Methanol Toxicity

Methanol, also known as wood alcohol, is a commonly used organic solvent that, because of its toxicity, can cause metabolic acidosis, neurologic sequelae, and even death, when ingested. It is a constituent of many commercially available industrial solvents and of poorly adulterated alcoholic beverages. Methanol toxicity remains a common problem in many parts of the developing world, especially among members of lower socioeconomic classes. (See Etiology and Pathophysiology and Presentation.)[1]

Sophisticated imaging techniques have enabled a better understanding of the clinical manifestations of methanol intoxication. Additionally, neurologic complications are recognized more frequently. This is possible because of early recognition of the toxicity and because of advances in supportive care. Hemodialysis and better management of acid-base disturbances remain the most important therapeutic improvements. (See Workup, Treatment, and Medication.)

According to a study by Jaff et al, methanol intoxication can lead to several ECG changes, with sinus tachycardia and non-specific T-wave changes being the most common. In the study, the changes were more prominent in cases of severe acidosis. A retrospective chart review of 9 patients between 2006 and 2011 revealed that lower pH and higher plasma methanol concentration were associated with multiple ECG changes. On admission, ECG changes included sinus tachycardia (44%), PR prolongation (11%), QTc prolongation (22%), and non-specific T-wave changes (66%). One patient developed a type-1 Brugada ECG pattern.[2]

According to Zakharov et al, S-formate measurement can help in the laboratory diagnosis and clinical management of acute methanol poisoning. In their study of 38 patients from a Czech methanol mass poisoning in 2012, S-formate levels ≥3.7 mmol/L were seen to lead to the first clinical signs of visual toxicity, indicating hemodialysis. S-formate ≥11-12 mmol/L was associated with visual/CNS sequelae and a lethal outcome. The probability of a poor outcome (death or survival with sequelae) was higher than 90% in patients with S-formate levels ≥17.5 mmol/L, S-lactate levels ≥7.0 mmol/L, and/or pH < 6.87.[3]

Complications

Vision loss

The mechanism by which the methanol causes toxicity to the visual system is not well understood. Formic acid, the toxic metabolite of methanol, is responsible for ocular toxicity in animal models and is rightly presumed to be responsible in human studies. (See Etiology and Pathophysiology.)

Serum methanol levels of greater than 20 mg/dL correlate with ocular injury. Funduscopic changes are notable within only a few hours after methanol ingestion and range from retinal edema in the perimacular region to the entire fundus. Optic disc edema and hyperemia are observed within 48 hours.

Visual injury may be prevented with prompt antidote therapy or via elimination of the metabolites from the system with hemodialysis; however, this is not always the case. (See Treatment and Medication.)

Movement disorders

Parkinsonian motor impairment has been described in some long-term survivors of methanol poisoning. This is thought to be due to formic acid’s predilection for accumulating in high concentrations within the putamen, but the reasons for this phenomenon are unclear. One proposed reason is that formic acid has the ability to impair dopaminergic pathways and increase enzymatic activity of dopa-B-hydroxylase. (See Etiology and Pathophysiology.)[4]

Symptom onset is usually delayed several weeks after methanol exposure. Common parkinsonian symptoms, such as tremor, cogwheel rigidity, stooped posture, shuffling gait, and hypokinesis, have been well described. In addition, the development of dystonia and corticospinal tract signs has been established.

Several case reports have indicated symptom response to standard antiparkinsonian agents, particularly levodopa, amantadine, and bromocriptine.[5]

Muscle spasms have also been reported in methanol poisoning. As expected, this symptom responds poorly to traditional therapy.[6]

Rarely, lesions in the lobar regions of the cerebrum and cerebellum have been observed.[7]

Prognosis

The prognosis in methanol poisoning correlates with the amount of methanol consumed and the subsequent degree of metabolic acidosis; more severe acidosis confers a poorer prognosis. The prognosis is further dependent on the amount of formic acid that has accumulated in the blood, with a direct correlation existing between the formic acid concentration and morbidity and mortality. Little long-term improvement can be expected in patients with neurologic complications. (See Treatment and Medication.)[8]

The minimal lethal dose of methanol in adults is believed to be 0.3-1 g/kg of body weight.[9] The exact rates of morbidity and mortality from methanol intoxication are not available.

Methanol has a relatively low toxicity. The adverse effects are thought to be from the accumulation of formic acid, a metabolite of methanol metabolism.

Upon ingestion, methanol is quickly absorbed in the gastrointestinal tract and metabolized in the liver. In the first step of degradation, methanol is transformed into formaldehyde via the enzyme alcohol dehydrogenase (ADH). This reaction is slower than the next step, the transformation of formaldehyde into formic acid via the enzyme aldehyde dehydrogenase. This may explain the reason for the latency of symptoms between ingestion and effect. The half-life of formaldehyde is estimated to be 1-2 minutes.[10]

Formic acid is further oxidized to carbon dioxide and water in the presence of tetrahydrofolate. The metabolism of formic acid is very slow; thus, formic acid often accumulates in the body, which results in metabolic acidosis.[10]

The eye damage caused by methanol has been well described; however, the mechanism behind this phenomenon is not well understood. Vision loss is thought to be caused by interruption of mitochondrial function in the optic nerve, resulting in hyperemia, edema, and optic nerve atrophy.

