COCAINE
Cocaine is an alkaloid extracted from the leaves of the plant Erythroxylon coca,1 the active base of which is benzoylmethylecnonine.2,3 The chemical molecule has two active sites, an amine end, which is hydrophilic and an aromatic ring that is lipid soluble. The leaves of the plant can be chewed or it can be prepared in concentrated forms.1 The most frequently consumed form is cocaine hydrochloride, a water-soluble salt grounded to a fine powder, which is rapidly absorbed across mucous membranes.3
Cocaine abuse has been associated with effects on cerebral vessels, uterus, placenta, as well as heart and skeletal muscle.4,5 It is also a potent neurotoxin that causes agitation and seizures.2 Cocaine has a short biologic half-life and great reinforcing properties, which result in compulsive use.1 It produces local anesthesia by blocking nervous impulses, causes the activation of the parasympathetic nervous system by blocking uptake of catecholamines, and creates a sensation of a “high” by blocking dopamine reuptake.1,6
The neurovascular complications of cocaine use have increased since the introduction of free base cocaine otherwise known as “crack” in 1983.7 Crack is made by heating an aqueous solution of cocaine hydrochloride with sodium bicarbonate or ammonia. The resulting product contains impurities but is smokable. Crack achieves higher central nervous system levels in less time than intranasal administration of cocaine.8
PATHOLOGY
Several central nervous system complications have been described in cocaine abusers including cerebrovascular insults and atrophy (Table 1).
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TABLE 1: Effects of Cocaine in the Central Nervous System
Cerebrovascular Events
There is clear documentation of cerebrovascular events including intracranial hemorrhage and ischemic stroke in cocaine abusers.8-12 These changes are thought to be caused by a combination of factors including the inhibition of the reuptake of catecholamine neurotransmitters at the synaptic junction, which causes a rise in the levels of epinephrine and norepinephrine and leads to activation of the sympathetic system, which includes contraction of the arterial smooth muscle, elevation in blood pressure, and tachycardia.1,4 Cocaine also blocks the flux in calcium channels causing vasospasm1,4 by a direct effect on smooth muscle,3 which seems to be the main mechanism of central nervous system (CNS) toxicity (with or without intravascular thrombosis).2,13 Another described effect is blockage of the reuptake of serotonin in the brain, the most potent vasoconstrictive amine of the central nervous system.3,7,14-16 An inflammatory reaction to adulterants contained in the prepared form of cocaine may be another explanation for the complications seen in cocaine abusers.1,5
Both acute and chronic cerebrovascular changes have been described in abusers of cocaine.7,11 Acute findings include hemorrhagic and ischemic events. An increased frequency of intracranial hemorrhage is found when cocaine is smoked in the form of crack; however, no statistically significant difference has been found between occurrences of ischemic versus hemorrhagic events when the drug is snorted.8
Hemorrhagic Strokes
Hemorrhagic CNS events may be explained by an elevation in blood pressure and heart rate secondary to the sympathomimetic effect of the drug, especially in patients with predisposing conditions such as arteriovenous malformation (AVM) or cerebral aneurysm.7 Approximately 50% of patients with cocaine-related hemorrhagic events have underlying vascular pathology1 leading to early presentation of symptoms.3 Another explanation for the hemorrhagic events that occur with cocaine abuse is the occurrence of parenchymal hemorrhage in areas of previous ischemic injury due to the acute increase in blood pressure (reperfusion hemorrhage).5,7,17,18
The combination of ethanol and cocaine use further increases the risk of hemorrhagic stroke.8 The described locations of these hemorrhages include the subarachnoid space, brain parenchyma (hemispheres, basal ganglia), and ventricles (Fig. 1).7
FIGURE 1: (A) and (B) Non-enhanced CT images in a 47-year-old male with history of cocaine use and sudden headache. Increased attenuation within the left parietal parenchyma (arrowheads) and left intraventricular (short arrow) spaces producing mass effect into the left atrium is observed.
Ischemic Strokes
An increased incidence of ischemic stroke has been described in cocaine abusers. The mechanisms of stroke remain unclear; however, they seem to be multifactoral including hemodynamic alterations and vasoconstricting events.
