In the 1970s, recreational use of cocaine became widespread due to the production of crack cocaine, a purer and cheaper form of cocaine. The late 1980s saw an epidemic of cocaine: 30 million people of all socioeconomic backgrounds were cocaine users and 6 million were cocaine addicts (Agarwal and Sen 2010). In 2009, cocaine was the second-most commonly used illicit drug in the United States after marijuana. Of one million illicit drug-related ED visits yearly in the United States, nearly half are related to cocaine, making cocaine the most frequent cause of illicit drug-related ED visits (The DAWN report 2010).
Cocaine comes in two chemical forms: the hydrochloride salt, which is the powdered form of cocaine that is water soluble, and cocaine alkaloid, a free base that is lipid soluble. The effects of cocaine include local anesthesia, vasoconstriction, and central nervous system stimulation. Cocaine prevents neurotransmitter (dopamine, norepinephrine, serotonin, and acetylcholine) reuptake at presynaptic nerve terminals, thereby increasing the amounts of neurotransmitters available for stimulation of sympathetic nerves. The euphoria related to cocaine use is a result of accumulation of dopamine and serotonin in the mesolimbic and mesocortical areas of the brain (Treadwell and Robinson 2007). These reward circuits are related to drug-seeking behavior, addiction, and dependence, making cocaine one of the most potent and highly addictive chemicals (Goforth et al. 2010).
|Cocaine||• Vasospasm||• Hypertensive surges||• Aneurysm rupture from hypertensive surges|
| ||• Enhanced platelet aggregation||• Mycotic aneurysm rupture from cardioembolic event||• Facilitation of aneurysm formation|
| ||• Vasculitis||• Hemorrhagic transformation of embolism|| |
| ||• Accelerated atherosclerosis|| || |
| ||• Cardioembolism|| || |
| ||○ Arrhythmia|| || |
| ||○ Cardiomyopathy|| || |
| ||○ Septic embolism|| || |
|Amphetamines||• Cardioembolism||• Hypertensive surge||• Aneurysms|
| ||○ Arrhythmias with thrombosis|| || |
| ||○ Cardiomyopathy|| || |
| ||• Vasculitis|| || |
| ||• Microinfarcts from blood vessel injury and accelerated atherosclerosis|| || |
|Ecstasy||• Cardioembolism from:||• Hypertensive surge||• Aneurysm formation and rupture|
| ||○ Arrhythmias||• Vasodilation from decreased serotonin from chronic use|| |
| ||○ Cardiomyopathy||• Consumptive coagulopathy = spontaneous bleed|| |
| ||• Vasospasm → Vessel wall damage|| || |
| ||• Direct vasoconstrictive effect of Serotonin|| || |
| ||• Hyperthermia→Clotting cascade/DIC → microinfarcts|| || |
| ||○ Endocarditis|| || |
| ||○ Foreign bodies|| || |
| ||• Arteritis/Vasculitis|| || |
| ||• Hypotension/Hypoxemia|| || |
|PCP||• Vasospasm? (only in vitro)||• Hypertensive effect||• Weakened arterial walls|
| ||• Direct vasoconstrictive effect of Serotonin|| || |
| ||• Vasospasm?|| || |
| ||• Cardioembolism from arrhythmias?|| || |
Cocaine and stroke
As crack cocaine use increased in the 1970s and 1980s, case reports of cocaine-associated AIS, ICH, and SAH became more prevalent, which is especially striking given the young age at which strokes occurred. A review article in the late 1980s found that the mean age of patients with cocaine-related stroke was 32.5 years (Klonoff et al. 1989).
Case series characterizing the brain location and etiology of each type of cocaine-related stroke have been performed. Cocaine-associated AISs have been reported in nearly every vascular territory in the brain; anterior circulation, posterior circulation, spinal cord, brainstem, and retina have been affected (Brust 2002). Both cortical and subcortical strokes can occur (Daras et al.; Jacobs et al. 1989). The etiology of ischemic infarcts varies as well; large artery, small artery, and cardioembolic strokes all appear to be of relatively equal incidence (Martin-Schild et al. 2009).
While AIS is far more common than ICH or SAH overall, the frequency of hemorrhagic stroke is disproportionately high in cocaine-related strokes (Treadwell and Robinson 2007). Intracerebral hemorrhages are found throughout the brain, including basal ganglia, thalamus, lobar, brainstem, and cerebellar locations. While one study found mostly lobar locations (73% of 34 patients) (Kaku and Lowenstein 1990), a recent study of 45 cocaine users with ICH found predominantly ICH in the basal ganglia (Martin-Schild et al. 2010). This may depend on the prevalence of underlying hypertension in different populations. The prevalence of underlying vascular lesions in patients with cocaine-related ICH has been variable, ranging from 10% (Martin-Schild et al. 2010) to nearly 50% related to ruptured aneurysms or arterio-venous malformations (AVMs) (Brust 2002; Enevoldson 2004).
Mechanisms of strokes
The main etiologies that have been suggested include hypertensive surges, vasospasm, enhanced platelet aggregation, cerebral vasculitis, accelerated atherosclerosis, and cardioembolism (Treadwell and Robinson 2007).
