1998)
Young strokes
9.0%
Sloan et al. (1991)
Young strokes
9.5% had drug use; about half were cocaine
Strokes Associated With Cocaine Use Chapter | 4
Certain demographic groups have a higher incidence of cocaine-associated strokes. Cocaine-associated stroke patients were more likely to be younger and male (Bhattacharya et al., 2011). They were also more likely to be smokers, and less diabetics. Prevalence of other stroke risk-related comorbid conditions were similar between cocaine users and nonusers (Bhattacharya et al., 2011). A large proportion (73% in one study) may have no prior cardiovascular risk factors (Daras et al., 1991). The clinical features of cerebral ischemia depend on the location of the infarction. Ischemic strokes have been reported in the anterior and posterior circulations. Retinal and spinal cord infarcts are also described (Devenyi et al., 1988; Sawaya & Kaminski, 1990). The symptoms of cerebral ischemia may be transient, presenting as a transient ischemic attack. Involvement of the left hemisphere may present with right-sided paralysis and numbness, difficulty with forming speech and inability to comprehend. Strokes affecting the right hemisphere may result in left-sided paralysis and numbness and patients may not attend the paralyzed half of the body. If the stroke affects the posterior circulation, the patient may develop changes in their coordination, vision, swallowing, and speech, and may get confused, drowsy, and stuporous (Daras et al., 1991). The majority of the reports of cocaine-related stroke involve the anterior circulation. However, reports of basilar artery thrombosis following cocaine use are available (Vallee et al., 2003). About a quarter of patients monitored during their hospitalization developed some form of arrhythmia (Bhattacharya et al., 2011), such as sinus bradycardia or tachycardia, sick sinus syndrome, atrial and ventricular premature contractions, supraventricular tachycardia, atrial flutter, and fibrillation (Bhattacharya et al., 2011).
Compared with patients without cocaine in their urine, those who were cocaine positive have similar severity, mechanisms, and outcomes (as measured by the discharge destination) (Bhattacharya et al., 2011; Silver et al., 2013) (see Fig. 4.1). Intracranial hemorrhages secondary to cocaine use can be intracerebral, SAH, or intraventricular in location (Kibayashi et al., 1995; Nolte et al., 1996). The presentation is not different from intracerebral hemorrhage due to other causes such as hypertension. Typical cases have acute onset of headache, paralysis, speech problems and depending on the size of the hemorrhage, there may be alteration of consciousness. A CT scan of the head will distinguish whether the paralysis is due to cerebral ischemia or an intracerebral hemorrhage. The classic presentation of SAH is a thunderclap headache described as the worst headache in the patient’s life. For a significant proportion of patients, the bleeding is so severe that death may occur even before arrival at the hospital. The clinical course of SAH can be complicated by vasospasm within the first few days of illness, resulting in delayed cerebral ischemia, which can be potentially disabling. The presentation on admission with aneurysmal SAH is similar to those without cocaine with regards to severity of clinical features. In-hospital mortality was significantly higher among those with cocaine use (26% vs 17%) (Chang et al., 2013). In an adjusted analysis, cocaine use was an independent predictor of mortality (2.9 times the odds compared to nonusers). The only other predictors in this study were age and severity of clinical presentation. In a series of 150 patients with SAH, the authors found a fivefold increased risk of high-grade SAH among cocaineassociated SAHs compared to those that were not associated with cocaine (Howington et al., 2003). In another
FIGURE 4.1 Comparison of modified Rankin scores (mRS) among cocaine users and nonusers at discharge from hospital (Bhattacharya, Taraman et al., 2011). There were no significant differences. Distribution of mRS among cocaine (n 5 41) and noncocaine (n 5 221) related strokes.
