Increased rupture risk in small intracranial aneurysms associated with methamphetamine use

Abstract

Background

Aneurysmal subarachnoid hemorrhage (SAH) is the most common cause of nontraumatic SAH. Current guidelines generally recommend observation for unruptured intracranial aneurysms smaller than 7 mm, for those are considered at low risk for spontaneous rupture according to available scoring systems.

Objective

We observed a tendency for SAH in small intracranial aneurysms in patients who are methamphetamine users. A retrospective, single center study to characterize the size and location of ruptured and unruptured intracranial aneurysms in methamphetamine users was performed.

Materials and methods

Clinical characteristics and patient data were collected via retrospective chart review of patients with intracranial aneurysms and a history of methamphetamine use with a specific focus on aneurysm size and location.

Results

A total of 62 patients were identified with at least one intracranial aneurysm and a history of methamphetamine use, yielding 73 intracranial aneurysms (n = 73). The mean largest diameter of unruptured aneurysms (n = 44) was 5.1 mm (median 4.5, SD 2.5 mm), smaller than for ruptured aneurysms (n = 29) with a mean diameter of 6.3 mm (median 5.5, SD 2.5 mm). Aneurysms measuring less than 7 mm presented with SAH in 36.5%. With regard to location, 28% (n = 42) of anterior circulation aneurysms less than 7 mm presented with rupture, in contrast to 70% (n = 10) of posterior circulation aneurysms which were found to be ruptured.

Conclusions

Methamphetamine use may be considered a significant risk factor for aneurysmal SAH at a smaller aneurysm size than for other patients. These patients may benefit from a lower threshold for intervention and/or aggressive imaging and clinical follow-up.

Introduction

The management of small intracranial aneurysms remains a matter of debate and controversy for various reasons, including a) limited understanding of the natural history of aneurysms, b) increasing appreciation of a higher prevalence, and a low rupture rate for most intracranial aneurysms in the general population, c) currently incomplete definitions of groups at risk reflected in current guidelines and scoring systems, and d) concern about treatment risk.

Although initially thought to occur in 1–2% of the population,¹ it appears that the prevalence of intracranial aneurysms may range between 5–8%^2,3 and up to 11%.⁴ Large population studies have estimated the annual risk of rupture to range between 0–1% for intracranial aneurysms smaller than 7 mm.^5–8 In order to assist decision-making when following patients with unruptured aneurysms, scoring systems for the estimation of hemorrhagic risk have been developed, which take into account various risk factors, both patient-related and aneurysm-related.^9–11

Recent studies have suggested that methamphetamine use is associated with poorer outcomes in patients with aneurysmal subarachnoid hemorrhage, independent of tobacco use and other recreational drugs.^12,13 Considering the potential for poor outcomes in these patients, we sought to characterize possible correlations between methamphetamine use and aneurysm size and location in patients with both ruptured and unruptured intracranial aneurysms.

Methods

A retrospective review of our institution’s internal electronic database was undertaken on all patients admitted between January 2010 and November 2016 with intracranial aneurysms. Only intracranial saccular aneurysms were included in the study; mycotic and fusiform aneurysms were excluded. In those patients, a search of the electronic medical record was conducted for a history of methamphetamine use, defined as either a positive clinical history obtained from the patient, or from a positive urine toxicology screen. Also, a search for hypertension was made; a positive history was defined as hypertension being included in the patient’s problem list, or if an anti-hypertensive medication was prescribed with hypertension listed as indication. This retrospective, Health Insurance Portability and Accountability Act (HIPAA)-compliant study was approved by our institutional review board.

A review of the original imaging was performed by neuroradiology faculty to provide aneurysm size measurements and location. Aneurysm size was measured in three dimensions, with the largest dimension used in statistical analysis. Aneurysm location was categorized as either within the anterior or posterior circulation. Anterior circulation was defined to include internal carotid arteries, middle cerebral arteries, anterior cerebral arteries, and anterior communicating arteries. Posterior circulation was defined as posterior communicating arteries, posterior cerebral arteries, vertebral arteries, and basilar arteries. Aneurysms were considered ruptured if subarachnoid and/or intraventricular hemorrhage was present on imaging.

In addition to demographics, statistical analysis of mean, median, and standard deviation of largest diameter was performed. The proportion of aneurysms measuring less than 7 mm that were found to be ruptured was also calculated. The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health (NCATS, NIH), through grant number UL1 TR001860. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Results

A total of 62 eligible patients were identified and found to have at least one intracranial aneurysm and history of methamphetamine use. Ten patients had multiple intracranial aneurysms at initial presentation. Nine subjects had two aneurysms; one patient had three. Female/male ratio was 61/39%. Average age was 52 years. Forty-four patients (71%) had a history of hypertension. In these 62 patients, a total of 73 individual intracranial aneurysms were found and assessed for size and location.

