addicted brain: imaging neurological complications of ...media and arteriolar brosis, among other...

Radiología. 2017;59(1):17---30

www.elsevier.es/rx

UPDATE IN RADIOLOGY

The addicted brain: Imaging neurological complications

of recreational drug abuse�

A. Montoya-Filardi ∗, M. Mazón

Área Clínica de Imagen Médica, Hospital Universitario y Politécnico La Fe, Valencia, Spain

Received 12 January 2016; accepted 14 September 2016

KEYWORDSRecreational drugs;Biochemicalmechanisms;Magnetic resonanceimaging;Functional imaging;Infarction;Hemorrhage;Leukoencephalopathy;Atrophy;Marchiafava---Bignami

Abstract Recreational drug abuse represents a serious public health problem. Neuroimaging

traditionally played a secondary role in this scenario, where it was limited to detecting acute

vascular events. However, thanks to advances in knowledge about disease and in morpholog-

ical and functional imaging techniques, radiologists have now become very important in the

diagnosis of acute and chronic neurological complications of recreational drug abuse.

The main complications are neurovascular disease, infection, toxicometabolic disorders, and

brain atrophy. The nonspecific symptoms and denial of abuse make the radiologist’s involve-

ment fundamental in the management of these patients. Neuroimaging makes it possible to

detect early changes and to suggest an etiological diagnosis in cases with specific patterns of

involvement.

We aim to describe the pattern of abuse and the pathophysiological mechanisms of the drugs

with the greatest neurological repercussions as well as to illustrate the depiction of the acute

and chronic cerebral complications on conventional and functional imaging techniques.

© 2016 SERAM. Published by Elsevier Espana, S.L.U. All rights reserved.

PALABRAS CLAVEDrogas de abuso;Mecanismobioquímico;Resonanciamagnética;Imagen funcional;Infarto;

El cerebro adicto: imagen de las complicaciones neurológicas por el consumo de

drogas

Resumen Las drogas constituyen un gran problema sociosanitario. Tradicionalmente, la neu-

roimagen ha tenido un papel secundario limitado a la detección de eventos vasculares agudos.

En la actualidad, el radiólogo ha adquirido gran relevancia en el diagnóstico de las complica-

ciones neurológicas agudas y crónicas, debido al avance en el conocimiento de la enfermedad

y al desarrollo de las técnicas de imagen morfológicas y funcionales. Las principales com-

plicaciones son la patología neurovascular, la infección, los trastornos tóxico-metabólicos y

� Please cite this article as: Montoya-Filardi A, Mazón M. El cerebro adicto: imagen de las complicaciones neurológicas por el consumo de

drogas. Radiología. 2017;59:17---30.∗ Corresponding author.

E-mail address: [email protected] (A. Montoya-Filardi).

2173-5107/© 2016 SERAM. Published by Elsevier Espana, S.L.U. All rights reserved.

Document downloaded from http://www.elsevier.es, day 04/05/2018. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.Document downloaded from http://www.elsevier.es, day 04/05/2018. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

dx.doi.org/10.1016/j.rxeng.2016.12.003

http://www.elsevier.es/rx

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mailto:[email protected]

18 A. Montoya-Filardi, M. Mazón

Hemorragia;Leucoencefalopatía;Atrofia;Marchiafava---Bignami

la atrofia cerebral. La sintomatología inespecífica y la negación del consumo hacen que la

implicación del radiólogo pueda resultar fundamental en la atención de estos pacientes. La

neuroimagen permite detectar alteraciones precoces y plantear el diagnóstico etiológico ante

patrones de afectación específicos. Nuestro objetivo es describir el patrón de consumo y el

mecanismo fisiopatológico de las drogas con mayor repercusión neurológica, así como ilustrar

las complicaciones cerebrales agudas y crónicas mediante técnicas de imagen convencional y

funcional.

© 2016 SERAM. Publicado por Elsevier Espana, S.L.U. Todos los derechos reservados.

Introduction

Human kind has always wanted to experience new sensa-tions, to reach different states of consciousness and, onoccasion, to mask reality. The substances used with thispurpose have targeted, whether intentionally or not, thecentral nervous system (CNS). Consumption patterns havechanged and conditions of use have improved, but they allhave deleterious effects that we can see and quantify.