Chronic uncontrolled hypertension is a major risk factor for stroke. Repeated use of cocaine can raise blood pressure, increasing the risk for stroke, even in patients who do not have baseline hypertension. Hypertensive surges may be responsible for the majority of hemorrhagic strokes associated with cocaine use.
Vasospasm is a fascinating mechanism for cocaine-induced stroke. Defined as sudden and usually reversible changes in vascular caliber due to vascular smooth muscle changes, vasospasm is more commonly encountered as a complication of SAH. A case study of cocaine users, however, found tunica media and elastic lamina damage in vessels in multiple locations in the brain possibly due to chronic vasospasm (Konzen et al. 1995). Radiographic studies (Kaufman et al. 1998) confirmed animal studies (He et al. 1994) that demonstrated a dose-dependent vasoconstriction of cerebral vessels on magnetic resonance angiography in response to cocaine.
The pathophysiology of vasospasm in cocaine use is multifactorial. Cocaine has effects on the calcium channels in smooth muscle cells in vascular walls. It promotes the release of calcium from the sarcoplasmic reticulum and also may allow influx of external calcium into the smooth muscle cells, causing contraction of the vessel walls. Accumulation of catecholamines caused by prevention of reuptake may result in smooth muscle contraction by an effect on several receptors in the vessel walls. This latter mechanism is supported by dopamine antagonist (haloperidol) and calcium channel blocker (verapamil) prevention of vasospasm in cocaine-exposed smooth muscle cells (He et al. 1994). Endothelin-1, an endogenous vasoactive peptide, has been implicated in the development of atherosclerosis and vasoconstriction. Endothelin-1 has been detected in the urine and serum of cocaine users. An endothelin-1 antagonist reversed cocaine-induced vasospasm in animal models (Fandino et al. 2003). Vasoconstriction may play a role in cocaine-related stroke even days after last cocaine use. Metabolized by the liver, cocaine has a half-life of approximately 1 hour, but major provasoconstrictive metabolites can last for days. There is also large variation among individuals, with metabolites lingering in chronic users for up to 3 weeks (Enevoldson 2004).
Vasospasm may cause endothelial injury, resulting in intimal hyperplasia and platelet activation and aggregation, ultimately occluding vessels (Treadwell and Robinson 2007). This may be why microvascular white matter changes are found on MRI in chronic cocaine users (Volkow et al. 1988; Goforth et al. 2010). Cocaine administration activates platelets resulting in α-granule release and the formation of platelet-rich microaggregates (Heesch et al. 2000). It also increases platelet responsiveness to arachidonic acid, and causes the release of thromboxane β2 and plasminogen activating factor-1 inhibitor (PAI-1). All of these factors promote platelet aggregation (Togna et al. 1985; Kolodgie et al. 1995) and facilitation of thrombus formation.
Very few cases of biopsy-proven vasculitis associated with cocaine exposure have been reported. These cases describe a hypersensitivity-type vasculitic morphology that differs from the typical inflammatory central nervous system vasculitis. Supporting this is the fact that in cases of presumed cocaine-induced vasculitis, steroids failed to improve the patient's symptoms in the short term (Merkel et al. 1995). Most studies have failed to demonstrate these findings on autopsy (Brust 2002; Enevoldson 2004).
Cocaine may promote accelerated atherosclerosis, leading to longer term increased risk for AIS in cocaine users. Rabbits with high cholesterol that were exposed to cocaine demonstrated a greater extent of cholesterol plaque in the proximal thoracic aorta than control rabbits (Kolodgie et al. 1993). In the presence of cocaine, cell membranes are more permeable to atherogenic lipoproteins (Kolodgie et al. 1993, 1995, 1999).
Cardioembolism is a well-known cause of cocaine-related stroke. Mechanisms of embolism and ischemic stroke include infective endocarditis in patients who inject cocaine hydrochloride, arrhythmia, acute and chronic dilated cardiomyopathy, and myocardial infarction (Sloan and Mattioni 1992). Cocaine use is highly associated with infective endocarditis: in one study of drug users with endocarditis, 79% were cocaine users (Chambers et al. 1987). In addition to embolization, endocarditis can cause a septic cerebral arteritis. Endocarditis provokes ICH from rupture of mycotic aneurysms and hemorrhagic transformation of embolic stroke (Hart et al. 1987; Enevoldson 2004; Hagan and Burney 2007).
Hypertensive surge with or without an underlying vascular malformation is the most common implicated etiology for ICH and SAH. The indirect sympathomimetic effects of cocaine transiently raise the systolic blood pressure, which can cause spontaneous bleeding in existing AVMs, aneurysms, or areas of old ischemic strokes, or may actually facilitate aneurysm formation (Nolte et al. 1995). Cocaine users with ICH have very high blood pressure on admission (Martin-Schild et al. 2009), and have blood in classic hypertensive locations. Brainstem hemorrhages were over-represented in patients with cocaine-associated ICH. Cocaine users with ICH have worse short-term functional outcome compared to patients with hemorrhage who are not cocaine users. In fact, cocaine users with ICH were nearly five times more likely to be dependent and three times more likely to die than patients with ICH who did not use cocaine (Martin-Schild et al. 2010). When SAH occurs in cocaine users, aneurysms are often detected on angiography (Oyesiku et al. 1993; Fessler et al. 1997).