45 40 35
%
30 25 Cocaine negative Cocaine positive
20 15 10 5 0
33
0
1
2 3 4 Modified Rankin score
5
6
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PART | I General Aspects, Features of Ill Health and Setting the Scene
series, patients with SAH may have an increased prevalence of vasospasm with recent cocaine exposure (Conway & Tamargo, 2001). On cardiac evaluations, there is an increased risk of regional wall motion abnormalities in patients with SAH who have used cocaine. This might explain some of the poorer outcome among patients with cocaine and SAH (Kothavale et al., 2006).
4.4 PATHOPHYSIOLOGY There are a number of mechanisms through which cocaine results in cerebral ischemia (Table 4.2). Some mechanisms have extensive research, whereas other mechanisms are based on isolated case reports.
4.4.1 Vasospasm Several lines of evidence demonstrate vasospasm as a mechanism following cocaine use. Chronic intracisternal injection of cocaine produced angiographic vasoconstriction of the rabbit basilar artery, which could be reversed if cocaine was coinfused with an endothelin A and B receptor antagonist: PD145065 (Fandino et al., 2003). Infusions of cocaine resulted in spasm of the basilar artery in a proportion of the rabbits (Wang et al., 1990). An autopsy study on a patient’s brain after a cocaineassociated stroke demonstrated narrowing of intradural blood vessels without inflammation (Konzen et al., 1995). There are various proposed mechanisms of vasospasm secondary to cocaine.
TABLE 4.2 Mechanisms of Ischemic Stroke Among Patients Using Cocaine Vasospasm G Proadrenergic effects of cocaine G Disorder of calcium magnesium homeostasis G Elevation of endothelin levels Platelet activation Endothelial dysfunction Premature atherogenesis Apoptosis of cerebral vascular smooth muscle cells Vasculitis Cardiac embolism G Thromboembolism G Infective endocarditis Hypercoagulability Autoregulatory failure G Posterior reversible encephalopathy syndrome (PRES) G Reversible cerebral vasoconstriction syndrome (RCVS) Embolization of injected contaminants
1. The proadrenergic mechanism: Cocaine exerts sympathomimetic effects by preventing the uptake of norepinephrine, serotonin, and dopamine at presynaptic nerve terminals. This leads to vasoconstriction. Destruction of adrenergic nerve endings in cats, using 6-hydroxydopamine reversed the cocaine-mediated constriction (Madden et al., 1995). Yet administration of phentolamine, an alpha-1 and -2 adrenergic antagonist did not reverse cocaine-mediated vasoconstriction, suggesting additional mechanisms. Also, other drugs that inhibit norepinephrine uptake, such as tricyclic antidepressants, are not associated with cerebrovascular accidents (Havranek et al., 1996). 2. Disorder of calcium magnesium homeostasis: Pretreatment with diltiazem, a calcium channel blocker, will block cocaine-mediated vasospasm (Isner & Chokshi, 1989). Magnesium is a naturally occurring calcium antagonist. It gates the release of intracellular calcium in vascular smooth muscle cells, and promotes relaxation, contrary to calcium which promotes vascular smooth muscle contraction and thereby vasoconstriction. In situ studies on the rat brain show that perfusion of the cerebral microcirculation with CSF depleted in extracellular magnesium results in rapid and progressive spasm followed by rupture of venules and capillaries. This results in formation of focal hemorrhages and brain edema (Altura & Gupta, 1992). Various experiments have studied the effects of cocaine exposure on magnesium homeostasis. Exposure of cultured canine cerebral vascular smooth muscle cells to cocaine decreases the intracellular magnesium within seconds. This contributes to intracellular calcium increase (Zhang et al., 1996). Wistar rats injected intravenously with cocaine showed a dramatic decrease in the magnesium levels down to over 50% within about 10 minutes of injection (Altura & Gupta, 1992). There was a decrease in intracellular pH and ATP production indicating intracellular acidosis and energy failure (Altura & Gupta, 1992). When cocaine was applied to canine cerebral vascular smooth muscle cells, there was a significant increase in the intracellular calcium levels, released from the sarcoplasmic reticulum (Zhang et al., 1996). Smooth muscle cells from cerebral arteries in male mongrel dogs were superfused with progressively increasing concentrations of cocaine. Intracellular calcium levels rose significantly even with the smallest concentration of cocaine, within the first minute (Zhang et al., 1996), and continued to rise up to 5 minutes. When the cells were washed with cocaine free solution, the calcium levels reduced, but did not return to baseline levels up to 30 minutes after exposure (Zhang et al., 1996).