Each substance has multiple forms of presentation whichare modified all the time, the absorption pathways of thebody are limited and they cause complications that over-lap one another. Neuro-imaging findings frequently pose thepossibility of consumption, and even in view of character-istic patterns, it would be possible to suggest the specifictype of drug. The role of the radiologist, therefore, is evermore relevant both finding urgent conditions and visualizingchronic effects.

Our goal is to describe the consumption pattern and thephysiopathological mechanisms of the drugs that have themost neurological repercussion (cocaine, amphetamines,heroin, alcohol, cannabis and toluene), as well as to illus-trate the acute and chronic cerebral complications throughconventional and functional image modalities (positronemission tomography [PET], single photon emission com-puted tomography [SPECT] and perfusion by magneticresonance [MRI]).

Cocaine

Cocaine is the main alkaloid obtained from the leaves of ashrub belonging to the family Erithroxylon coca, present inthe Western regions of South America. There are two formsof presentation: hydrochloride (with the appearance of afine powder) and alkaloid (also known as crack).1 The mostpopular route of administration is intranasal, which reachesconcentrations in the CNS in 3---5 min. The main actionof cocaine is summarized in the sympathomimetic effectdue to the blockage of catecholamine reuptake.1---4 It alsoblocks the reuptake of serotonin and dopamine transmitters,increasing their extracellular concentrations, especially inthe accumbens nucleus.2,5,6

Addiction caused by cocaine is due to its rapid actionmechanism, since its effect is almost immediate afteradministration.1 A feeling of euphoria or high is experiencedafter its consumption mediated mainly by the occupation ofdopamine receptors called DA-D2.1,3---5

The main cerebral complications derived from cocaineabuse are vascular ones, especially subarachnoid hem-orrhages and intraparenchymatous hemorrhages; overallhemorrhagic events are twice as frequent as ischemicinfarctions.1,7,8 Nevertheless, the form of the drug and theroute of absorption influence on the type of adverse event.When cocaine is smoked in the form of crack the incidenceof hemorrhagic events is greater, while there are no signifi-cant differences between ischemic and hemorrhagic eventswhen the drug is sniffed.9,10

The physiopathological mechanisms involved in the pro-duction of ischemic cerebrovascular accidents are multipleand synergic, but vasoconstriction or vasospasm stand outamong them2,11 (Table 1). This phenomenon can causeendothelial damage consisting of disruption of the tunicamedia and arteriolar fibrosis, among other alterations.12

However, the significant vasculitis component stands out,confirmed by the existence of focal stenoses of the vascu-lar lumen and enhancement of vessel walls in angiographicstudies.5,13

Ischemic infarctions commonly affect the territoriesof mid and posterior cerebral arteries (Fig. 1), and theborder territories, the internal capsule and the hippocam-pus, without a specific disorder pattern.1,5,9 Mesencephalicinfarction has been associated with the simultaneous use ofcocaine and amphetamines.14 Since it does not show a char-acteristic distribution, concomitant findings are speciallyrelevant, such as perforation of the nasal septum, acceler-ated atherosclerosis in young people without cardiovascularrisk factors (Fig. 2) and generalized vasospasm.

Table 1 Mechanisms implied in the production of cocaine-

induced ischemic cerebrovascular accidents.

Ischemic mechanism Biochemical phenomenon

Vasoconstriction Calcium channel blockade1,4

Increase of serotonin levels2,5

Prothrombotic

phenomena

Increase of thromboxane levels

and platelet aggregation5,9,10

Procoagulant diathesis Reduction of antithrombin III

and protein C7,8

Atherosclerosis Nitric oxide inhibition in the

endothelium11

Vasculitis Impurity-activated paracrine

and immune mechanisms5,9,13


The addicted brain: Imaging neurological complications of recreational drug abuse 19

Arteria

MTT

A B C D

Figure 1 Acute ischemic cerebrovascular accident in the territory of the left medial cerebral artery associated with cocaine

consumption. (A) CT without IV contrast showing hypodensity of the caudate head, the left lenticular nucleus and the insula

(arrowheads). (B) Parametric map of the mean transit time (MTT) showing a large ischemic area with an increased MTT (in blue),

mostly corresponding to salvable tissue (represented in green in C), and a small ischemic core of unviable tissue mass with diminished

cerebral blood volume (red in C). (D) Diffusion-weighted images identifying restriction of the ischemic area in the Sylvian territory.

