DOI: https://doi.org/10.21203/rs.3.rs-2646242/v1
Methamphetamine use causes spikes in blood pressure. Chronic hypertension is a major risk factor for cerebral small vessel disease (cSVD). The aim of this study is to investigate whether methamphetamine use increases the risk of cSVD. Consecutive patients with acute ischemic stroke at our medical center were screened for methamphetamine use and evidence of cSVD on MRI of the brain. Methamphetamine use was identified by self-reported history and/or positive urine drug screen. Propensity score matching was used to select non-methamphetamine controls. Sensitivity analysis was performed to assess the effect of methamphetamine use on cSVD. Among 1369 eligible patients, 61 (4.5%) were identified to have a history of methamphetamine use and/or positive urine drug screen. Compared with the non-methamphetamine group (n = 1308), the patients with methamphetamine abuse were significantly younger (54.5 ± 6.9 vs. 70 ± 12.4, p < 0.001), male (77% vs. 54%, p < 0.001) and White (78.7% vs. 51%, p < 0.001). Sensitivity analysis showed that methamphetamine use was associated with increased white matter hyperintensities, lacunes, and total burden of cSVD. The association was independent of age, sex, acute hypertension, and stroke severity. Our findings suggest that methamphetamine use increases the risk of cSVD in young patients with acute ischemic stroke.
Methamphetamine abuse has emerged as a risk factor for both hemorrhagic and ischemic stroke in recent years [1–10]. Although population-based study and forensic analysis of fatal strokes showed significant predominance of hemorrhagic stroke in methamphetamine users [3, 6, 7], methamphetamine abuse has also been increasingly reported to be associated with acute ischemic stroke (AIS) [1, 2, 4–6].
The mechanisms by which methamphetamine causes stroke are still unknown. Case studies and forensic analysis showed atherosclerotic stenoses, arterial dissection, and berry aneurysms in patients with methamphetamine-associated stroke [2, 4, 6, 7]. Methamphetamine abuse was also shown to produce a dose-dependent elevation of blood pressure and chronic hypertension [11–13].
Chronic hypertension is a major risk factor for cerebral small vessel disease (cSVD) and stroke [13–16]. cSVD refers to a group of pathological processes that affect the small perforating vessels and capillaries in the brain [16, 17]. Radiographically, it is characterized by deep white matter hyperdensities (WMHs), lacunar infarcts, microbleeds, and enlarged perivascular spaces (PVS) on magnetic resonance imaging (MRI) of the brain [17]. cSVD is a common cause of stroke, cognitive impairment, and vascular dementia [15–17].
The aim of this study is to investigate whether methamphetamine abuse increases the risk of cSVD in patients with acute ischemic stroke.
This retrospective study was approved by the University of California Irvine Institutional Review Board (IRB) and the Ethics Committee. Informed consents were waived due to retrospective study design and minimal harm to the patients. All methods in the study were performed in accordance with the relevant guidelines and regulations.
Consecutive AIS patients admitted at the University of California Irvine Medical Center from January 1, 2013 to December 30, 2018 were included. The patient list was generated from the prospectively maintained American Heart Association (AHA)'s Get-With-The-Guideline stroke data registry at our medical center. The registry uses a web-based patient management tool to collect clinical data on consecutively admitted patients, to provide decision support, and to enable real-time online reporting [19]. Patients with TIA, stroke mimics, subacute stroke, inpatient stroke, and primary brain hemorrhage were excluded. Stroke transfers from outside facilities were also excluded.
All patients underwent standard diagnostic evaluation and treatment per AHA guidelines [20]. Based on the history of methamphetamine abuse and/or urine drug screen (UDS), patients were divided into Meth and Non-Meth group. The UDS was performed using EMIT II Plus Amphetamines Assay (Beckman Coulter, Inc) with a sensitivity and specificity of 94.3% and 93.3%, respectively [18].
