The Role of Optic Nerve Diffusion Restriction on Visual Prognosis in Methanol Poisoning

ABSTRACT

The aim of this study was to investigate the role of optic nerve diffusion status on cranio-orbital magnetic resonance imaging (MRI) in predicting visual prognosis in cases of methanol intoxication. Diffusion-weighted imaging (DWI) from 16 eyes of eight patients who were admitted to our clinic due to methanol intoxication was analysed retrospectively. The relationship between clinical and laboratory findings, treatment regimen, visual prognosis, and imaging findings was investigated. Diffusion restriction (DR) of the optic nerve on DWI was observed in seven (43%) eyes. Regardless of the clinical and laboratory characteristics and treatment regimen, visual acuity (VA) improved in eyes in which restricted diffusion regressed over the follow-up period. DWI of the optic nerve during the acute phase of methanol poisoning may provide prognostically important data. Improvement of DR during follow-up may be an indicator of an increase in VA.

Introduction

Methanol is produced by distilling wood and is used as a solvent in various products, including perfume, paint, plastics, cleaning solutions, and antifreeze. It is one of the most used additives in illicit liquors since it is inexpensive. Although it is non-toxic, its metabolism produces formaldehyde and formic acid, which are highly toxic. These metabolites are responsible for the clinical manifestations of methanol poisoning including acidosis, circulatory instability, mental depression, blindness, and even death.¹ Symptoms of methanol poisoning often occur 12–24 hours after oral consumption, and visual symptoms are seen in approximately 50% of the cases. Patients who survive the initial phase may develop permanent sequelae such as neurological impairments and optic atrophy. Permanent loss of vision has been observed in 20–40% of the patients who survive the acute injury.^2,3

Magnetic resonance imaging (MRI) studies have shown that methanol poisoning affects the optic nerve and the central nervous system (CNS). The most well-known neuropathological change following methanol poisoning is optic atrophy, which is mainly caused by myelin loss in the optic nerve.⁴ Post-mortem examinations of patients with a history of methanol intoxication reveal a distinct pattern of brain injury characterised by bilateral putaminal necrosis and white matter haemorrhagic necrosis affecting the basal ganglia in particular.⁵

Diffusion-weighted imaging (DWI) works by signal contrast generation based on the alterations in the movement of water molecules in tissues.⁶ In cases of acute arterial brain ischaemia, the cerebral tissue experiences a sudden deprivation of essential energy sources, specifically oxygen and glucose. The failure of the Na⁺/K⁺ ATPase pump results in the accumulation of sodium and water within the cell, leading to intracellular (cytotoxic) oedema. Intracellular oedema is characterised by restricted water proton mobility within the cell membrane and a narrowing of the extracellular space. The manifestation of limited molecular mobility, specifically diffusion of protons, is evidenced by elevated signal intensity on ‘trace’ images obtained through DWI. Moreover, it is feasible to quantify the diffusion occurring in a specific area of the brain by means of the apparent diffusion coefficient (ADC). The implementation of DWI in MRI enhances its diagnostic capabilities by increasing its sensitivity. Furthermore, it facilitates the development of treatment strategies and provides valuable prognostic insights. The use of this technique is prevalent in the assessment of stroke and identification of diverse pathological states such as CNS abscesses, epidermoid cysts, and Creutzfeldt-Jakob disease, among others.^7,8 There are few reported specific findings for methanol intoxication on MRI of the optic pathway and fewer on DWI.^9–11 Therefore, the aim of our study was to find out whether optic nerve diffusion status on cranio-orbital DWI-MRI in cases of acute methanol poisoning is related to clinical and laboratory findings associated with the course of the disease, and whether it may predict the visual prognosis.

Methods

Patient selection

This study included retrospective evaluation of the patients who presented with visual loss secondary to methanol poisoning at Dokuz Eylul University Hospital, Department of Ophthalmology, between January 2019 and January 2022. All of them were diagnosed with acute methanol intoxication after the examinations performed in the emergency department (ED). Patients’ demographic properties, ophthalmological examination findings, laboratory findings during the acute phase, treatment history, and MRI results were recorded. Patients were included in the study if they were diagnosed with alcohol intoxication confirmed by laboratory findings after methanol exposure, had no known history of optic neuritis or optic neuropathy, had no better explanation for optic nerve involvement, had no ocular disease causing vision loss, such as glaucoma or diabetes, and had DWI of the brain and optic nerves. Patients with missing data for the investigated parameters and without a follow-up examination were excluded from the study. The study was performed in accordance with the principles of the Declaration of Helsinki and was approved by the institutional Ethics Committee. Informed consent was obtained from all participants.

