Macula and Optic Disc Characteristics in Methamphetamine and Crystal Methamphetamine Abusers Using Optical Coherence Tomography


 Purpose

Methamphetamine and Crystal Methamphetamine abusers were compared with healthy subjects using optical coherence tomography to assess their retinal nerve fiber layer, macula, and optic disc characteristics.
Methods

Forty-one Methamphetamine and Crystal Methamphetamine abusers and 42 healthy subjects (mean ± SD of age: 35.82 ± 8.6 and 37.67 ± 9.1 years, respectively) were incorporated in this cross sectional study. The drug abusers had a history of at least five years of substance use through smoking. Fourier-domain optical coherence tomography was used to image and assess the characteristics of retinal nerve fiber layer, macular thickness, and optic disc in the study groups.
Results

The retinal nerve fiber layer thickness was significantly lower in the superior and temporal retinal quadrants of drug abusers than healthy subjects (P = 0.008 and P = 0.028, respectively). This study did not find a significant difference between drug abusers and healthy controls regarding optic to disc ratio, rim area, and disc area (P > 0.05). The comparison between the study groups showed that the reductions in perifovea and the superior quadrant of parafoveal thickness were statistically significant (P < 0.001 and P = 0.029, respectively).
Conclusion

Fourier-domain optical coherence tomography measurements showed that the retinal nerve fiber layer and macular thickness were different between Methamphetamine and Crystal Methamphetamine abusers and healthy subjects, which should be considered in clinical practice. It seems that these drug abuses can cause alterations in retinal morphology.


Introduction
Methamphetamine (Meth) and Crystal Methamphetamine (Crystal Meth) are synthetic psychoactive substances belonging to the amphetamine class. There are sympathomimetic drugs that have a wide range of effects on the central nervous system. Meth and Crystal Meth stimulate the central nervous system by releasing monoamine neurotransmitters, including dopamine, norepinephrine, and serotonin [1][2][3]. These highly addictive substances can be taken by oral ingestion, nasal inhalation, intravenous injection, and smoking; however, the most common route of administration is smoking [4]. Because of their euphoric properties, ease of synthesis, and easy availability, Meth and Crystal Meth abuse rates have widely increased worldwide. Consequently, current rates of abuse and dependences, the burden of care, side effects, and complications of these drugs have become a worldwide public health crisis [1,5,6]. Importantly, cardiovascular, respiratory, cerebrovascular, neurotoxic, and neurocognitive de cits, as well as psychosis, suicide, and premature death, are some of the physical and mental health problems following Meth and Crystal Meth use [7][8][9].
Ocular complications associated with Meth and Crystal Meth abuse include retinal vasculitis, endophthalmitis, episcleritis, panophthalmitis, scleritis, corneal ulceration, retinopathy, and transient visual losses [10,11]. The majority of reports on Meth-induced retinal complications are animal experimental studies or rare case reports [10,12]. Therefore, the in vivo assessment of retinal characteristics in humans with long-term Meth and Crystal Meth abuses is important for clinical purposes. To the best of our knowledge, there have been few reports on the impact of Meth and Crystal Meth on retinal nerve ber layer (RNFL) characteristics, macular thickness, and optic nerve head (ONH) features. Only in a recent study, Talebnejad et al. evaluated RNFL thickness without investigation of the fovea, perifovea and parafovea features in Meth abusers and found an adverse association with RNFL thickness using optical coherence tomography (OCT) modality [12]. OCT is an imaging technique that enables non-contact direct observation and high-resolution cross-sectional images of the retinal tissue and ONH in a noninvasive manner. It provides in vivo measurements of macula characteristics, optic disc features, and RNFL thickness. Fourier-domain OCT represents a modi cation of the OCT system and is capable of accurate and high-speed imaging of the retina [13].
While the effects of Meth and Crystal Meth abuses on the retina have been reported in experimental animal studies or case reports [10,[14][15][16][17], it seems necessary to design a study that can assess the impact of Meth and Crystal Meth-induced retinal changes in chronic drug abusers as compared to the results with retinal characteristics of healthy subjects. Therefore, this study was designed to evaluate RNFL, ONH, and macula characteristics in long-term Meth and Crystal Meth abusers and compare them with healthy subjects using a Fourier-domain OCT.