MRI images of the brain were reviewed by an experienced neurologist (ZZ) to assess cSVD using modified Fazekas scale [13–15, 21]. Both deep and periventricular WMHs were rated from 0 to 3 on fluid-attenuated inversion recovery (FLAIR)- and T2-weighted sequences [15]. Lacunes were defined as small (< 15 mm) subcortical infarcts [13, 21]. Cerebral microbleeds (CMBs) were rated on susceptibility-weighted imaging (SWI) based on their numbers (< 5, 5–10, or > 10). Enlarged perivascular spaces (PVS) were defined as small (< 3 mm) punctate hyperintensities on FLAIR or T2-weighted images and rated from 0 to 3: 0 (absent), 1 (< 10), 2 (10–25), and 3 (> 25).
Total burdens of cSVD were rated from 0 to 4 [13]. One point was added for each of the following findings: confluent deep or periventricular WMHs (Fazekas grade 2 and 3), ≥ 1 lacune, ≥ 1 CMBs, and > 10 enlarged PVS in the basal ganglia on at least one side of the brain.
Propensity score matching with a 1:1 ratio was performed to select patients from the Non-Meth group as control. The propensity score was estimated using a logistic regression model based on age, sex, hypertension, diabetes mellitus, hyperlipidemia, obesity, and initial NIHSS score as described (1:1 match, nearest neighbor approach) [22].
Continuous variables were described by mean ± standard deviation (SD) or median with interquartile range (IQR) based on the results of normality testing. Categorical variables were expressed by counts with percentages. Baseline characteristics and outcome at discharge were compared between Meth and Non-Meth groups by Mann Whitney test for continuous variables and chi-square test for categorical variables. Sensitivity analysis was performed to investigate the effect of methamphetamine abuse and other variables on the development of cSVD. All statistical analyses were performed using SPSS software (version 23.0). A 2-tailed value of p < 0.05 was considered statistically significant.
From the 1,369 patients with AIS (Fig. 1), 61 (4.5%) were found to have a history of methamphetamine abuse or positive UDS (Meth group). Four patients had no MRI study of the brain and were excluded for the investigation of cSVD. In the remaining 57 patients, 24 patients had both history of methamphetamine use and positive UDS (Meth + group). A 1:1 propensity score-matched control group (n = 57) was selected from the Non-Meth group for sensitivity analysis.
The characteristics of the Meth and Non-Meth groups are summarized in Table 1. Compared with Non-Meth group, patients in the Meth group were significantly younger (54.5 ± 6.9 vs. 70 ± 12.4, p < 0.001), more likely male (77% vs. 54%, p < 0.001) and White (78.7% vs. 51%, p < 0.001). There appeared to be proportionally less Asians with methamphetamine-associated stroke (3.3% vs. 23.9%, p < 0.001).
There was no significant difference between the two groups in history of hypertension, diabetes, hyperlipidemia, obesity, or initial NIHSS score. However, patients in the Meth group were more likely using cocaine than those in the Non-Meth group (11.5% vs. 0.7%, p < 0.001).
Sensitivity analysis was performed to investigate the effect of methamphetamine use as independent variable. Compared with age- and sex-matched control group, there were proportionally more White and less Asian patients in the Meth and Meth + group (Table 2). There was no significant difference in history of hypertension, diabetes, hyperlipidemia, obesity, or initial NIHSS score between the Meth or Meth + group and control group.
The representative MRI images of cSVD were shown in Fig. 2. Both Meth and Meth + group were found to have more WMHs, lacunes, and total burdens of cSVD than propensity score-matched control group (Table 2). The increase of lacunes in the Meth + group (n = 24) was not statistically significant possibly due to small sample size.
There were no significant differences in systolic or diastolic blood pressure (BP) at admission or hospital discharge, BP reduction during hospitalization, and numbers of antihypertensives required for BP control between the Meth or Meth + group and propensity score-matched control group. The increased burdens of cSVD in the Meth and Meth + group are independent of age, sex, comorbidities, acute hypertension, and stroke severity as measured by initial NIHSS scores.