Figure 2 Thirty-eight-year-old man with accelerated atherosclerosis without the classical cardiovascular risk factors --- usual

cocaine consumer. (A) Doppler duplex ultrasound image of the cervical segment of the internal carotid artery showing a relatively

homogeneous soft plaque (white arrows), with irregular surface, ulceration (arrowhead) conditioning a serious stenosis of the lumen

with high-speed turbulent flow (black arrow) and peak systolic speed of approximately 300 cm/s. (B) CT volumetric reconstruction of

both carotid arteries showing marked bilateral atherosclerotic damage (plaques marked with arrows). (C) Detail of the transversal

image of a CT study in bone window where we can identify perforation of the nasal septum (arrow).



Figure 3 Thirty-three-year-old woman showing intense headache and left hemiparesis whose toxic urine analysis reveal cocaine

consumption. (A) Transversal CT image without IV contrast showing right intraparenchymatous cortico-subcortical frontal parafal-

cine hematoma (arrows). (B) T2-weighted transversal MRI showing the markedly hypointense hematoma (arrows), vasogenic edema

on its lateral edge and, on its medial edge, one tubular flow vacuum nidus corresponding to an arteriovenous malformation (arrow-

heads). (C) T1-weighted sagittal MRI with IV contrast showing the nidus of the malformation (arrow) with drainage into the superior

longitudinal sinus. (D) Digital subtraction arteriography sagittal image confirming the arteriovenous malformation (arrow).

Up to 50% of patients with cocaine-induced hemorrhagiccomplications show underlying vascular condition such asaneurysms and vascular malformations.1 The greater preva-lence of aneurysms is explained by the maintained increaseof blood pressure.1,2,15 The mechanism involved in aneuris-mal rupture and arteriovenous malformations is high systolicpeak and increase of heart rate after acute consumptions4,5

(Fig. 3). The combined abuse of cocaine and ethanol is notuncommon, which increases synergically the odds of suffer-ing subarachnoid hemorrhages.10

The intraparenchymatous hematoma is usually lobar andsubcortical while there is greater incidence of bleeding inthe encephalon.5,16 Hematomas are larger and they tendto spread themselves to the ventricles more easily than in

non-users, which conditions greater neurological deficits.16

Hemorrhagic transformations of the ischemic areas is notuncommon due to damage to hematoencephalic barrier andincrease of arterial pressure.7,9

Chronic addicts characteristically show structural atro-phy in the frontal lobes and to a lesser extent, inthe temporal ones,8,9 where reduction of metabolicactivity has been confirmed in PET examinations with 18-fluorodeoxyglucose.17 Perfusion studies with SPECT withhexamethyl propylene or amino oxyme marked withmetastable technetium 99 (99mTc-HMPAO) have shown ageneralized reduction of 30% in global cerebral blood flowadding a specific reduction of the relative cerebral bloodflow in the prefrontal cortex, anterior cingulate gyrus, the



thalami, the basal ganglia, the occipital cortex and thecerebellum.18

In addition to the withdrawal syndrome, many usersexperience an intense crave to consume after it has gone(the so-called craving stage), which can be triggered bymultiple stimuli. In this complex stage, there is a selec-tive activation of the limbic system in perfusion studies,19

hypermetabolism in the orbitofrontal cortex19,20 and eveninvolvement of the mu opioid system.21 Functional studiesbased on oxygen consumption (BOLD sequence) in activeusers confirm an increase of activity in the craving stage anddependence located in the limbic, paralimbic regions, theaccumbens nucleus, the frontal and inferior frontal orbitalcircumvolutions and the anterior cingulum.22 This activationhas also been shown during the craving for consumptionwhen videos showing the drug were played.23 However,after administration of the substance, these regions aredeactivated.22

Amphetamines and derivatives

Amphetamine was synthesized for the first time in1887 and it was the first substance of a group thatshares properties, called the same way as a whole.Later there appeared methamphetamine and MDMA (3,4-methylenedioxymetanphetamine), commonly known as‘‘ecstasy’’ or ‘‘crystal’’. There is rigorous legal control ofamphetamine derivatives in research studies and for thetreatment of disease (obesity and hyperactivity). The con-sumption profile of MDMA is associated with night-timeleisure; it is the second most consumed illegal drug amongyoung people after cannabis.24 The most common route ofadministration is orally, in the form of powder or ‘‘crystal’’

or pills. It causes a rapid feeling of euphoria and an increasedsensory perception this is why it is considered both stimulantand hallucinogenic.8,25

