Acute brain injury following illicit drug abuse in adolescent and young adult patients: spectrum of neuroimaging findings

Abstract

The use of illicit drugs is currently a major medical problem among adolescents. Several illicit drugs have a high abuse potential and can be neurotoxic causing high morbidity and mortality. The clinical manifestation of adolescents with acute drug-induced neurotoxicity is often characterized by non-specific symptoms and findings. Early diagnosis is important to prevent death and permanent long-term neurological impairments. We report on clinical and neuroimaging findings in five adolescents with acute brain imaging following illicit drug intoxication to highlight the role of neuroimaging findings in the diagnostic work-up of pediatric acute drug-induced neurotoxicity. Our patients reveal two main neuroimaging patterns of brain injury: diffuse symmetric subcortical white matter injury with preferential cerebellar involvement (leukoencephalopathy pattern) or multiple foci of ischemic infarctions in a non-arterial territory distribution (ischemic pattern). Familiarity with these two neuroimaging patterns of findings in the evaluation of magnetic resonance imaging studies in adolescents with acutely altered mental status may suggest the correct diagnosis, narrow the differential diagnosis, and consequently allow early initiation of targeted laboratory investigations and treatment, potentially improving outcome.

Introduction

Currently, substance abuse is a major medical problem among adolescents.¹ It has been reported that up to 20% of high school students have used recreational drugs other than marijuana at least once. Adolescents are also reported to engage in illicit use of prescription opioid medications. Approximately 1% of American high school seniors reported 1.2% lifetime heroin use.² Familiarity with the imaging patterns of acute drug-induced brain injury is important, particularly for the pediatric and adolescent population as awareness of illicit drug use is relatively low among radiologists.

We present the imaging findings in five adolescent patients who presented with acute drug-induced brain toxicity. In addition, we discuss the main differential diagnosis and pathophysiology.

Materials and methods

The patients included in this study were collected by the senior author (TAGMH) between 2005 and 2016. Review of the clinical histories provided information about neurological features and the causative illicit drug. In a retrospective analysis, all available neuroimaging datasets including head computed tomography (CT) and brain magnetic resonance imaging (MRI) were qualitatively evaluated for morphological and signal abnormalities within the supra and infratentorial brain. All neuroimaging datasets were acquired acutely following the intoxication episode for clinical indication, and the local departmental protocols were used. This retrospective study did not require approval by the institutional review boards.

Results

Key clinical and neuroimaging findings are summarized in Table 1. Our patients all presented with acute altered mental status, two patients also showed extrapyramidal signs and one patient had myelopathic signs. Opiates were the most common substance, there were two cases of heroin and one case of methadone intoxication. Data about the long-term outcome were available only for two patients: one child died and the other was in a vegetative state.

Table 1.

Key clinical and neuroimaging findings of the patients presented with acute brain imaging following illicit drug intoxication.

Patient	Sex	Age, years	Presumed substance	Clinical presentation	Imaging modalities	Distribution						Rhabdomyolysis (elevated CPK)	Prognosis
						Cerebral white matter	Cerebral cortex	Cerebral deep gray matter	Cerebellum	Brain stem/spine	DWI
1	M	16	Heroin	AMS	MRI	Symmetrical FL, PL, OL, TL	–	–	Symmetrical bilateral	–	RD	+(CPK 23,900)	Vegetative state
2	M	16	Heroin	AMS	MRI	Symmetrical FL, PL, OL	–	Symmetrical putamen	Symmetrical bilateral	–	NP	Unknown	Unknown
3	F	16	TCA	AMS, seizures, EPS	CT	Symmetrical FL	–	Caudate and putamen	Diffuse hypodensity	–	NP	–	Death
4	M	22	Cocaine	AMS, paraparesis and C5 sensory level	MRI	Ill-defined T2 hyperintensity in FL and PL	–	–	Multiple infarctions	Multisegmental cervical cord edema (C4–T1)	CBL lesions – RD, Spine – NP	+(CPK 28,000)	Unknown
5	F	15	Methadone	Encephalopathy and EPS	CT, MRI	Subcortical T2 hyperintensity (PL, OL)	Scattered watershed infarctions	Multiple small infarctions in caudate and putamen	Symmetrical bilateral	–	Cortical infarctions – RD, WM and CBL lesions –RD	Unknown	Unknown

AMS: altered mental status; BG: basal ganglia; CBL: cerebellar; CPK: creatine phosphokinase; DWI: diffusion-weighted imaging; EPS: extrapyramidal symptoms; FL: frontal lobe; NP: not performed; OL: occipital lobe; PL: parietal lobe; RD: restricted diffusion; TCA: tricyclic antidepressant; TL: temporal lobe.