A delay between the administration of the drug and the onset of symptoms of stroke occurs and is explained by a vasorelaxation secondary to endothelial damage in long-term cocaine users or by formation of secondary metabolites with a longer vasoactive half-life.19,20
Cocaine enhances the response of platelets to arachidonic acid resulting in increased levels of thromboxane, which, in turn, results in increased platelet aggregation7,8,15,21 and may result in a higher risk for thrombus formation. Some reports have shown concurrent myocardial and cerebral infarction after the use of cocaine.22,23
Cerebral vasculitis may also occur in cocaine abusers.7,24-26 Often the drug contains foreign substances that can cause vasculitis secondary to foreign body reaction and result in consequent cerebral infarction (Fig. 2).5 Cocaine “snorters” have shown evidence of abnormal internal elastic lamina, tunica media disruption, and arteriolar fibrosis, suggesting that vasospasm can lead to endothelial injury.5,27 Vasculitis involving the large vessels at the base of the brain has been described; however, these changes may represent an example of induced vasospasm and not true vasculitis.1,9,25,28
FIGURE 2: A 34-year-old male cocaine drug abuser. Recent history of stroke-like symptoms and diagnosis of drug-induced vasculitis. (A) T1-weighted image shows a low intensity focus within the subcortical region of the right frontal lobe (arrowhead). (B) T2-weighted image reveals high signal intensity within the subcortical region of the frontal lobe bilaterally. (C) Axial T1-weighted image with gadolinium: frontal predominance leptomeningeal enhancement and diffuse vascular enhancement with hypoperfused right frontal subcortical region (arrows). (D) Diffusion WI: Bifrontal high signal intensities representing restricted diffusion.
Ischemic infarcts often involve the subcortical white matter and most frequently in the middle cerebral artery (MCA) territory. Other areas involved include internal capsule, posterior cerebral artery (PCA) territory, and hippocampus.1,7,29 Mesencephalic stroke has been associated with the combination of cocaine with amphetamines (Fig. 3).30
FIGURE 3: A 56-year-old female with history of cocaine and methamphetamine abuse. (A) Axial T2WI shows hyperintense lesion in right midbrain (arrow). (B) Axial FLAIR demonstrates a hyperintense area in the right midbrain (arrow). (C) DWI and (D) Apparent diffusion coefficient (ADC) show restricted diffusion in the right midbrain compatible with subacute infarct (arrow).
Areas of acute ischemia are better demonstrated by magnetic resonance (MR) than by computed tomography (CT),1,31 which is especially so with the inclusion of MR diffusion (MRD). Early acute ischemic lesions may not be detected with CT or conventional MR images; however, they become apparent as areas of diffusion restriction in MRD sequences. An optimal MR protocol in acute stroke related to cocaine abuse should include diffusion-weighted images. MR perfusion (MRP) studies may also be helpful to demonstrate brain perfusion abnormalities.32 MR angiography (MRA) is useful to document vasospasm in the main branches of the intracranial circulation (Fig. 4).30
FIGURE 4: A 55-year-old male cocaine abuser. (A) Non-enhanced CT shows hypoattenuated region in the right occipital lobe (arrow). (B) T1WI shows a hypointense area in the territory of the PCA (arrow). (C) T2WI shows hyperintensity in the same region (arrow). (D) DWI reveals restricted diffusion in the occipital lobe (arrow). (E) and (F) MRA demonstrates occlusion of the right PCA (arrow head).
Both positron emission tomography (PET) and MR perfusion imaging demonstrate cerebral blood flow abnormalities associated with cocaine abuse and are seen as widespread perfusion defects in patients with CNS symptoms.1,28,30,33,34 Even those patients without neurologic symptoms have a statistically significant increase in the incidence of white matter T2 hyperintensities located in the cerebral hemispheres and insular region (MCA vascular territory). It is theorized that these hyperintensities are the result of partial occlusion of a vessel, which may cause incomplete infarction.2
Atrophy
Cerebral atrophy, seen as increased size of the lateral ventricles and increased width of the sylvian fissures,35 is encountered in habitual cocaine users. The described atrophy is more commonly seen in the temporal and frontal lobes although more prominent in the latter1,35,36 and thought related to primarily gray matter volume reduction.37 It is thought that the development of atrophy may be ischemic in nature (Fig. 5).1
FIGURE 5: A 47-year-old male chronic cocaine abuser. (A) and (B) Axial T2WI show prominence of sulci and enlargement of the ventricles as well as multiple hyperintense lesions in the periventricular white matter and centrum semiovale (arrows).