Amphetamines, as a whole, increase the synaptic con-centrations of biological amines (dopamine, noradrenalinand serotonin/5-hydroxytryptamine); the main and mostcharacteristic action of MDMA is the release of 5-hydroxytryptamine.8,11,25 This neurotransmitter is the aminewith the greatest vasoconstrictor effect in the brain.5

Although the biochemical mechanism of amphetaminescauses long-term ischemia, the most common urgentcomplications are hemorrhages due to blood pressureincrease. Just as it happens with cocaine consumption,blood pressure increases after consumption conditionsgreater risk of rupture of arteriovenous malformations andpreexisting aneurysms.9,26

Vasoconstriction in cerebral microcirculation ultimatelycauses necrosis of irrigated tissue.8,9,26 The areas that aremore commonly affected by this ischemia are the globus pal-lidus (as it happens with heroin) and the occipital cortex,where the largest concentration of 5-hydroxytryptaminereceptors are located (called 5HT 2A)8,9; in fact, the mostcommon finding in autopsies is necrosis of the globuspallidus26 (Appendix B Fig. S2 online). This spatial speci-ficity explains why it is in these areas where structural andfunctional complications develop.

Another complication that stems from blood pressureincrease is posterior reversible encephalopathy syndrome(Fig. 4). This is an unspecific disorder of cerebrovascularself-regulation showing a preference for posterior circu-lation and borderline cortical areas. On the computedtomography (CT), findings can be subtle, identifying hypo-density non-confluent cortical---subcortical, bilateral areasoften located in the posterior parietal occipital lobes.

Figure 4 Forty-two-year-old woman---sporadic consumer of 3,4-methylenedioxymetanphetamine (MDMA) going to hospital with

headache, visual alteration and hypertensive crisis due posterior reversible encephalopathy syndrome. The urine toxicology exam

reveals 3,4-metilendioximetanfetamine (MDMA). (A) T2-weighted transversal MRI showing extensive confluent cortico-subcortical

bilateral edema predominantly parieto-occipital posterior (arrows). (B) T2-weightred FLAIR coronal MRI showing the edema (arrows)

and its mass effect with fissure collapse (arrowheads). The clinical manifestations and the radiological findings were resolved a few

days later with support measures and blood pressure control.



The MRI is more sensitive for its diagnosis and findingsare detected early, showing high signal intensity in T2-weighted/FLAIR sequences.

When it comes to long-term effects, selective atrophy inthe occipital and frontal cortex, the left temporal lobe andthe brainstem has been confirmed compared to users thatabused other substances exclusively or jointly (polyabuse).25

Methamphetamines can cause gray matter volume loss whichcan range from generalized to unilobar.25,27,28 However,an increase in the volume of the striatum has been con-firmed (caudate and putamen) in adult methamphetamineconsumers for over two years. Volume increase is due tomechanisms of initial response to neurotoxicity --- above allswelling. This reaction evolves subsequently to atrophy ifthe neurotoxic dose continues to increase.25,29 In childrenexposed to methamphetamines in utero there is striatumvolume loss initially, since there is no such compensation todopaminergic damage.25,30

With PET, it is possible to observe selective dam-age in serotoninergic neurons and a reduction of itstransmitters.31,32 When it comes to SPECT-measured per-fusion we have been able to confirm a decrease of therelative cerebral blood flow in the visual cortex, thecaudate, the superior parietal lobe and the dorsolateralregion of the frontal lobe, associated with MDMA-inducedvasoconstriction.31,33 Keeping with it, we have been able todetect reduction in relative cerebral blood volume of suchdorsolateral region of the frontal cortex through MRIs as thefirst functional manifestation after the first contacts withMDMA in young subjects.34

Heroin

Heroin or diacetylmorphine is the most widely consumedillegal compound within the opioid group. It was commer-cialized for the first time in 1898 as an analgesic substituteto morphine, but it was withdrawn after the physical andpsychological dependence that it caused was confirmed.Its appearance is that of a white, fine crystalline powder,although it can vary. There are three main types: numbertwo or freebase; number three, known as brown sugar dueto its earthy aspect; and number four or Thai variety of a 90%purity. The IV is the most effective, filling route of adminis-tration with respect to its effect, and it was the most widelyused until AIDS appeared. Today, the inhaled and smokedroutes of administration are more widely used.