Methods
This cross-sectional study was conducted at Al-Zahra Eye Hospital, Zahedan, eastern Iran. All participants in this study were residents of Zahedan with the same ethnicity. Center. The participants received a comprehensive ophthalmic examination, including full patient history, slit-lamp biomicroscopy, ophthalmoscopy, noncontact tonometry (Topcon CT-1/CT-1P, Tokyo, Japan), autorefraction (Topcon KR-1, Tokyo, Japan), and best-corrected distance visual acuity. A refractive error between − 3.00 to + 3.00 diopters with a best-corrected distance visual acuity of 0.2 Log MAR was added to the inclusion criteria to avoid the manifestations of high refractive errors on the retina [18]. The exclusion criteria for both study groups involved any systemic or ocular disease, history of ocular surgery, and consumption of a speci c drug. Also, women who were currently pregnant were excluded.
Considering the mentioned criteria, 41 Meth and Crystal Meth abusers with at least 5 years of Meth and Crystal Meth abuse were enrolled in this study. Notably, the route of Meth and Crystal Meth usage was smoking with a mean daily dose of 0.0074 ± 0.0034 gr. Forty-two healthy individuals of matching ethnicity to the addicted group and without a history of smoking were included in the study as the control group.
RNFL, ONH, and macula images of the participants were obtained using a Fourier-domain OCT (Optovue, RTVue™, Inc., Fremont, CA), which is the rst United States Food and Drug Administration-approved FD-OCT system. Optovue Fourier-domain OCT system can take 26,000 A-scans per second with an axial resolution of 5 microns using a high wavelength light source. This technique utilizes a superluminescent diode that is compact, reliable, and more economical [13]. Repeatability of RNFL and macular thickness measurements have been studied in previous studies using Optovue Fourier-domain OCT [19,20]. This device allows for automatic and manual imaging by the clinician. In this study, the manual imaging technique was used to examine RNFL, ONH, and macular thickness. The same examiner (M.M) obtained all OCT measurements based on the manufacturers' user guide and previous studies [21]. Measurements based on the quality state provided by the instrument were accepted and erroneous captures were repeated after ve minutes. It should be mentioned that the mechanism of the RTVue OCT has been described in previous studies [21,22]. The manufacturer's representative checked the calibration of OCT before the study. Lastly, only the right eye per subject was selected for analysis.

RNFL Measurements
The ONH protocol was used to obtain RNFL measurements. This protocol generates an RNFL thickness map measured along a circle of 3.45 mm in diameter centered at the ONH. The overall average, superior hemisphere, inferior hemisphere, temporal quadrant, superior quadrant, nasal quadrant, and inferior quadrant are provided [21,22].

ONH Measurements
The ONH protocol was used to obtain ONH measurements. It consists of 12 radial scans of 3.4 mm in length (455 A-scans each) and 13 concentric circular scans ranging from 1.3 to 4.9 mm in diameter (425-965 A-scans each) centered at the ONH. The ONH parameters measured by the software involved the rim area, vertical cup-to-disc ratio, horizontal cup-to-disc ratio, cup area, cup-to-disc area ratio, and disc area [22]. Macular Measurements: The ganglion cell complex (GCC) protocol was used to obtain macular measurements. This protocol consists of one horizontal line scan of 7 mm in length (467 A-scans) followed by 15 vertical line scans of 7 mm in length (400 A-scans each) at 0.55-mm intervals. This protocol provides 14,810 A-scans in 0.58 seconds of a rectangular area. The GCC protocol provides a segmentation of macular B-scans in two layers: GCC layer and outer retinal layer. The GCC layer is composed of the ganglion cell layer, the nerve ber layer, and the inner plexiform layer [22].
Statistical analysis was performed using the SPSS program (SPSS version 19 for Windows; SPSS Inc., Chicago, IL, USA). The normality of data distribution was assessed using the Kolmogorov-Smirnov test.
The independent T-test was utilized to compare the meant of the studied variables in addict and healthy groups. The descriptive results of comparisons are presented using the mean and 95% con dence interval of differences. In this study, P-values smaller than 0.05 were considered signi cant.

Results
Forty-one eyes of 41 Meth and Crystal Meth abusers (36 males and 5 females) and 42 eyes of 42 healthy individuals (34 males and 8 females) were enrolled in this study. The age means of the drug abusers and healthy subjects were 35.82 ± 8.6 years and 37.67 ± 9.1 years, respectively. No signi cant differences were found between the two groups in sex and age (P = 0.326 and P = 0.397, respectively). There were no signi cant differences in refractive errors and RNFL and macula features between the two eyes (P > 0.05). Therfore, statistical analysis was performed only for the right eye of all participants The mean of spherical equivalent refractive errors in the two groups were − 0.47 ± 1.68 diopter and − 0.70 ± 0.98 diopter, respectively. There were no signi cant differences in refractive errors between drug abusers and healthy subjects (P = 0.496).
The results of the independent T-test showed signi cant differences in RNFL thickness between the two groups in superior and temporal quadrants (-6.65, 95% CI: -11.49, -1.08, P = 0.008 and − 4.65, 95% CI: -8.81, -0.50, P = 0.028, respectively) ( Table 1). Examination of RNFL thickness showed no statistically signi cant difference in other quadrants, namely, inferior and nasal, between drug abusers and healthy subjects (P = 0.346 and P = 0.696, respectively). A comparison of ONH features measured by the OCT between the two groups is presented in Table 2. The results showed approximately similar values in the two groups. The difference in optic disc ratio (total, vertical, and horizontal), rim area, and disc area was not statistically signi cant between drug abusers and healthy subjects (P > 0.05).  Table 3 demonstrates the macular characteristics of the drug abusers and healthy subjects. The results showed a statistically signi cant reduction in perifovea thickness and its quadrants in the drug abusers compared to healthy subjects (P < 0.001). Compared with healthy subjects, a statistically signi cant reduction was found in the superior parafoveal quadrant in the drug abusers (-5.79, 95% CI: -10.97, -0.60, P = 0.029). Pearson correlation test showed a signi cant relationship between decreased thickness of RNFL and perifovea with duration of Meth and Crystal Meth abuse (perifovea thickness: P = 0.006, r=-0.297, RNFL thickness in superior quadrant: P = 0.004, r=-0.310, RNFL thickness in temporal quadrant: P = 0.025, r=-0.246).