Laboratory tests

According to the standard blood test protocol applied to patients presenting with alcohol intoxication, serum glucose, electrolyte, blood urea nitrogen (BUN), and creatinine levels, as well as blood gas analysis including pH, pCO₂, glucose, lactate, HCO₃⁻, and electrolytes were obtained. Because the blood methanol level could not be measured at our institution, the ethanol level was measured and the patient was diagnosed with methanol intoxication only in the case of a normal blood ethanol level accompanied by a compatible patient history as well as clinical status.

Magnetic resonance imaging acquisition and analysis

All MRIs were done using a 1.5-T MR scanner (Philips Achieva, the Netherlands). Orbital imaging included axial 3 mm T1- and T2-weighted images, 3 mm coronal short tau inversion recovery images, and post-gadolinium 3 mm axial and coronal fat-saturated T1-weighted images.  Brain imaging included 5 mm proton density and T2 weighted, and fluid attenuated inversion recovery (FLAIR), axial diffusion weighted, sagittal T1 weighted and post contrast axial T1 weighted images.  When abnormal signal was seen in optic nerves, 4 mm coronal and sagittal diffusion weighted images through the optic nerves were also obtained. We used axial 5-mm-thick and coronal and sagittal 4-mm-thick DWI images in the orbital imaging. We did not use thinner DWI images to preserve ‘signal to noise’ ratio. In addition to axial DWI images through the orbit we obtained coronal and sagittal images to compensate for probable partial volume averaging in the axial images. Furthermore imaging in three orthogonal planes provided scanning of the whole trace of the optic nerve. The analysis of MRI data was performed by the same experienced radiologist specialized in neuroimaging. Follow-up cranio-orbital MRI was performed only if the patient had diffusion restriction (DR) on the initial imaging.

Ocular examination

All patients underwent a detailed ophthalmological examination including corrected visual acuity (VA) with Snellen charts, colour vision (CV), biomicroscopy, and fundus examination. Detailed medical history and treatment applied after methanol poisoning was noted. The data were extracted and analysed by means of descriptive statistics.

Results

All patients reported acute, painless, bilateral visual loss after consumption of alcohol in over a few days. There were two (25%) female and six (75%) male patients with a mean age of 52.8 ± 14.3 years (range 25–73). The mean time between the initial exposure to methanol and the ophthalmological examination of the patients in our department was 10 days (range 1–25). The demographic features and ophthalmological examination findings of the patients are given in Table 1.

Table 1.

Demographic information, ocular examination, and initial diffusion weighted imaging findings in the patients.

		Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6	Patient 7	Patient 8
Age		62	54	53	73	60	25	54	42
Gender		Female	Male	Male	Male	Male	Female	Male	Male
Time from injestion to review in the clinic		4 days	9 days	8 days	24 days	1 day	1 day	10 day	24 days
RAPD		Left eye (+)	Right eye (+)	(-)	(-)	(-)	(-)	Right eye (+)	(-)
Initial BCVA	OD	20/40	NPL	20/25	20/20	CF at 4 m	20/40	20/200	20/200
	OS	CF at 50 cm	NPL	20/25	20/50	CF at 4 m	20/25	20/80	20/200
Final BCVA	OD	20/20	CF at 1 m	20/32	P+ P+	.2	20/20	20/200	CF at 2 m
	OS	20/32	20/50	20/32	CF at 30 cm	CF at 1 m	20/20	20/100	CF at 50 cm
Initial CV	OD	8/21	0/21	3/21	0/21	0/21	11/21	7/21	0/21
	OS	9/21	0/21	3/21	0/21	0/21	12/21	9/21	0/21
Final CV	OD	20/21	0/21	3/21	0/21	1/21	20/21	4/21	0/21
	OS	4/21	4/21	3/21	0/21	0/21	20/21	5/21	0/21
Fundoscopy		Normal optic nerve with no cupping; normal retinal findings bilaterally	Normal optic nerve with no cupping; normal retinal findings bilaterally	Optic nerve with C/D ratio of .7; normal retinal findings bilaterally	Optic atrophy; normal retinal findings bilaterally	Normal optic nerve with no cupping; normal retinal findings	Normal optic nerve with no cupping; normal retinal findings	Temporal optic nerve pallor; normal retinal findings	Optic atrophy; normal retinal findings bilaterally

BCVA = best-corrected visual acuity; C/D = cup-to-disc; CF = counting fingers; CV = colour vision; NPL = no perception of light; RAPD = relative afferent pupil defect.