The mechanism of action of heroin is mediated by theactivation of three types of receptors: mu, kappa and delta.Mu receptors are responsible for the feeling of euphoria andpositive reinforcement, in addition to analgesia, respiratorydepression and miosis.35,36 Kappa and delta receptors con-tribute to the analgesic effect, the feeling of dysphoria andthe psychomimetic effect.35,36

A sharp, positive feeling after the first contacts (hon-eymoon) occurs initially. When the state of intoxicationadvances, the effects fade. The degree of tolerance turnsthe drug into a means to avoid withdrawal syndrome andless and less often into a source of pleasure.

Ischemic conditions, toxic leukoencephalopathies andatrophies are among the most common complications asso-ciated with heroin abuse.

Ischemia is the most common neurovascular complicationof the compounds derived from opioids and morphine.8,11

The physiopathological mechanisms involved are vasospasmsdue to smooth muscle contraction, vasculitis phenomenaand embolisms due to additives.37---39 Borderline vascular ter-ritories are the most vulnerable ones, but the anatomicalstructure that is most commonly affected is the globus pal-lidus (up to 5---10% in chronic users).40 Chronic ischemia iscommon which is shown on the MRI as confluent hyperinten-sities in the periventricular and subcortical white matter.This finding gains special importance if patients are youngand without any other risk factors.11,35

A specific complication of the heroin addict who usesthe inhaled route is a phenomenon known as chasing thedragon. This denomination comes from the way the smokeis inhaled when the heroin is heated over an open flame.It became popular as an alternative to IV administrationto avoid HIV contagion. The neurological complication con-sists in a leukoencephalopathy with edema. It is probablydue to a mechanism of mitochondrial toxicity, triggeredby impurities that are activated when heating aluminumfoil.41 These manifestations can occur with cerebellar andextrapyramidal signs, and in the most serious cases pseudobulbar manifestations, spasms, hypotonic muteness or evendeath occur.11 Anatomopathologically, a spongiform degen-eration of the corticospinal tracts and of the cerebral andcerebellar white matter has been reported.8,41 T2/FLAIR MRIsequences show bilateral symmetric hypersignal of whitematter in these locations. Cerebellar disorders and of theposterior limb of the internal capsule --- not affecting theanterior limb, is the most characteristic sign.42 These find-ings are not exclusive to heroin-induced leukopathy and theycan be secondary other substance abuse. Spectroscopy find-ings complement diagnosis and increase their specificity;they show an abnormal descent of the N-acetylaspartatepeak, an increase of lactate and myoinositol, and stabilityof lipid peaks11 (Fig. 5). Resolution of the clinical disorderhas been described when heroin use is interrupted thoughimage findings can persist.43

In addition to the complications derived from the sub-stance itself, both the impurities (lipophilic substances)used in the mixture and the unsterile conditions in the IVadministration make infections be relatively common andespecially important.8,11,41 Half the users develop endocardi-tis, occlusion of small vessels due to septic emboli andformation of abscesses. In the MRI, abscesses are shownas rounded lesions that are enhanced in a ring shape afterthe administration of contrast, they show perilesional vaso-genic edema and its purulent content restricts diffusion(Fig. 6). The organism involved in most cases is Staphylo-coccus aureus, which enters the blood stream from the skinthrough the needle.44

The chronic consumption of heroin leads to encephalicatrophy, hypometabolism and hypoperfusion. Gray-matterloss, confirmed through volumetry on the MRI, prevails inthe prefrontal bilateral cortex, the temporal lobes and theinsulae,45 with a correlation between the duration of use andthe degree of atrophy suggestive of a cumulative effect.46

White matter has been assessed in image studies throughdiffusion tensor imaging, in which it has been possible toobserve a reduction in the fractional anisotropy translatinga disruption of fibers in bilateral frontal regions, the right



A B

C D E

Cho

NAA

Cr

Glx Lipids

4 3 2 1 0

Cr2 Ins

Figure 5 Man with predominantly supratentorial leukoencephalopathy associated with heroin consumption---typically known as

chasing the dragon. (A) and (B) CT transversal images without IV contrast showing generalized white matter hypodensity of the corona

radiata (asterisks) spreading throughout the corticospinal tracts into the posterior limbs of the internal capsules (arrowheads). (C)

and (D) T2-weighted transversal MRIs in the same locations where we can more clearly see white matter damage with signal increase.