Strokes Associated With Cocaine Use Chapter | 4
3. Endothelin-based mechanisms: Endothelin (ET), a potent vasoconstrictor, is increased following cocaine use. First, in cultures of pig, bovine, and human endothelial cells, application of cocaine increased ET-1 release (Hendricks-Munoz et al., 1996; WilbertLampen et al., 1998). Second, cocaine-abusing mothers have elevated plasma levels of ET-1 (Samuels et al., 1993). Third, cocaine-intoxicated patients show elevated plasma and urine levels of ET-1 (Fandino et al., 2003). Suffusion of rabbit basilar artery with cocaine resulted in progressive vasoconstriction that plateaued for 2 hours after stopping suffusion (Yoon et al., 2007). When the artery was suffused with PD145065, an endothelin A and B receptor antagonist, the constriction reversed, and the artery dilated to a caliber greater than baseline, before cocaine suffusion (Yoon et al., 2007). In another human study, chronic cocaine users had elevated ET-1 levels. After 4 weeks of abstention, the levels came back to normal, at par with controls (Saez et al., 2011). Levels of other endothelial markers such as SDF-1 (stromal-derived factor-1), sICAM (soluble intracellular adhesion molecule), and hsCRP (high-sensitivity C reactive protein) were elevated initially and reverted to control levels after 4 weeks of abstention (Saez et al., 2011). The endothelin release following cocaine use is mediated by endothelial sigma receptors that are activated by cocaine. Activated sigma receptors release ET-1 causing vasoconstriction. Sigma receptor antagonists will prevent ET-1 release (Wilbert-Lampen et al., 1998).
35
2011). Moreover, patients with longer duration of exposure and higher intake of cocaine had higher levels of sCD40L, suggesting a higher degree of activation with prolonged exposure.
4.4.3 Endothelial Dysfunction From Chronic Cocaine Use Chronic cocaine users had significantly lower rises in the forearm blood flow in response to infusions of nitroprusside and acetylcholine using forearm plethysmography. Intracoronary infusion of acetylcholine in these subjects showed vasoconstriction of the coronaries instead of the normal response of dilatation. Following intranasal cocaine administration, coronary vasoconstriction is greater in diseased segments. This suggests that there may be focal areas of endothelial dysfunction with loss of nitric oxide due to cocaine (Flores et al., 1990). These experiments indicate impairment of endothelium-dependent vasorelaxation following cocaine (Havranek et al., 1996). Dysfunctional endothelium is prothrombotic. Repeated cocaine use has toxic effects on the endothelial cells, resulting in repeated cycles of cell loss followed by proliferation; which makes the endothelium unable to respond to G protein-mediated releasing agents for nitric oxide (Havranek et al., 1996). Secondly, the ratio of thromboxane B2 to prostaglandin F1alpha is increased after cocaine (Eichhorn et al., 1992). This altered ratio creates a thrombotic state.