Two main neuroimaging patterns of brain injury were found. The first was diffuse symmetric subcortical white matter injury with preferential cerebellar involvement (leukoencephalopathy pattern) and the second was multiple foci of ischemic infarctions in a non-arterial territory distribution (ischemic pattern). Three patients presented with symmetric subcortical white matter involvement (patients 1–3), one patient presented with multiple foci of acute infarctions (patient 4) and one patient presented with both patterns of brain injury (patient 5). All patients had cerebellar involvement (Figures 1–3): four patients had diffuse symmetrical cerebellar edema (characterized as white matter T2 hyperintensity, Figure 1(a) and Figure 2(a), or hypodensity on head CT, Figure 3(a) and (b)) and one patient had multiple cerebellar infarctions. Supratentorial cerebral edema was also common (n = 5, Figure 1(d), Figure 2(d) and Figure 3(c)), but was variable in extent. Diffuse white matter T2 hyperintensity was associated with restricted diffusion consistent with cytotoxic edema, both in the infra and supratentorial white matter (Figure 1(b) and (c), (e) and (f) and Figure 2(b) and (c)). Even though one patient had watershed cortical and subcortical infarctions (Figure 2(e) and (f)), the cerebral cortex was generally spared. In three patients there was also involvement of the basal ganglia, one patient presented with diffuse edema, one patient had multiple foci of acute infarctions (Figure 2(d–f)) and a third patient, following intoxication with tricyclic antidepressant (TCA), showed focal hypodensities in the basal ganglia on head CT, which can represent either areas of infarction or vasogenic edema (Figure 3(a) and (b)). The thalami were not involved in any of our patients. When diffusion weighted imaging was obtained, foci of acute cerebellar and watershed infarctions showed restricted diffusion (patients 4 and 5, respectively). Patients 1 and 4 had presented with rhabdomyolysis, which demonstrated on MRI the cervical region as increased T2 signal in the paraspinal muscles (Figure 1(g) and (h)).

Figure 1.

A 16-year-old boy (patient 1) presented with acute altered mental status following inhalation of heroin vapor. Brain magnetic resonance imaging demonstrates diffuse symmetrical infratentorial (a–c) and supratentorial (d–f) white matter T2 hyperintensities. This T2 prolongation shows restricted diffusion with increasing signal on diffusion-weighted images (b) and (e) with corresponding decreased diffusion scalars on the matching ADC map (c) and (f). There is increased T2 signal of the posterior paraspinal muscles seen on axial (g) and sagittal (h) images of the cervical spine compatible with a clinical diagnosis of rhabdomyolysis affecting predominantly the posterior neck musculature.

Figure 2.

A 15-year-old boy (patient 5) presented with encephalopathy and extrapyramidal signs following methadone ingestion. On brain magnetic resonance imaging, there are multiple foci of acute infarctions in the caudate and in the putamina, as well as parietal watershed cortical infarctions. Diffuse cerebellar T2 hyperintensity showing moderate restricted diffusion is also evident.

Figure 3.

A 16-year-old girl (patient 3) presented acute confusional state following the ingestion of tricyclic antidepressant. Head computed tomography shows diffuse cerebellar hypodensity. Hypodense foci in the caudate and putamen are also demonstrated. Reproduced with kind permission from Frontiers (Huisman et al.)³.

Discussion

Our adolescent and young adult patients had presented acutely with non-specific altered mental status following drug intoxication, which can be related to various etiologies. Early brain imaging plays an important role in making the appropriate diagnosis of drug-induced neurotoxicity, although imaging patterns are not necessarily specific for particular drugs. Two main imaging patterns were recognized. One is diffuse symmetric subcortical white matter injury with preferential involvement of the cerebellum (acute leukoencephalopathy). The second is multiple bilateral small infarctions in a non-arterial territory. The presence of leukoencephalopathy with cerebellar involvement was associated with poor outcome (death and vegetative state) in two patients.

Of all the drugs used, acute leukoencephalopathy following inhalation of heroin vapor (‘chasing the dragon’) is most frequently described. The earliest reports described diffuse cerebellar and cerebral white matter hypodensities on head CT.⁴ On brain MRI there is diffuse symmetric white matter T2 hyperintensities.^5–7 Classically, there is diffuse and symmetrical cerebellar involvement.^6–8 The supratentorial involvement includes the periventricular and corticospinal tracts symmetrically. The subcortical white matter can also be symmetrically involved in more severe cases. Less commonly, deep gray matter structures, including thalami and basal ganglia, are involved with predominantly symmetric T2 hyperintensities.^6,9,10 Interestingly, white matter diffuse T2 prolongation can be associated with either restricted^10,11 or facilitated diffusion,^5,12 which might suggest a continuum from early vasogenic edema to evolving more severe injured white matter showing cytotoxic edema. Acute leukoencephalopathy following non-inhalational exposure to heroin or exposure to non-heroin drugs is far less frequently reported in the literature. Nevertheless, diffuse white matter injury was reported following the ingestion of methadone and other opiates^13–17 as well as following non-opiate drugs, such as cocaine and TCA.^18–20