(E) The single-voxel spectroscopy study with short echo time showed a decrease of the N-acetylaspartate peak and a slight increase

of lipids and lactate.

precentral gyrus and the left cingulum.47 Studies in chronicaddicts have confirmed a global decrease of perfusion48 andometabolism31,49 and a greater reduction of both parametersin the frontal and temporal lobes (Fig. 7). When it comes toacute effects, it has been confirmed that there is a drop inperfusion quantified through ASL (arterial spin labeling) inthe anterior left cingulate cortex, the left prefrontal cortexand the insulae.50

Alcohol

Alcohol is a socially accepted legal drug. Excessive, chronicconsumption of alcohol is associated with an increase ofmorbimortality and it reduces life expectancy in up to 15years.51 Based on its process of manufacturing, alcoholicbeverages are divided into fermented and distilled. Themain component of alcohol is ethanol, a CNS depressor thatprogressively numbs brain and sensory functions. It is mis-takenly confused with a stimulant because at the onset ofintoxication there is lack of behavioral inhibition.

There are three main neurological damage mechanisms:direct toxicity, derivative-mediated damage (methanoland acetaldehyde) and effects secondary to cirrhosisand nutritional deficits. There are multiple direct dam-age mechanisms proposed, but the common outcome isgreater susceptibility of N-methyl-d-aspartate receptors ofexcitement and glutamate cytotoxicity, the so-called upre-gulation.

Wernicke’s encephalopathy is one of the maincomplications of chronic alcoholics due to deficit of thi-amine coenzyme (vitamin B1). Wernicke’s encephalopathycauses the classic triad of ophthalmoplegia, confusion andgait disorder though the complete clinical manifestationsonly occur in one third of the patients.52 Delayed diagnosisand treatment can lead to Korsakoff’s psychosis, charac-terized by memory alterations and confabulation. Osmoticchanges due to thiamine reduction cause intracellular andextracellular edema, especially in areas near the cere-brospinal fluid, where the hematoencephalic barrier is morepatent. Lesions are commonly located around the third ven-tricle and the lateral ventricles, the thalamus dorsomedial



Figure 6 Habitual IV heroin consumer going to the ER with disorientation. (A) CT without IV contrast where we can identify

multiple subcortical supratentorial abscesses (arrows)-predominantly right and mesencephalic. (B) T2-weighted transversal MRI

confirming the findings and showing an important vasogenic perilesion edema. (C) In the diffusion sequence, the content of the

abscesses shows restriction since it consists of purulent material. (D) After the administration of contrast the abscesses are totally

enhanced looking like ring shapes. The microorganism involved is Staphylococcus aureus.

pulvinar nuclei, the mammillary bodies, and the pineal andperiaqueductal region.52 In the most serious cases, the deepwhite matter and even the cortex can also be affected.In the affected areas, the MRI will show hyperintensityin T2/FLAIR,8,11 and after the administration of contrastthey can be enhanced due to rupture of hematoencephalicbarrier, and intense enhancement of mammillary bod-ies is pathognomonic of this disorder in acute stagesand even in the absence of T2 hyperintensity51---53

(Fig. 8).Another manifestation of chronic alcohol abuse is

Marchiafava---Bignami disease, consisting of corpus callosum

demyelination and necrosis.51,54 A toxic agent from red winehas been identified that, in conjunction with vitamin defi-ciency, can be the cause of these manifestations.55 Thedisorder begins in the trunk and it can spread to the knee andeven the splenius.51,54 The corpus callosum necrosis occursin three stages characteristically (layer necrosis), typicalof this disease. There are two subtypes: A, where there iscomplete damage of the corpus callosum showing greaterimpairment of consciousness and leading to worse progno-sis; and B, where damage of the corpus callosum is partialshowing less impairment of consciousness and more favor-able evolution. MRIs are especially important due to the fact



Figure 7 Forty-eight-year-old man chronic heroin male consumer showing cognitive impairment and behavioral alterations. (A)

T1-weighted transversal MRI where we can identify an important frontal bilateral atrophy with anteroposterior damage gradient.