Past treatment history in ED included hemodialysis in seven patients (87.5%) and additional pulse steroid therapy in one (P8) patient (12.5%). Only one (12.5%) patient (P2) did not undergo dialysis and was followed up with pulse steroid therapy. After applying to our department, two (25%) patients (P5, P8) were not given any additional treatments, while the remaining patients were started on vitamin B₁₂ and folic acid. Oral methylprednisolone treatment was added to the regimen of four patients (P1, P2, P3, and P4).

The results of the blood tests performed when the patients were admitted to the ED were obtained by retrospective chart scanning. Acidosis was present in seven (87.5%) of the patients, while serum bicarbonate levels were found to be low in seven (87.5%) of them. Seven (87.5%) patients had an elevated anion gap, while three (37.5%) of the patients’ creatinine levels were above normal limits. The initial serum and arterial blood gas analysis results of the patients seen in the ED are given in Table 2. The serum and blood gas analysis results of the patients were within normal limits when they applied to our department.

Table 2.

Arterial blood gas analysis results of the study patients during the acute period.

	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6	Patient 7	Patient 8
Arterial pH	7.43	7.28*	7.13*	7.27*	7.30*	6.82*	7.26*	7.13*
Anion gap	10.2*	23*	29*	8.3	19*	29.5*	24*	28*
NaHCO3 (mmol/L)	22.1	9.3*	6.7*	14.5*	18.9*	6.5*	8.8*	8.0*
Base deficit	−4.3	−18.3	−20.5	−12.8	−6.2	−22.3	−16.6	−19.5
Urea (mmol/L)	46	39.7*	39*	16.7	5.2	18.3	29*	28*
Creatinine (mg/dL)	0.67	0.81	1.34*	0.51	1.4*	1.32*	0.80	0.89
Potassium (mEq/L)	3.7	3.45	4.87	4.1	3.2	5.77*	3.52	3.9
Calcium (mEq/L)	9.5	9.44	10.18	9.21	10.4	10.83*	10.1	9.5

*Abnormal result.

DWI within the first 4 weeks after initial exposure revealed DR of the optic nerves in four (50%) patients, while no abnormalities were seen in the remaining four patients. While three (37.5%) patients had bilateral optic nerve DR, only one patient (P5) had asymmetrical DR. When follow-up DWI was undertaken for those with DR, it was seen that in all patients optic nerve DR had disappeared. The results of DWI-MRI are given in Table 3. The course of bilateral symmetrical segmental DR of the optic nerves of Patient 2 on DWI is given in Figures 1 and 2. Figure 3 shows bilateral symmetrical diffusion restriction in 3 mm segment of the optic nerves of Patient 1 on DWI.

Table 3.

Diffusion-weighted imaging findings in the optic nerves of the patients during the acute phase.

Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6	Patient 7	Patient 8
Symmetrical diffusion restriction in a 5–6 mm segment at the junction of the optic nerve with the papillae	Symmetrical diffusion restriction in a 1 cm segment in the retrobulbar area in both optic nerves	Normal	Normal	Diffusion restriction in right retrolaminar optic nerve	Bilateral diffusion restriction in both optic nerves	Normal	Normal

Figure 1.

Bilateral symmetrical segmental diffusion restriction of the optic nerves of patient 2 on diffusion-weighted imaging (DWI). The involved segment was 1 cm long, slightly swollen and adjacent to the papilla. Orbital magnetic resonance imaging including T1, fat-saturated T2, and post-contrast fat-saturated T1-weighted imaging were unremarkable. Axial (a) and coronal (b) DWI trace images showing bilateral symmetrical high signal in a 1 cm long segment of the optic nerves adjacent to papilla (white arrows). These segments are slightly enlarged compared with the rest of the optic nerves. Sagittal apparent diffusion coefficient map (c) and DWI trace image map (d) showing the compromised segment of the right optic nerve is better appreciated on this sagittal oblique DWI study (white arrows).

Figure 2.

Two month follow-up diffusion-weighted imaging of patient 2 showing disappearance of the optic nerve diffusion restriction.

Figure 3.

Patient 1 diffusion weighted imaging (DWI) findings. (a) axial DWI trace image showing bilateral symmetrical high signal in a 3 mm long segment of the optic nerves adjacent to papillae (white arrows). The corresponding apparent diffusion coefficient (ADC) map (b) showing diffusion restriction in these optic nerve segments (black arrows). Follow-up DWI (c) and ADC map (d) showing no optic nerve diffusion restriction.