4.4.2 Cocaine-Induced Platelet Activation
4.4.4 Premature Atherogenesis Among Chronic Cocaine Users
Platelet-rich thrombi were first discovered in coronary vessels in myocardial infarction following cocaine use (Kolodgie et al., 1991). Pathology studies of thrombectomy specimens in acute cocaine-associated stroke showed a bland thrombus, which suggests platelet dysfunction (Konzen et al., 1995). Fourteen healthy cocaine-naı¨ve volunteers received cocaine intranasally and saline placebo. Following cocaine inhalation, bleeding time decreased and there was an increase in platelet microaggregates. Levels of platelet factor 4 and beta thromboglobulin were also increased. Thus acute cocaine exposure results in platelet activation (Heesch et al., 2000). Baseline blood and samples after 4 weeks of abstinence were evaluated in 23 chronic cocaine abusers admitted to a rehabilitation facility (Pereira et al., 2011). There were higher monocyte platelet aggregates than controls, which reduced to control levels after 4 weeks of abstinence. Similarly, levels of soluble CD40 ligand (sCD40L), a marker of activated platelets, were elevated initially and reduced to control levels (Pereira et al.,
In blood samples from 23 chronic cocaine users, RANTES (regulated on activation normal T cells expressed and secreted) was elevated; a chemokine that recruits leukocytes into areas of inflammation in the endothelium, leading to premature atherosclerosis (Pereira et al., 2011). Further, chronically activated platelets release elastase that causes degradation of arterial elastic tissue, a precursor to atherogenesis (Heesch et al., 2000). In chronic cocaine abusers, levels of circulating endothelial cells (CEC) were markedly elevated. After 4 weeks of abstention, the levels had reduced but were still significantly elevated compared to controls. CECs are a marker of endothelial injury. The persistent elevation of CECs after the short period of abstention suggests that the effects on vascular endothelial injury are more sustained in chronic cocaine users. Such endothelial injury initiates atherosclerosis, often in the absence of traditional cardiovascular risk factors. In this study, the levels of MCP-1 (monocyte chemotactic protein-1), an endothelial marker,
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PART | I General Aspects, Features of Ill Health and Setting the Scene
were significantly elevated among chronic cocaine users and did not return to normal after 4 weeks of cocaine abstention. MCP-1 is responsible for mononuclear infiltration; another important step in atherogenesis (Saez et al., 2011). SDF-1 works to attract endothelial progenitor cells to enable endothelial repair following injury. The return of SDF-1 to normal in the face of persistently elevated CECs and MCP-1 suggest that the body’s repair response to endothelial injury following cocaine use is inadequate (Saez et al., 2011).
4.4.5 Cocaine-Induced Apoptosis of Cerebral Vascular Smooth Muscle Cells Smooth muscle cells from the basilar arteries of dogs were treated with cocaine in increasing concentrations. Morphological features of apoptosis such as nuclear fragmentation and condensation of chromatin were examined (Su et al., 2003). Cells cultured with cocaine had a higher death rate than controls. The percentage of apoptotic cells was also increased in cocaine-treated samples, and the proportion of these cells varied depending on the dose of cocaine and the time of exposure (Su et al., 2003). Cocaine-mediated apoptosis is believed to be set off by the rapid rise in intracellular calcium that occurs within minutes of cocaine exposure. The pathway from the onset of apoptosis to the occurrence of vascular thrombosis is also unclear. However, it is thought to contribute to the rupture of plaques (Su et al., 2003).
Cocaine can induce a cardiomyopathy and an intracavitary thrombus (Petty et al., 1990). Finally, strokes can occur from septic emboli from infective endocarditis in intravenous drug users (Brown et al., 1992).
4.4.8 Other Mechanisms 1. Cocaine can induce a hypercoagulability related to a depletion of antithrombin III and protein C (Isner & Chokshi, 1989). 2. The adrenergic surge induced by cocaine can result in a hypertensive crisis. This can cause an alteration of cerebral autoregulation (Treadwell & Robinson, 2007): reversible cerebral vasoconstriction syndrome (RCVS) or posterior reversible encephalopathy syndrome (PRES), both of which can result in ischemic stroke. 3. Impurities such as talc or sugar in street cocaine when injected intravenously, may embolize to the cerebrovascular system (Brown et al., 1992). Use of adulterants such as procainamide, quinidine, and antihistamine may also have toxic effects (Treadwell & Robinson, 2007). 4. Cocaine is implicated in causing a moyamoya-like vasculopathy resulting in bilateral strokes (Schwartz & Scott, 1998).