This single center data demonstrates that methamphetamine abuse is seen in 4.5% of the patients with acute ischemic stroke at our medical center. The patients with methamphetamine use are significantly younger (54.5 ± 6.9 vs. 70 ± 12.4, p < 0.001) and more likely male (77% vs. 54%, p < 0.001). In addition, sensitivity analysis with propensity score-matched controls showed that methamphetamine abuse is associated with increased burdens of cSVD, independent of age, sex, comorbidities, acute hypertension, and stroke severity.
Previous studies showed that elevated blood pressure levels are associated with each of the MRI markers of cSVD [14–15]. Effective treatment of hypertension may reduce the rates of cSVD and stroke [13, 15]. In this retrospective study, there was no significant difference in blood pressures at admission or hospital discharge, blood pressure reduction during hospitalization, and the numbers of antihypertensives required to control hypertension between the Meth or Meth + group and propensity score-matched Non-Meth controls. It is possible that chronic hypertension from methamphetamine abuse plays an important role in the development of cSVD [13].
Advanced age and male sex were reported to be major risk factors for cSVD [16, 23–25]. In a recent study, cerebral SVD was seen in 18.9% of age group 70s as compared to 3% in age group 40s [23]. In a Chinese population-based study, advanced age was shown to be independently associated with the prevalence of cSVD [24]. In our study, we demonstrated that methamphetamine abuse increases the risk of cSVD in young stroke patients.
In a cohort study of homeless and unstably housed women (n = 30) from San Francisco community, 86% patients had a history of cocaine use and 54% patients had WMHs [25]. In our cohort, more patients in the Meth group had a history of cocaine abuse than the Non-Meth group (11.5% vs. 0.7%). The relatively low proportion of patients (11.5%) with concomitant cocaine use may be a confounding factor in our study.
Since cSVD increases the risk of cognitive impairment and vascular dementia, methamphetamine abuse in young adults may have more significant long-term public health concerns than stroke and other detrimental effects.
Our study has a few limitations. First, some patients were unable to provide history of drug use due to aphasia or severe neurological deficit. and was unable to provide history of drug abuse. Others tested positive but denied history of drug abuse. In addition, only 932 patients (71%) in the Non-Meth group had a UDS. The rate of methamphetamine abuse was highly likely underestimated. Second, there was no information regarding the route, frequency, and duration of methamphetamine abuse. Third, the sample size of this retrospective is relatively small. Therefore, additional studies are warranted to establish the temporal relationship between methamphetamine abuse and cSVD.
Of note, it was challenging to get accurate information on polysubstance abuse, particularly, in patients with neurological deficit. It may be also unethical to conduct randomized controlled studies on methamphetamine abuse. Well-designed prospective registry may be a good option to further investigate the effect of chronic methamphetamine use on cSVD.
In conclusion, our preliminary results demonstrates that methamphetamine abuse is common in young adults with acute ischemic stroke and increases the risk of cSVD. Given increased prevalence of methamphetamine abuse in young adults, additional studies are warranted to investigate the effects of chronic methamphetamine use on the pathogenesis of stroke, cSVD, and vascular dementia.
Acknowledgements
We thank Xiaoqi Cheng & Dongmei Liao International Stroke ResearchScholarship for generous support of this research project.
Authors Contributions
Z.Z. contributed to study design, data acquisition, analysis, and interpretation. B.V., D.S., and H.B. contributed to data acquisition and analysis. M.S., JE.S., D.C., and P.C. contributed to interpretation and draft revision. W.Y. contributed to study design, data interpretation, wrote the draft and finalized the manuscript.
Data availability Statement
Data of this study are available from the corresponding author on reasonable request.
Conflict of Interest Statement
All authors had no conflict of interest.
Tables 1-2 are available in the Supplementary Files section.