When the patients with increased VA were examined (both eyes of P1, P2, and P6 and the right eye of P5), the serum and blood gas analyses in the acute stage showed acidosis and low bicarbonate levels in three (75%) patients (P2, P5, and P6) and increased BUN in one (25%) patient (P2). Also, increased creatinine levels in two (50%) patients (P5 and P6) and increased K⁺ and Ca²⁺ levels in only one (25%) patient (P6) was observed. Three (75%) of these patients were put on dialysis during their admission; only one (25%) of these patients received pulse steroid therapy. The initial VA level of the eyes with increased VA ranged from no light perception to 20/25.  In eyes with no increase, this range was counting fingers from 4 meters to 20/25. Baseline DR of the optic nerves in these eyes was the sole finding that was present in all of the eyes with increased VA. Follow-up DWI at least 1 month after the initial DWI showed normal optic nerve diffusion in all of these eyes.

Discussion

In our study, we have reported eight patients who had methanol poisoning as a result of consuming illicit alcohol. DWI of the optic nerves, a novel examination for this condition, was performed in this patient group and revealed DR in seven eyes, confirming that the optic nerve is a susceptible target. We also observed that, regardless of initial visual function (VA and CV), treatment applied, acidosis status, and blood gas analysis results, the eyes with improved DR had better visual prognosis with improved VA.

The optic nerve and basal ganglia are the tissues most susceptible to metabolic or apoptotic injury following methanol intoxication. Although the exact pathogenesis for this selective toxicity is not known, several theories exist. Formic acid, the end product of methanol, exerts its toxic effects by inhibiting the activity of cytochrome oxidase, which is the terminal enzyme in the mitochondrial electron transport chain essential for adenosine triphosphate (ATP) synthesis and the subsequent failure of the Na⁺/K⁺ ATPase pump.^12,13 This results in histotoxic anoxia, particularly in vascular watershed areas, including the basal ganglia and the retrolaminar optic nerves.¹⁴ Therefore, the localisation of those structures may explain their vulnerability to formic acid toxicity. This mechanism may account for the DR of the optic nerves in our study by causing cytotoxic oedema similar to an acute infarction of neural tissue. Hypothetically, the time-dependent recovery of Na⁺/K⁺ ATPase pump in ischaemia-induced neuronal injury might explain the reconstructable diffusion in the follow-up in our study, but experimental studies are needed to confirm this.¹⁵ Moreover, the greater susceptibility of the optic nerve, macular area of the retina and basal ganglia to anoxia and ischaemia following methanol intoxication might be due to their high metabolic rates compared with other organs. Another hypothesis to account for this selective toxicity could be related to the expression of aquaporins, particularly aquaporin 1, 3, and 4.^16–18 These water-channel proteins play a crucial role in maintaining water and osmotic balance within brain cells and the optic nerve. They also facilitate the transport of polar molecules, such as glycerol and methanol, to these tissues. The differential expression or function of aquaporins in these regions might contribute to their increased vulnerability to formic acid toxicity. In addition, the increasing pressure around the optic nerve in the visual pathway, as shown in methanol toxicity cases, might further aggravate the deterioration due to ischaemic changes and may explain the higher susceptibility of optic nerves.¹⁹ A final proposed mechanism for the toxicity is selective demyelination of the optic nerve due to the myelinoclastic effect of formic acid.²⁰ The retrolaminar regions of the optic nerves are most vulnerable to damage. In support of this theory, several studies employing visual evoked potentials have demonstrated reduced latency during the recovery period.^21,22 In their respective analyses, the authors suggested that this observation might be attributed to remyelination.

Tanrivermis Sayit et al.⁹ observed in a patient treated for acute methanol poisoning during the first 24 h, that the DR in the optic nerve regressed and the patient’s VA and visual field improved. On the other hand, a case report of chronic methanol intoxication via dermal and inhalational route by Mojika et al.¹⁰ had DR in both optic discs at the time of diagnosis, while the DR regressed 2 weeks later. However, VA, which was at the level of bilateral hand motion perception, increased slightly in one eye and decreased to no light perception in the other. In the study conducted by Elkhamary et al.¹¹ which evaluated the MRI findings of 58 patients with a history of prolonged methanol intoxication, no patients exhibited DR. However, the authors reported that no patients underwent MRI during the acute phase. In our study, we observed that DR was detected within the first 4 weeks after the initial exposure. Therefore, we may hypothesise that this finding is likely encountered in the early stage of optic nerve damage. Furthermore, we noted that the follow-up DWI one month after the first imaging showed the disappearance of DR. In cases of ischaemia, the cell membrane restricting the water protons within the cell in the acute-stage ruptures and the whole structure of the tissue reorganises in the subacute stage. Thus, the movement of water protons is not restricted any more. This results in an increase of the ADC values in the subacute stage. We hypothesise that the compromise of the optic nerve and retina is also a consequence of energy depletion, so destruction and/or reorganisation of the intracellular structures leads to disappearance of the DR.