Concentric enhancement of the middle cerebral artery, demonstrated on MRI studies in the setting of cocaine use, suggests vasculitis as a possible mechanism; although the speculation is mainly due to extrapolation of similar enhancement noted in other vasculitis, such as giant cell arteritis or cerebral vasculitis (Han et al., 2008). Biopsyproven vasculitis with cocaine use is a rare event but case reports are described (Krendel et al., 1990; Levine et al., 1990; Fredericks et al., 1991; Merkel et al., 1995; Morrow & McQuillen, 1993).
There has not been much systematic research into the mechanisms by which cocaine results in intracerebral or SAH. Presumably, the adrenergic surge that follows cocaine use results in rupture of microscopic Charcot Bouchard aneurysms in small blood vessels in the depths of the brain resulting in intracerebral hemorrhage (Brown et al., 1992). Alternatively, ischemic infarction may result in hemorrhagic conversion within ischemic areas (Brown et al., 1992). Finally, septic emboli from infective endocarditis can result in mycotic aneurysm resulting in intracerebral hemorrhage (Esse et al., 2011). For SAH, the acute elevation of blood pressure that occurs minutes within ingestion of cocaine results in rupture of a preexisting vascular lesion (Brown et al., 1992). Reversible cerebral vasoconstriction, a recently described arteriopathy, can occur with cocaine and result in SAH.
4.4.7 Cardiac Embolism
4.5 TREATMENT
Cocaine results in cardiac embolism through many mechanisms. Cocaine-associated strokes are often associated with cardiac arrhythmias, that can result in formation of intracavitary thrombi. Cocaine can result in cardiac ischemia, which can result in partial or global ventricular wall abnormality, which can potentiate the development of a cardiac thrombus (Alqahtani et al., 2015). Similarly, cocaine can result in myocardial infarction, which can be complicated by thromboembolism (Brown et al., 1992).
Treatment of ischemic stroke following cocaine use is not much different from the routine treatment of ischemic stroke. Within the first 4.5 hours after the onset of symptoms, patients should be considered for administration of thrombolytics in order to limit disability in the long term. The concern with giving tPA is that cocaine use may be associated with surges in blood pressure which may increase the risk of intracerebral hemorrhage (MartinSchild et al., 2009). In a large series of cocaine-associated
4.4.6 Vasculitis
Strokes Associated With Cocaine Use Chapter | 4
ischemic strokes, 33.3% received tPA. There were no hemorrhages. This is in spite of the fact that chronic cocaine users had an increased rate of preexisting intracranial small vessel disease (Martin-Schild et al., 2009). Patients with cocaine-associated strokes tended to get tPA if they had more severe strokes. The rate of home discharge or discharge to an inpatient rehabilitation unit was the same. The rate of favorable functional outcome at discharge was also similar to those not getting tPA (MartinSchild et al., 2009). Patients with cocaine-associated strokes who got tPA did not show large surges of blood pressure during close monitoring as anticipated (MartinSchild et al., 2009). The biggest intervention for secondary prevention is the cessation of cocaine abuse. Getting patients the appropriate help and referral to deaddiction centers is paramount. As with other ischemic strokes, whether or not the underlying blood vessels are abnormal, antiplatelet agents such as aspirin are mandatory. As noted in the pathophysiology section, platelet activation occurs during the acute phase of cocaine ingestion. This is the basis for the use of antiplatelet agents following ischemic stroke following cocaine use. Control of underlying vascular risk factors, such as hypertension and diabetes, is the next important intervention. For the treatment of hypertension, there may be some basis to choose calcium channel blockers. However this is based on experimental models rather than on realworld clinical data. As we understand the pathophysiology of cocaine-related strokes better, specific treatment strategies may evolve.