Of 73 intracranial aneurysms, 29 were ruptured and 44 were unruptured (Table 1). Females made up the majority of both ruptured and unruptured groups (72% vs 59%, respectively). Median age for both groups was similar (51 and 53.5 years of age respectively). Hypertension was present in 70% in the unruptured group compared to 76% in the ruptured group. Anterior circulation aneurysms (n = 56) were more common than posterior (n = 17), representing 62% of the ruptured group and 86% of the unruptured group. Anterior circulation aneurysms presented with rupture in 32%. Comparatively, 65% of posterior circulation aneurysms were ruptured.

Table 1.

Demographics, location, and size of aneurysms.

	Ruptured (n = 29)	Unruptured (n = 44)
Demographics
Female Sex	21 (72%)	26 (59%)
Median Age	51	53.5
Age 25–40	2 (7%)	3 (7%)
Age 41–55	24 (83%)	25 (57%)
Age 56+	3 (10%)	16 (36%)
Aneurysm Location
Anterior	18 (62%)	38 (86%)
Posterior	11 (38%)	6 (14%)
Aneurysm Size
Median	5.5	4.5
Mean	6.3	5.1
STD	2.5	2.5

Average aneurysm size was relatively small for both ruptured and unruptured groups. Median size of ruptured aneurysms was 5.5 mm in largest diameter (Figure 3). Mean size was greater, measured at 6.3 mm with a standard deviation of 2.5 mm. Comparatively, the median size of unruptured aneurysms was 4.5 mm in largest diameter and the mean size was 5.1 mm. The standard deviation was also 2.5 mm for the unruptured group. Of all aneurysms measuring less than 7 mm (n = 52) in largest diameter, 19 were found to be ruptured (36.5%). With regard to location, 28% of anterior circulation aneurysms less than 7 mm (n = 42) were found to be ruptured. This is in contrast to 70% of posterior aneurysms less than 7 mm (n = 10) found to be ruptured (Figure 2).

Figure 2.

Small ruptured anterior communicating artery aneurysm, lateral oblique (a) and 3D (b) views. The aneurysm measures approximately 5 mm in maximum dimension. More importantly, a daughter sac is present (a and b, arrow), and aneurysm wall is irregular throughout.

Discussion

In our cohort of patients with known methamphetamine abuse, median ruptured aneurysm size was 5.5 mm (Figures 1 and 2), and median unruptured aneurysm size was 4.5 mm. These findings suggest that patients with a history of methamphetamine use may be at increased risk of rupture in comparison to the general population.

Figure 1.

Stacked bar graph demonstrating the frequency of rupture (light gray) in aneurysms measuring less than 7 mm in the largest diameter. The proportion of rupture in the anterior group was 28%, compared to 70% of the posterior group.

Figure 3.

Small ruptured aneurysm arising from the right A1-2 ACA junction, antero-posterior view. The aneurysm measures 5.5 mm in maximum dimension, and is bilobed, with an irregular and pointy appearance to its dome (3, arrow).

Methamphetamine use is a growing public health problem in the United States, particularly prevalent in rural and semirural communities, such as the California Central Valley region. Methamphetamine-related admissions to publicly-funded treatment centers gradually increased throughout the 1990s and into the 2000s.¹⁴

Methamphetamine was first synthesized during WWII and used by soldiers to increase energy and reduce appetite in German, Japanese and American soldiers.¹⁵ Before the detrimental effects of methamphetamine became widely understood, use of this drug spread throughout Japan, prompting the first methamphetamine epidemic in 1945. Widespread synthesis and use of methamphetamine began in California in the 1960s after several amphetamine-containing medications were removed from the pharmaceutical market. Since its introduction into the United States, methamphetamine has taken multiple forms and street names and poses a significant public health threat.

Methamphetamine toxicity is a common reason for visits to emergency departments,¹⁶ accounting for 102,961 emergency department visits in 2011 according to data from the Drug Abuse Warning Network (DAWN).¹⁷ Methamphetamine has known cardiotoxicity, producing a wide swath of cardiovascular complications including arrhythmia, vasospasm, accelerated atherosclerosis.^18–20 Other commonly described cardiovascular adverse effects of methamphetamine include hypertension, aortic dissection, acute coronary syndromes, pulmonary arterial hypertension and methamphetamine-associated cardiomyopathy.²¹

Cerebrovascular complications of methamphetamine have long been reported, in the form of both ischemic and hemorrhagic stroke. For ischemic stroke, mechanisms which have been identified include cardiac arrhythmias, cardioembolism, hypoxia, vascular toxicity, arterial spasm, a direct thrombotic mechanism (as well as an indirect mechanism from increased eryhropoiesis).²² For hemorrhagic stroke, acute hypertension, aneurysm formation/rupture and angiitis-like changes have been implicated. Acute hypertension is an important factor, which results from massive catecholamine release from sympathetic terminals triggered by methamphetamine.^22–24 However, a lesser known central pressor mechanism is also likely, as the drug can penetrate the blood-brain-barrier and may give rise to glutamate release in the rostral ventrolateral medulla, leading to the activation of mGluR5-PKC (metabotropic glutamate receptor mGlusR5 via protein kinase C phosphorylation) pathways, which would serve as a central mechanism for a sustained methamphetamine-induced pressor effect.²⁵

In addition to hypertension, a direct effect of methamphetamine and related molecules such as beta-aminopropionitrile on the vasculature has been characterized, including a necrotizing angiitis,^26,27 neurovascular inflammation and weakening of vessel walls via matrix metalloproteases and inflammatory cytokines.^28–30 Also, rapid growth of intracranial aneurysms after methamphetamine abuse²⁸,³¹ has been demonstrated.