Maternal Abuse
Maternal abuse of cocaine is associated with an increased incidence of CNS abnormalities and cerebrovascular events. Vasoconstriction secondary to the excess of catecholamines causes a decrease in maternal uterine blood flow, which results in fetal hypoxemia, tachycardia, and hypertension.38,39 These effects on uterine blood flow are accounted responsible for the pathogenesis of congenital malformations.38,40,41
A 1.4% to 14% increase in midline CNS abnormalities such as exencephaly, holoprosencephaly, encephalocele, and skull dysraphism has been reported,38,42-45 accompanied by urinary tract anomalies as well.38,46 Brain findings can be explained by a partial deletery effect on the closure of the neural tube.38 Deep brain cysts and leukoencephalomalasia have also been seen.1
Cerebral infarctions have proven to be more frequent in babies whose mothers have abused cocaine during pregnancy. Cerebrovascular hemorrhages, such as subependymal, intraventricular, and intraparenchymal hemorrhage, have been reported with no statistically significant values.38
CANNABIS
A direct connection between cerebrovascular disease and cannabis use has not been established.47
Cannabis is the most commonly used illicit drug.47 The major psychoactive ingredient in marijuana is delta-9-tetrahydrocannabinol (THC), which is a lipid soluble substance.6,48-50 Smoking remains the most efficient way to deliver the drug, but it can also be taken orally.49
THC activates the CB1 cannabinoid receptor, which is the most abundant G-protein-coupled receptor in the brain. These receptors are heterogeneously distributed, but show highest densities in the basal ganglia, substantia nigra, globus pallidus, dentate gyrus of the hippocampus, limbic cortices, and cerebellum. There is another receptor (CB2) found peripherally, and thought to play an immune role.48,49
The use of Cannabis sativa leaves (marijuana) or resin (ganja) leads to intoxication with signs of cognitive dysfunction, memory and time assessment alterations, motor incoordination, poor executive function, and sedation.48
There are a number of cardiovascular effects attributed to the use of marijuana, many of which can lead to neurologic complications. During the time it takes to smoke a marijuana cigarette and the following 2 to 3 hours, the patient exhibits an increase in heart rate of 20% to 100%. Other cardiovascular changes include an increase in cardiac output, an increase in blood pressure while in the supine position, and orthostatic hypotension. These changes have been attributed to central, vagal, and sympathetic mechanisms.50-53 Marijuana abusers also show increased levels of catecholamines.53
Orthostatic hypotension is an important side effect of marijuana smoking, as individuals with a decreased cerebrovascular reserve who experience this postural drop in blood pressure show an increased risk for ischemic stroke.52 Furthermore, carboxyhemoglobin levels that imply decreased oxygen supply and development of arrhythmias are also considered factors that may increase the likelihood of an adverse cerebrovascular event.50,52-54
Chronic use of marijuana rapidly induces tolerance development to many of the cardiovascular effects such as increased heart rate and blood pressure changes. However, as soon as the use is interrupted tolerance is lost.52,55
Side effects attributed to the use of marijuana include psychiatric and behavioral abnormalities, as well as an increased risk to develop schizophrenia.50 Neurovascular side effects are of an ischemic nature and have been occasionally reported in the literature.52 The relationship between drug use and stroke is however, difficult to establish. The role of cannabis as a risk factor for stroke is therefore, not evident.50 Some authors believe that stroke in young marijuana smokers might not be associated to the use of the drug, but as a coincidence of events.52
Ischemic strokes due to marijuana consumption are thought to be caused by more than one mechanism. Sporadic cases of stroke in young marijuana smokers with no remarkable family history are thought to be the result of vasospasm. This idea is supported by the fact that most of these strokes happen while the patient is smoking the marijuana cigarette and by the absence of abnormal angiographic findings.50,52,53,56,57 Cerebral vasospasm has been suggested to be the result of either a toxic side effect of marijuana or a side effect in predisposed individuals.52
Another suggested mechanism, as mentioned before, is the development of postural hypotension associated with abnormal regulation of the cerebral blood flow;50,53,56,57 nevertheless this appears to be more significant in patients with decreased cerebrovascular reserve.52 Some authors have included as a third possible mechanism a vasculitic process; supported by the fact that a cannabis arteritis has been described, which resembles Buerger's disease. However, there have been no reports of cerebral vasculitis to support this mechanism.50,52
Allowing for the postural hypotension as well as increased cardiac work, catecholamines, and carboxyhemoglobin, older individuals with some degree of cerebrovascular disease are expected to be at increased risk of developing an adverse neurologic event such as a transient ischemic accident or stroke.52
Imaging
Infarcts in the basal ganglia, periventricular white matter, striatocapsular region, cerebellum temporal, parietal and occipital lobes have been described with CT and MR after the use of cannabis.47,50,53,56,58,59 In the acute setting diffusion-weighted MR has better sensitivity than CT for the early detection of ischemic cerebral parenchyma (Fig. 6).53
FIGURE 6: (A) DWI and (B) ADC show an area of restricted diffusion in a patient with recent history of marijuana smoking (arrows).