Discussion
The main cause of Meth and Crystal Meth-related disorder in humans and laboratory animals has been attributed to central nervous system stimulation and sympathomimetic effects on peripheral adrenergic structures [23]. Moreover, there are numerous reports of ocular sequel associated with using these drugs [10,11]. The present study evaluated the characteristics of the macula, RNFL, and ONH in Meth and Crystal Meth abusers with a minimum ve-year history of their abuse.
According to the results of this study, long-term Meth and Crystal Meth abuses had a signi cant impact on RNFL thickness in superior and temporal quadrants. In addition, a statistically signi cant decline in perifovea and superior parafovea thickness was observed in the drug abusers group as compared to healthy controls. In contrast, cup-to-disc ratio, rim area, and disc area were similar between the drug abusers and healthy subjects.
Concerning the effects of long-term Meth and Crystal Meth abuse on RNFL thickness, the results of the present study showed a signi cant reduction in the thickness of RNFL, that this decrease was greater with increasing the duration of drug addiction. The result of this study is consistent with the ndings of a study by Talebnejad et al [12]. As they have noted, RNFL thickness showed a signi cant reduction in Meth abusers compared to the healthy group [12]. Gemelli et al. also reported that the average RNFL thickness in the cocaine users was signi cantly thinner compared to that of healthy subjects [24]. It should be mentioned that cocaine is a psycho-stimulant drug with a similar function to Meth. A suggested mechanism for the decreased RNFL thickness in drug abusers involves neural damage caused by microvascular alterations and oxidative stress induced by long-term abuse, which might lead to the development of retinal microstructural changes [25,26].
Interestingly, Meth and cocaeine-induced topographic changes of RNFL differ from study to study.
Talebnejad et al. demonstrated thinner RNFL thickness in temporal, superior temporal, and inferior nasal areas in Meth users compared to healthy subjects [12], while Gemelli et al. observed an RNFL thinning due to cocaine consumption in the superior, inferior, and nasal quadrants [24]. On the other hand, our results showed RNFL thinning in the superior and temporal quadrants. Given that RNFL thinning in each quadrant helps differentiate some ocular diseases such as glaucoma and neuro-ophthalmic disorders from normal conditions [12], a new RNFL thickness threshold seems to be needed for Meth and Crystal Meth abusers.
There are scarce studies that have investigated the effects of chronic Meth and Crystal Meth consumption on macular thickness by using Fourier-domain OCT. The results of the current study demonstrated that Meth and Crystal Meth abusers have a decreased perifovea (all quadrants) and superior parafovea thickness compared to healthy controls. Given that macula is supplied by a dual circulation, these ndings could be attributed to the retinal ischemia secondary to vasospasm of the choroidal capillary due to a sympathetic effect of the drugs [2,27]. Two cases of bilateral acute macular neuroretinopathy following intranasal cocaine use have been reported by Introni et al [27]. It seems that ischemia of the deep capillary plexus is the cause of early outer plexiform layer lesions in macular neuroretinopathy [28]. However, Gemelli et al. have reported no signi cant differences in macular thickness in cocaine users in comparison to the control group [24]. Compared with other studies reporting the impact of cocaine on macular thickness [24], the present study is the rst report of the effects of chronic Meth and Crystal Meth abuse on the macular thickness pro le using Fourier-domain OCT.
One of the limitations of this study is that the study did not evaluate vascular problems associated with the consumption of drugs. It is suggested that further research be conducted to evaluate vascular problems associated with the consumption of drugs using OCT angiography of the optic nerve.

Conclusion
This study revealed that chronic Meth and Crystal Meth abuse can have signi cant effects on RNFL and perifovea thickness. Statistically signi cant RNFL thickness reductions were observed in the superior and temporal quadrants and perifovea and superior parafovea thickness of Meth and Crystal Meth abusers compared to healthy subjects. Clinicians can use these ndings in their clinical approaches towards these patients. Declarations