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Ischemic stroke: The most common type of stroke that occurs due to blockage of blood supply to a part of the brain due to either narrowing of the blood vessel caliber or obstruction of the blood vessel by a blood clot. Intracerebral hemorrhage: Bleeding into the substance of the brain resulting in loss of function corresponding to that part of the brain. It is more disabling than ischemic stroke and can be fatal. Subarachnoid hemorrhage: Bleeding that occurs into the space surrounding the brain, usually from an aneurysm in one of the main blood vessels supplying the brain. Endothelium: Inner lining of the blood vessels that is very sensitive to stimuli that can cause dilatation or constriction of blood vessels as well as initiate plaque formation within vessels. Apoptosis: The process of programmed cell death that normally occurs as a genetically regulated process, but can be provoked by exposures to different stimuli.
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Vasculitis: Inflammation of the wall of the blood vessel that results in blockages of blood vessels, causing stroke. tPA (tissue plasminogen activator): This is a widely used medication to treat ischemic stroke within 4.5 hours of the start of symptoms. It works by dissolving the blood clot that blocks the blood vessel in a stroke.
REFERENCES Alqahtani, S. A., Burger, K., et al. (2015). Cocaine-induced acute fatal basilar artery thrombosis: Report of a case and review of the literature. American Journal of Case Reports, 16, 393 397. Altura, B. M., & Gupta, R. K. (1992). Cocaine induces intracellular free Mg deficits, ischemia and stroke as observed by in-vivo 31P-NMR of the brain. Biochimica et Biophysica Acta, 1111(2), 271 274. Bessen, H. A. (1982). Intracranial hemorrhage associated with phencyclidine abuse. JAMA, 248(5), 585 586. Bhattacharya, P., Taraman, S., et al. (2011). Clinical profiles, complications, and disability in cocaine-related ischemic stroke. The Journal of Stroke & Cerebrovascular Diseases, 20(5), 443 449. Brown, E., Prager, J., et al. (1992). CNS complications of cocaine abuse: Prevalence, pathophysiology, and neuroradiology. American Journal of Roentgenology, 159(1), 137 147. Brust, J. C., & Richter, R. W. (1976). Stroke associated with addiction to heroin. The Journal of Neurology, Neurosurgery, and Psychiatry, 39 (2), 194 199. Brust, J. C., & Richter, R. W. (1977). Stroke associated with cocaine abuse--? New York State Journal of Medicine, 77(9), 1473 1475. Chang, T. R., Kowalski, R. G., et al. (2013). Impact of acute cocaine use on aneurysmal subarachnoid hemorrhage. Stroke, 44(7), 1825 1829. Conway, J. E., & Tamargo, R. J. (2001). Cocaine use is an independent risk factor for cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Stroke, 32(10), 2338 2343. Daras, M., Tuchman, A. J., et al. (1991). Central nervous system infarction related to cocaine abuse. Stroke, 22(10), 1320 1325. Daras, M., Tuchman, A. J., et al. (1994). Neurovascular complications of cocaine. Acta Neurologica Scandinavica, 90(2), 124 129. de los Rios, F., Kleindorfer, D. O., et al. (2012). Trends in substance abuse preceding stroke among young adults: A population-based study. Stroke, 43(12), 3179 3183. Devenyi, P., Schneiderman, J. F., et al. (1988). Cocaine-induced central retinal artery occlusion. CMAJ, 138(2), 129 130. Eichhorn, E. J., Demian, S. E., et al. (1992). Cocaine-induced alterations in prostaglandin production in rabbit aorta. The Journal of the American College of Cardiology, 19(3), 696 703. Esse, K., Fossati-Bellani, M., et al. (2011). Epidemic of illicit drug use, mechanisms of action/addiction and stroke as a health hazard. Brain and Behavior, 1(1), 44 54. Fandino, J., Sherman, J. D., et al. (2003). Cocaine-induced endothelin-1dependent spasm in rabbit basilar artery in vivo. Journal of Cardiovascular Pharmacology, 41(2), 158 161. Flores, E. D., Lange, R. A., et al. (1990). Effect of cocaine on coronary artery dimensions in atherosclerotic coronary artery disease: Enhanced vasoconstriction at sites of significant stenoses. The Journal of the American College of Cardiology, 16(1), 74 79.