See dilation of the subarachnoid spaces of frontal convexities and Sylvian fissures (arrows). (B) PET transversal image with 18F-

fludeoxyglucose where we can see frontal bilateral hypometabolism (arrows) with the same distribution as the atrophy in the

structural image.

that clinical manifestations are unspecific. Hyperintensity inT2/FLAIR without mass effect in the central region of thecorpus callosum is the common presentation (Fig. 9); it canbe enhanced peripherally after the administration of con-trast on the acute stage.55 The white matter in the brainhemispheres can also be damaged --- a finding described in upto 40% of necropsies of patients with Marchiafava---Bignamidisease. Spread to the cortex --- known as Morel’s corticallaminar sclerosis consists of gliosis of the third cortical layerin the frontal and lateral regions.56 In PET studies with FDGit has been possible to confirm a metabolic reduction inthe cortex frontal of temporo-parieto-occipital associationdue to the disruption of commissural fibers that alter thisassociation network.51,57

Chronic hepatic encephalopathy is due to and inade-quate cleansing of nitrogenated compounds and other toxinsthat accumulate in the brain parenchyma. Image findingsof this disease are practically undetectable through CT andMRI T2-weighted sequences. In the T1-weighted sequencesthere is bilateral and symmetrical hyperintensity compati-ble with manganese deposits, located in the base ganglia(in particular in the globus pallidus), the hypothalamus, themesencephalon and the adenohypophysis51 (Appendix B Fig.S1 online). MRI spectroscopy study obtained with short echotime is characteristic in patients with chronic hepatic ence-phalopathy, who show a significant reduction of myoinositoland choline, and an increase of glutamine/glutamatepeaks.51

Lastly, chronic alcoholism is associated with neuronalloss and atrophy, especially of the frontal superior andmotor cortex, and with white matter, bridge, thalamus,mammillary body and cerebellum volume loss, and greater

damage of the vermis superior.51 Concomitant use of alcoholwith other drugs, in particular with cocaine, contributes togreater white matter loss, due to the formation of a long-lasting vasoactive metabolite, cocaethylene, resulting fromthe co-administration of both substances.11

Cannabis

Cannabis is the most consumed illegal drug worldwide.58 Itis obtained from Cannabis sativa, a dioecious herb. Its mainpsychoactive component is a lipophilic substance calleddelta-9-tetrahydrocannabinol. The products obtained fromcannabis are marihuana (prepared with dry leaves), hashish(derived from its resin) and hashish oil (obtained from dis-tilling organic solvents).

All the parts of the plant contain delta-9-tetrahydrocannabinol. The most commonly used formof cannabis abuse is smoked marihuana. Its resin is usedin food for oral consumption; this form of administrationcauses a great amount of intoxications since the user doesnot control the time elapsed between ingestion and effects.Chronic consumption increases the risk of schizophreniaand behavioral changes.11

After its consumption a feeling of wellbeing is obtaineddue to the activation of cannabinoid receptors CB1, presentin the black matter, the hippocampus, the limbic cortex andthe cerebellum.8,9

Its wide use and polyconsumption are factors that makeit difficult to establish a direct connection between cannabisand cerebrovascular disease.9,58 It causes orthostatichypotension, which in people with little cerebral blood



Figure 8 Chronic alcoholic man with manifestations of confusion and ataxia due to Wernicke’s encephalopathy. (A) T2-weighted

transversal MRI where signal hyperintensity is identified around the Sylvian aqueduct (arrowheads). (B) T2-weighted coronal FLAIR

MRI where periventricular signal hyperintensity of the third ventricle can be easily identified (arrowhead). (C) and (D) Sagittal and

transversal MRIs with IV contrast showing bilateral enhancement of mammillary bodies (arrowheads and arrow).

Figure 9 Chronic red wine male consumer with Marchiafava---Bignami’s disease in subacute stage. (A) and (B) T2-weighted

FLAIR coronal and sagittal MRIs showing marked hyperintensity of the corpus callosum trunk posterior portion (arrowheads). No

enhancement after the administration of contrast.