When studied with MR perfusion or PET, long-term cannabis users have been found to present an overall decrease in regional cerebral blood flow in the frontal, parietal, temporal, and occipital lobes, which seems to be progressively normalized with abstinence.47,56,60 Inexperienced users show decreased cerebral blood flow (CBF) probably secondary to stress.47 The acute administration of marijuana, however, increases CBF.53,56,57
Using transcranial Doppler, the pulsatility index (as measure of cerebrovascular resistance) has been found increased in young adults who regularly use marijuana; this indicates an increased cerebrovascular resistance probably due to vasoconstriction.53,61 Patients presenting with orthostatic hypotension who have been evaluated with transcranial Doppler, characteristically show decreased blood flow velocity.52,62
Given that ischemic strokes are seldom seen, as a result of cannabis use, other of ischemic stroke causes such as an embolic event, risk factors for thrombosis, and cocaine abuse must be sought out before concluding that the ischemic event is the result of marijuana use.53
ECSTASY
3,4-methylenedioxymethamphetamine (MDMA) is a popular recreational drug derived from methamphetamine and is commonly referred to as “Ecstasy”.63,64
MDMA acts in the central nervous system in different ways. Its main action is an acute and rapid release of 5-HT from serotonergic terminals. Other actions include increase in synaptic dopamine levels in several areas of the brain.64-69 In the acute setting there is, therefore, depletion of 5-HT from serotonergic neurons that leads to a 5-HT2A receptor down-regulation.64,65
It has also been suggested that chronic MDMA use causes a loss of 5-HT neurons as a result of toxic injury64; however, Chang et al63 found that neurons might not be damaged by MDMA but only down-regulated at the axon.
5-HT is the most potent vasoconstrictive amine in the brain.7 Reneman et al found that MDMA users are prone to cerebrovascular accidents due to the high levels of 5-HT, which stimulates 5-HT2A receptors in small vessels.64 These receptors are thought to play a role in the regulation of brain microcirculation by a vasoconstrictive mechanism. Therefore, it is suggested that stimulation of 5-HT2A receptors leads to prolonged vasospasm, which in the end causes necrosis.64,70,71
The occipital cortex and globus pallidus are prone to injury by MDMA because these contain high levels of 5-HT terminals and are rich in 5-HT2A receptors. In consequence the most conspicuous postmortem finding in MDMA users is necrosis of the globus pallidus.64,70-72 In addition, reduced regional cerebral blood flow has been seen in the basal ganglia, frontal, parietal, and temporal regions in MDMA users.65,73
All of these findings are anticipated to appear as areas of ischemia on imaging studies of the brain of MDMA abusers. Thus, ischemic changes in the globus pallidus and in the occipital cortex are most expected in the event of an MDMA-related ischemic stroke.
Furthermore, lower gray matter concentration in the neocortex, brainstem, cerebellum, and anterior cingulate has been described in MDMA users as a result of toxicity, vascular ischemia, or neurotrophic effects.65
MDMA produces an increase in mean arterial pressure that is dose dependent. It is believed that this increase in blood pressure might augment the risk of intraparenchymal brain and subarachnoid hemorrhage. However, most reports have shown that the majority of MDMA abusers with either of these complications had an aneurysm or arteriovenous malformation in the cerebral vasculature that made them susceptible to these kinds of bleeds.67,74,75
CONCLUSIONS
Cocaine is an alkaloid that has vasoconstricting effects. Its use has increased since the introduction of “crack”. Acute and chronic cerebrovascular changes are seen in cocaine abusers. Acute changes include ischemic and hemorrhagic stroke, the latter being most frequent in patients who smoke cocaine. Atrophy and vasculitic events are also seen in these patients. Marijuana is the most commonly used illicit drug. It is thought to produce cerebrovascular events although this has not been well established. When dealing with a patient with history of marijuana abuse and CNS abnormalities, one should always exclude other causes and other drugs that cause these same findings before concluding th effects are due to marijuana use. MDMA (“Ectasy”) is a popular recreational drug that also causes vasospasm in the intracranial circulation mainly producing ischemic events. When used chronically it decreases the gray matter concentration developing atrophy. Although described are the most common complications and imaging findings for the given substance, the described patterns are not usually encountered in drug addicts as these abusers are commonly polydrug abusers who have imaging findings reflecting the superimposition of various effects.
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