Cocaine is well known for its cerebrovascular complications resulting in either intracranial hemorrhage or ischemic infarctions. Parenchymal or subarachnoid hemorrhage, the most common vascular complications, are likely secondary to elevated blood pressure from the sympathomimetic effect of the drug, especially if an underlying vascular pathology co-exists.²¹ Patient 4, following cocaine exposure, did not show any hemorrhagic complication, however, suffered spinal cord and multiple cerebellar infarctions. Typically, acute ischemic infarctions following cocaine exposure present as watershed or mesencephalic infarctions.^21,22 Drug-related ischemic infarctions are not specific for cocaine and were also reported following exposure to other drugs such as opiates (patient 5), marijuana or Ecstasy.^21,23

Relative symmetrical white matter injury strongly suggests an underlying direct toxic or metabolic etiology. It has been suggested that the heating of the heroin activates a lipophilic compound either in the heroin or one of the additives directly causing encephalopathy.^5,6 However, no consistent contaminant was identified. Interestingly, corresponding to preferential cerebellar involvement, there is a relative high density of opiate receptors in the cerebellum,²⁴ which can suggest direct heroin-induced neurotoxicity. Common extensive cerebellar and posterior cerebral white matter injuries can also suggest an underlying vascular etiology, either secondary to vasospasm from stimulation of vascular smooth muscle or as a consequence of vasculitis secondary to an inflammatory response.²¹ A relative lack of sympathetic innervation in the posterior circulation territory makes the posterior circulation territory more vulnerable to a breakdown of the autoregulation with subsequent evolving edema.²⁵ These vascular effects may play an even more prominent role in cocaine or amphetamine-related cases, in which vasospasm and vascular injury is well described.²⁶ Similar vascular mechanisms can underlie well-described acute ischemic infarctions, which are also commonly encountered in illicit drug users.²¹ To combine the pathophysiological and imaging patterns of brain injury, hypoxia might be synergistic with direct drug toxicity resulting in acute white matter damage resulting from toxic and ischemic injury to oligodendrocytes and impaired myelin production. Possible individual genetic variance in susceptibility to neurotoxicity might explain the frequency of insult and the contrasting infrequency of toxic leukoencephalopathy or drug-induced brain infarctions.²⁷ Accompanying rhabdomyolysis might further compromise brain perfusion.

Characteristic imaging findings in acute toxic leukoencephalopathy include injury to the deep white matter with sparing of the cortical grey matter. The pattern may resemble other conditions with posterior white matter predominance such as acute hypertensive encephalopathy and posterior reversible encephalopathy syndrome. Both conditions are usually transient whereas injuries from acute toxic leukoencephalopathy related to drug exposure are usually not reversible. Acute disseminated encephalomyelitis is an important differential diagnosis, particularly in children in whom neurological symptoms progress rapidly. Onset usually follows infection or vaccination that leads to immune-mediated brain and spinal cord damage. Typical symmetric and confluent parenchymal edema involving the cerebellum and to a lesser degree the supratentorial brain is more suggestive of acute toxic leukoencephalopathy than other encephalopathies. Delayed leukoencephalopathy following hypoxia also has a different time course following a recovery from coma, does not have a consistent relationship to toxin exposure and involves the supratentorial brain with relative sparing of the cerebellar and brainstem tracts.²⁸ Ischemic infarctions are relatively uncommon in adolescents. Often, underlying risk factors such as cardiac anomalies, sickle cell disease or pro-thrombotic states can be found.²⁹ Multiple acute infarctions in a non-arterial distribution/territory, especially involving watershed areas or deep gray mater, and in association with symmetric white matter injury should raise the differential diagnosis of drug-related brain injury.

Conclusions

Even though illicit drug use has been increasing in past decades, associated acute brain injury appears relatively uncommon. The neuroimaging findings following illicit drug use are relatively non-specific. However, familiarity with the most typical neuroimaging patterns of neurotoxicity may help radiologists suggest the correct diagnosis of illicit drug abuse in adolescents and young adults acutely presenting with altered level of consciousness that is inadequately explained by the clinical history.

Funding

SS is the recipient of a fellowship grant from the American Physician Fellowship for Medicine in Israel.

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.