Figure 10 Thirty-eight-year-old man who is a chronic consumer of cannabis showing hypoperfusive ischemic infarctions in the

right internal borderline territory. (A) CT transversal image without IV contrast in which a hypodensity area can be seen on the

right corona radiata (arrow). (B) T2-weighted transversal MRI showing infarctions as hyperintense. (C) Transversal diffusion-weighted

images showing restriction of the infarctions which in turn allows us to assess the typical linear distribution of the internal borderline

territory. See cortical atrophy---uncommon in a middle-aged patient (arrows).

reserve can cause cerebral infarctions---being this is themain mechanism of ischemic cerebrovascular accidents59

(Fig. 10). In addition to high blood pressure that acts as atrigger, there are other predisposing vascular alterations;in this sense, the presence of intracranial stenosis has beenconfirmed in 31% of cannabis consumers who have developedischemic cerebrovascular accidents.60 Vasospasms, vasculi-tis, development of arrhythmias and high concentrationsof carboxyhemoglobin are other factors that predisposeto adverse cerebrovascular events.8,9,61,62 The location ofthese ischemic infarctions is not specific: basal gangliapredominate, as well as periventricular white matter,the cerebellum and the temporal, parietal and occipitallobes.

Perfusion studies through PET and SPECT confirm anincrease of relative cerebral blood flow with acuteconsumption.63 However, there is reduction of generalizedrelative cerebral blood flow among chronic users that can bereverted with abstinence.31,58 Glucose metabolism in spo-radic users is usually diminished except for the cerebellum,probably due to the large number of cannabinoid receptorsin this area.31

Toluene

Toluene or methylbenzene is an aromatic hydrocarbon usedin the industry as antiknock agent in fuels, as paint thin-ner and adhesive solvent, among other uses. It can beused as a drug mainly by teenagers due to its low costand wide availability.64 It is inhaled and easily absorbed bythe lungs from which it spreads rapidly to nearby tissueswith a high lipid concentration such as the central nervoussystem.

Acute effects include behavioral changes, euphoria,headache and ataxia; during this stage, there are usuallyno identifiable structural alterations.8 Chronic consumption

causes irreversible lesions due to cumulative toxic effect,and it can occur clinically with cerebellar dysfunction,psychiatric diseases, spasticity, cognitive changes andsecondary Parkinsonism. In the MRI it is possible to identifywhite matter lesions that begin in the periventricular regionand in time, spread to U fibers; the degree of damage isassociated with the seriousness of the neurological deficitsand cognitive impairment.64,65 It causes white and graymatter atrophy without any specific distribution patterns.In morphometric studies it has been confirmed that there isgray matter loss in multiple locations of the brain cortex,while volume loss in frontal and parietal cortex is associ-ated with greater cognitive deficits.64 Using spectroscopictechniques low N-acetylaspartate levels in the white matterhave been identified as caused by neuroaxonal integrityimpairment though this finding is of non-specific nature.66

In SPECT studies, perfusion alteration in the frontal,parietal and temporal lobe cortex has been identified; alsohypoperfusion in the prefrontal region is associated withgreater behavioral alteration.67

Conclusion

Drugs are a serious social health issue, because they haveimportant short and long-term repercussions on the CNS.The main acute complications are ischemia and hemor-rhages whose early detection and urgent treatment isespecially important for the prognosis of the patient. Attimes image findings are specific like the spectroscopic pro-file of leukoencephalopathy due to heroin consumption,T1 hyperintensity in chronic hepatic encephalopathy orcontrast uptake in mammillary bodies in Wernicke’s ence-phalopathy. However in most cases diagnosis comes fromintegrating the images with the clinical context, such asthe posterior reversible encephalopathy syndrome in young



patients without other cardiovascular risk factors or pallidusnecrosis in heroin or MDMA addicts (Appendix B Table S2online). Functional modalities such as PET and MRI perfusionplay an ever more important role by showing the deleteriouseffects that have spatial specificity in some substances.

Ethical disclosure

Protection of people and animals. The authors declare thatno experiments with human beings or animals have beenperformed while conducting this investigation.

Confidentiality of data. The authors confirm that they havefollowed their center protocol on the publication of datafrom patients.

Right to privacy and informed consent. The authors con-firm that in this article there are no data from patients.

Authorship contribution

1. Manager of the integrity of the study: AMF and MM.2. Study idea: AMF and MM.3. Study design: AMF and MM.4. Data mining: AMF and MM.5. Data analysis and interpretation: N/A.6. Statistical analysis: N/A.7. Reference: AMF and MM.8. Writing: AMF and MM.9. Critical review of the manuscript with intellectually rel-

evant remarks: AMF and MM.10. Approval of final version: AMF and MM.

Conflicts of interests

The authors declare no conflict of interests associated withthis article whatsoever.

Appendix A. Supplementary data

Supplementary data associated with this article can befound, in the online version, at http://dx.doi.org/10.1016/j.rxeng.2016.12.003.

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