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PART | I General Aspects, Features of Ill Health and Setting the Scene
Fredericks, R. K., Lefkowitz, D. S., et al. (1991). Cerebral vasculitis associated with cocaine abuse. Stroke, 22(11), 1437 1439. Han, J. S., Mandell, D. M., et al. (2008). BOLD-MRI cerebrovascular reactivity findings in cocaine-induced cerebral vasculitis. Nature Clinical Practice Neurology, 4(11), 628 632. Havranek, E. P., Nademanee, K., et al. (1996). Endothelium-dependent vasorelaxation is impaired in cocaine arteriopathy. The Journal of the American College of Cardiology, 28(5), 1168 1174. Heesch, C. M., Wilhelm, C. R., et al. (2000). Cocaine activates platelets and increases the formation of circulating platelet containing microaggregates in humans. Heart, 83(6), 688 695. Hendricks-Munoz, K. D., Gerrets, R. P., et al. (1996). Cocainestimulated endothelin-1 release is decreased by angiotensinconverting enzyme inhibitors in cultured endothelial cells. Cardiovascular Research, 31(1), 117 123. Howington, J. U., Kutz, S. C., et al. (2003). Cocaine use as a predictor of outcome in aneurysmal subarachnoid hemorrhage. Journal of Neurosurgery, 99(2), 271 275. Isner, J. M., & Chokshi, S. K. (1989). Cocaine and vasospasm. The New England Journal of Medicine, 321(23), 1604 1606. Jacobs, I. G., Roszler, M. H., et al. (1989). Cocaine abuse: Neurovascular complications. Radiology, 170(1 Pt 1), 223 227. Kaku, D. A., & Lowenstein, D. H. (1990). Emergence of recreational drug abuse as a major risk factor for stroke in young adults. Annals of Internal Medicine, 113(11), 821 827. Kibayashi, K., Mastri, A. R., et al. (1995). Cocaine induced intracerebral hemorrhage: Analysis of predisposing factors and mechanisms causing hemorrhagic strokes. Human Pathology, 26(6), 659 663. Kittner, S. J., Stern, B. J., et al. (1998). Cerebral infarction in young adults: The Baltimore-Washington Cooperative Young Stroke Study. Neurology, 50(4), 890 894. Kolodgie, F. D., Virmani, R., et al. (1991). Increase in atherosclerosis and adventitial mast cells in cocaine abusers: An alternative mechanism of cocaine-associated coronary vasospasm and thrombosis. The Journal of the American College of Cardiology, 17(7), 1553 1560. Konzen, J. P., Levine, S. R., et al. (1995). Vasospasm and thrombus formation as possible mechanisms of stroke related to alkaloidal cocaine. Stroke, 26(6), 1114 1118. Kothavale, A., Banki, N. M., et al. (2006). Predictors of left ventricular regional wall motion abnormalities after subarachnoid hemorrhage. Neurocritical Care, 4(3), 199 205. Krendel, D. A., Ditter, S. M., et al. (1990). Biopsy-proven cerebral vasculitis associated with cocaine abuse. Neurology, 40(7), 1092 1094. Levine, S. R., Brust, J. C., et al. (1990). Cerebrovascular complications of the use of the “crack” form of alkaloidal cocaine. The New England Journal of Medicine, 323(11), 699 704. Madden, J. A., Konkol, R. J., et al. (1995). Cocaine and benzoylecgonine constrict cerebral arteries by different mechanisms. Life Science, 56 (9), 679 686. Martin-Schild, S., Albright, K. C., et al. (2009). Intravenous tissue plasminogen activator in patients with cocaine-associated acute ischemic stroke. Stroke, 40(11), 3635 3637. Merkel, P. A., Koroshetz, W. J., et al. (1995). Cocaine-associated cerebral vasculitis. Seminars in Arthritis and Rheumatism, 25(3), 172 183. Morrow, P. L., & McQuillen, J. B. (1993). Cerebral vasculitis associated with cocaine abuse. Journal of Forensic Science, 38(3), 732 738.