Therefore, there exists growing evidence that methamphetamine (and associated drugs) may trigger aneurysmal SAH in small aneurysms, and may possibly promote aneurysm formation.

Current predictive models of aneurysm rupture do not take into account drug use. The International Study of Unruptured intracranial aneurysms (ISUIA II)⁵ estimates the overall annual rupture rate at 0.8% for aneurysms smaller than 7 mm, and lists risk factors as prior SAH and posterior circulation location. For anterior circulation aneurysm smaller than 7 mm, the same study quotes a 0% annual hemorrhagic risk in non-smokers (0.3%/year for smokers). The Finnish study, which is a true natural history study of 142 untreated patients (92% with prior SAH) with aneurysms (average size 5.1 mm) followed between 1956 and 1978 quotes an annual rupture risk of 1.1%, and lists smoking, size >7mm and anterior communicating artery location as risk factors.⁶ The UCAS Japanese study of 5720 patients with a mean aneurysm size of 5.7 mm estimates annual rupture risk at 1% and lists anterior and posterior communicating artery location, irregular shape and daughter sac as risk factors.⁷ The Small Unruptured intracranial Aneurysm Verification study (SUAVe) study of 446 patients with 540 aneurysms 5 mm or smaller estimated the rupture risk at 0.54%/yr, and listed hypertension, age younger than 50, multiple aneurysm and anterior communicating artery location as risk factors.⁸

Consequently, the two most commonly used scoring systems used for patient counseling, i.e. the PHASES and ELAPSS scores do not take drug use into account.^9,10 Lastly, the Unruptured Intracranial Aneurysm Treatment Score (UIATS) score (a predictive treatment risk scoring system) takes into account current drug abuse (cocaine, amphetamine); however, such criterion receives a 2 point score, similar to ethnicity, presence of hypertension or autosomal polycystic kidney disease, whereas cigarette smoking and familial aneurysms receive a 3 point score, and a history of prior SAH counts for 4 points. The same scoring system grants 0 point to aneurysms smaller than 3.9 mm.¹¹

Despite those existing scoring systems, a recent survey showed that 42% of neurosurgeons and neuro-interventionalists in the USA were willing to treat preventively patients with intracranial aneurysms as small as 5 mms.³² Indeed, a large metaanalysis of primarily Asian countries has shown that in over 28% of patients with aneurysmal SAH, aneurysm size was 5 mms or less.³³

The other side of the equation is concern about complications from treatment. In reality, when aneurysms are treated by specialized teams, the risk of treatment is currently significantly lower than even a decade earlier. The prospective multicenter Analysis of Treatment by Endovascular Approach of Nonruptured Aneurysms (ATENA)³⁴ and Analysis of Recanalization after Endovascular Treatment of Intracranial Aneurysm (ARETA)³⁵ studies have reported rates of major complications of respectively 2.2% and 1.1%.

Our study has limitations, which include a retrospective and single-center design, and a relatively small sample size. Subjects in our study were enrolled retrospectively via imaging reports obtained after hospital or clinic visits; as such, we are unable to account for methamphetamine users harboring aneurysms who did not seek care. Also, documentation of methamphetamine was focal, such that that parameter was evaluated as a continuous rather than categorical variable. Most patients in our cohort were diagnosed with hypertension and were prescribed antihypertensives, but the degree of hypertension and compliance with medication were unclear, considering that many patients in that population group had limited interaction with the healthcare system. Additionally, lack of a control group of non-methamphetamine users prevents us from making a direct comparison between the two groups. However, we feel that these limitations do not interfere with the primary purpose of this study, which was to assess size and location of ruptured and unruptured intracranial aneurysms in this population. Lastly, we did not assess aneurysm geometry on imaging, i.e. daughter sacs, irregular shape (although Figures 1 and 2 show irregularly-shaped aneurysms); also we did not use vessel wall imaging (which may become a biomarker for prediction of hemorrhagic risk in these patients).

Our results suggest the need for additional research, especially given the prevalence of methamphetamine use in many urban and rural environments, and the magnitude of the resulting public health problem. Further prospective, multicenter, multiparametric studies may further delineate the effect of methamphetamine use on aneurysm formation, growth and rupture, and could provide evidence in support of early intervention.

Conclusion

Our small observational study suggests that smaller than expected intracranial aneurysms may rupture in methamphetamine drug users. In this small cohort, we observed that the median size of ruptured aneurysms was 5.5 millimeters, and the median size of unruptured aneurysms was 4.5 mm. Direct vascular damage caused by drugs in these patients may lower arterial compliance and increase susceptibility to wall shear stress. In this patient group (and possibly other groups at risk), it may be appropriate to lower current thresholds for intervention. Further research will help elucidate strategies for more effective diagnosis, monitoring and treatment of vulnerable patient populations with intracranial aneurysms.