DR in the optic nerve can be observed in other ischaemic and inflammatory lesions. Lee et al.²³ reported that they observed DR in the optic nerve in a patient with acute optic neuritis secondary to the neuromyelitis optica spectrum disorder. Chen et al.²⁴ observed bilateral optic nerve DR in a case of cavernous sinus thrombophlebitis and concluded that it was caused by venous ischaemia. No comment was made about the continuing presence of DR since no interval MRI was performed in the patient whose bilateral permanent blindness continued after treatment. DR may be seen not only in cases of arresting of water protons within the cell but also in conditions where the extracellular space is narrowed because of cellular crowding, as shown in cancer studies.²⁵

There have been several studies evaluating the factors affecting the visual prognosis in patients after methanol poisoning. In a study of 122 patients, the degree of acidosis was the only significant variable affecting the final VA, whereas early admission and treatment did not significantly alter the visual outcome, especially in severe poisoning. Patients having a pH of more than 7.2 at the time of the initial assessment were more likely to have transient visual abnormalities.²⁶ In our study, pH was above 7.2 in three of the four patients whose VA improved. Liu et al.²⁷ found a correlation between prolonged acidosis and a worse prognosis by comparing 12 patients who had recovered with treatment to seven cases with persisting visual abnormalities due to methanol poisoning at the time of hospital discharge. Also, in a 3-month follow-up study, Dethlefs and Naraqi showed that the presence of metabolic acidosis and the amount of methanol consumed were positively correlated with the development of permanent visual impairment.²⁸ Sanaei-Zadeh et al.²⁹ on the other hand, discovered no significant difference in age, gender, elapsed time to presentation, gastrointestinal symptoms, abnormal neurological and computerised tomography findings, or arterial blood gas results at presentation between the transient and permanent visual disturbance groups after methanol poisoning. The use of intravenous methylprednisolone has been linked to promising visual outcomes in several studies.^19,30 Two of our patients, both of whom underwent DWI during their initial admission to the ED, were initiated on pulse steroid treatment after the correction of their initial metabolic status while in the ED. Notably, only the patient with DR evident on DWI experienced an improvement in VA. We believe that the implementation of steroids could be a treatment option considered for individuals with DR after methanol poisoning due to its potential to alleviate the oedema component, which is known to contribute to the pathophysiology of DR, as supported by Shukla et al.‘s findings that oedema is an important component and is responsive to steroid treatment in methanol poisoning.¹⁹ However, it is important to note that this aspect falls beyond the scope of our study, and our findings do not provide sufficient evidence to make definitive comments regarding potential treatment modifications in cases with optic nerve DR in methanol poisoning.

In addition to traditional treatment modalities, which encompass haemodialysis, steroids, and vitamin B₁₂ supplementation, there are several emerging treatment options.¹² These include erythropoietin, known for its neuroprotective-antioxidative properties and capacity to restore blood supply.³¹ Another novel approach is photobiomodulation, which enhances mitochondrial function by stimulating the activity of the cytochrome c oxidase complex.³² Furthermore, newer antioxidants such as taxifolin and rutin have shown promise.¹² However, it is worth noting that their efficacy in methanol poisoning cases has only been demonstrated in a scarce number of studies.

In the light of the limited number of studies on orbital imaging in methanol intoxication, we believe it is important to report our novel finding despite the small size of our patient population. However, there are several limitations of our study. No imaging was available prior to methanol exposure to rule out the possibility of pre-existing abnormal optic nerve findings; nonetheless, we excluded individuals with co-morbidities that could induce similar visual symptoms. The fact that the optic nerves of the patients were not evaluated with optical coherence tomography is another limitation of our study. Finally, we were unable to measure blood methanol levels to confirm the diagnosis; however, we do not think this is a limitation of our study because this approach is not widely used in ED due to its cost, time, and limited availability in most of the institutions. Yet, while measuring serum methanol concentration is useful for diagnosing poisoning, it should be emphasised that this parameter is unrelated to the organism’s degree of intoxication and that measuring arterial blood pH is considerably more significant for this purpose.³³

To our knowledge, ours is the first study to evaluate the predictive role of optic nerve diffusion status in the visual prognosis of patients with methanol poisoning. We observed that an improvement in DR may accompany an improvement in VA during follow-up, regardless of any other clinical or laboratory parameters. We also believe that DR of the optic nerve can be encountered more frequently in the early stage of optic nerve damage. Further studies with larger sample size are required for the validation of our results.

Funding Statement

The authors reported that there is no funding associated with the work featured in this article.

Disclosure statement

No potential conflict of interest was reported by the author(s).