Nolte, K. B., Brass, L. M., et al. (1996). Intracranial hemorrhage associated with cocaine abuse: A prospective autopsy study. Neurology, 46(5), 1291 1296. Pereira, J., Saez, C. G., et al. (2011). Platelet activation in chronic cocaine users: Effect of short term abstinence. Platelets, 22(8), 596 601. Petitti, D. B., Sidney, S., et al. (1998). Stroke and cocaine or amphetamine use. Epidemiology, 9(6), 596 600. Petty, G. W., Brust, J. C., et al. (1990). Embolic stroke after smoking “crack” cocaine. Stroke, 21(11), 1632 1635. Qureshi, A. I., Safdar, K., et al. (1995). Stroke in young black patients. Risk factors, subtypes, and prognosis. Stroke, 26(11), 1995 1998. Rothrock, J. F., Rubenstein, R., et al. (1988). Ischemic stroke associated with methamphetamine inhalation. Neurology, 38(4), 589 592. Saez, C. G., Olivares, P., et al. (2011). Increased number of circulating endothelial cells and plasma markers of endothelial damage in chronic cocaine users. Thrombosis Research, 128(4), e18 e23. Samuels, P., Steinfeld, J. D., et al. (1993). Plasma concentration of endothelin-1 in women with cocaine-associated pregnancy complications. American Journal of Obstetrics & Gynecology, 168(2), 528 533. Sawaya, G. R., & Kaminski, M. J. (1990). Spinal cord infarction after cocaine use. The Southern Medical Journal, 83(5), 601 602. Schwartz, M. S., & Scott, R. M. (1998). Moyamoya syndrome associated with cocaine abuse. Case report. Neurosurgical Focus, 5(5), e7. Silver, B., Miller, D., et al. (2013). Urine toxicology screening in an urban stroke and TIA population. Neurology, 80(18), 1702 1709. Sloan, M. A., Kittner, S. J., et al. (1991). Occurrence of stroke associated with use/abuse of drugs. Neurology, 41(9), 1358 1364. Su, J., Li, J., et al. (2003). Cocaine induces apoptosis in cerebral vascular muscle cells: Potential roles in strokes and brain damage. The European Journal of Pharmacology, 482(1 3), 61 66. Treadwell, S. D., & Robinson, T. G. (2007). Cocaine use and stroke. Postgraduate Medical Journal, 83(980), 389 394. Vallee, J. N., Crozier, S., et al. (2003). Acute basilar artery occlusion treated by thromboaspiration in a cocaine and ecstasy abuser. Neurology, 61(6), 839 841. Wang, A. M., Suojanen, J. N., et al. (1990). Cocaine- and methamphetamine-induced acute cerebral vasospasm: An angiographic study in rabbits. American Society of Neuroradiology, 11(6), 1141 1146. Westover, A. N., McBride, S., et al. (2007). Stroke in young adults who abuse amphetamines or cocaine: A population-based study of hospitalized patients. Archives of General Psychiatry, 64(4), 495 502. Wilbert-Lampen, U., Seliger, C., et al. (1998). Cocaine increases the endothelial release of immunoreactive endothelin and its concentrations in human plasma and urine: Reversal by coincubation with sigma-receptor antagonists. Circulation, 98(5), 385 390. Yoon, S. H., Zuccarello, M., et al. (2007). Acute cocaine induces endothelin-1-dependent constriction of rabbit basilar artery. Endothelium, 14(3), 137 139. Zhang, A., Cheng, T. P., et al. (1996). Acute cocaine results in rapid rises in intracellular free calcium concentration in canine cerebral vascular smooth muscle cells: Possible relation to etiology of stroke. Neuroscience Letters, 215(1), 57 59.