Optic nerve demyelination has been reported to be due to formic acid destruction of myelin. The major damage occurs at the retrolaminar optic nerve, with intra-axonal swelling and organelle destruction. Little to no change is seen in the retina.[11]

Methanol also affects the basal ganglia. Hemorrhagic and nonhemorrhagic damage to the putamen are common problems in cases of severe intoxication. As a result of this damage, patients can develop parkinsonism or other dystonic/hypokinetic clinical pictures.[12]

The predilection for and mechanism of toxicity to the putamen is not understood. Some postulate that striatal neurons have a varying sensitivity to toxic metabolites of methanol. However, this remains to be proven.[6]

At-risk populations

Suicide attempts using methanol are uncommon.[13] However, unintentional methanol poisoning occurs under a variety of circumstances in several discrete populations, including the following:

• Children - Accidental overdose can be seen in children; methanol is found commonly in antifreeze, perfumes, paint solvents, photocopying fluid, and windshield washing fluid, all of which are readily available

• Persons with alcoholism - These individuals commonly consume methanol as a substitute for ethanol

• Populations of developing countries - In many parts of the developing world, methanol is often a component of "bootlegged alcohol," which is made in rural regions; because of its low cost, it is often consumed by members of lower socioeconomic classes

• Industrial workers - In the industrial setting, the inhalation of methanol fumes poses a health risk; methanol is used in the production of formaldehyde and in shellac processing; in addition, it is used as an extractant in chemical processes and as a denaturant in ethanol[14]

A careful history should be taken in high-risk patients who report typical symptoms of methanol poisoning.

Time course

Initial symptoms generally occur 12-24 hours after ingestion. The interval between ingestion and the appearance of symptoms correlates to the volume of methanol ingested and the amount of ethanol concomitantly ingested; competitive inhibition exists between the 2 compounds.[10]

Methanol blood levels peak at 30-90 minutes following ingestion and often do not correlate to the time to symptom appearance.

Neurologic manifestations

Initially, the symptoms of methanol intoxication are similar to those of ethanol intoxication, often with disinhibition and ataxia. Following a latent period, patients may develop headache, nausea, vomiting, or epigastric pain. In later stages, drowsiness may rapidly progress to obtundation and coma.

Seizures may occur, generally as a complication of the metabolic derangement or as a result of damage to the brain parenchyma.

Cases of axonal polyneuropathy in association with chronic exposure have been reported.[15] Further, motor neuron disease resembling amyotrophic lateral sclerosis has been documented in a case report.[16] It is likely that neuropathies and spinal cord dysfunction are underestimated.

Vision loss

Blindness from methanol inhalation was described as early as 1910. Formic acid accumulates within the optic nerve, which results in the classic visual symptoms of flashes of light and blurring.

Patients initially may present with diminished visual acuity, which can progress to scotomata and scintillations. The frank blindness that develops sometimes responds to immediate therapy; however, complete loss of vision is a common sequela.

Physical examination helps to rule out other causes of altered mental status and visual dysfunction, the 2 most common presenting signs of methanol intoxication. In cases of altered mental status and intentional overdose, the diagnosis of methanol intoxication may be difficult without a high clinical index of suspicion.

General physical examination

During the initial phase of methanol poisoning, individuals may experience effects similar to inebriation with alcohol and thus may not seek medical attention. As symptoms develop, most signs are related to metabolic acidosis; these are manifested as tachycardia, tachypnea, hypertension, and altered mental status. Pulmonary edema and acute respiratory distress may ensue, requiring intubation.

With large ingestions of methanol, depressed cardiac contractility heralds circulatory collapse and leads to signs of heart failure, cardiac arrhythmias, or both.

Neurologic examination

In addition to the progression of symptoms from drowsiness to stupor to coma, ocular findings in patients with methanol poisoning are prominent during a careful neurologic examination.

Visual symptoms necessitate a thorough examination of the fundi. Optic disc hyperemia occurs early in the course of methanol intoxication. Pupillary response to light is compromised and, subsequently, is lost. Little or no retinal damage is observed.

Renal profile

Significant methanol ingestion leads to metabolic acidosis, which is manifested by a low serum bicarbonate level. The anion gap is increased secondary to high lactate and ketone levels. This is probably due to formic acid accumulation.[17, 18] See the Anion Gap calculator.

Serum osmolarity

Methanol ingestion results in an elevated osmolar gap, so in cases of stupor of unknown cause, testing for an osmolar gap should be routine. However, the osmolar gap is a nonspecific finding because it may represent the presence of a low ̶ molecular weight solute, such as ethanol, other alcohols, mannitol, glycine, lipids, or proteins.

The osmolar gap can be calculated using a set formula. To find the osmolar gap, take the measured plasma osmolality and subtract the calculated osmolality. Calculated osmolality requires a serum glucose measurement and is derived as follows:

Calculated osmolality (mOsm/kg) = 2(Na+) + (glucose/18) + (blood urea nitrogen [BUN]/2.8)

Serum amylase

Hemorrhagic pancreatitis has been described in as many as two thirds of the patients with methanol poisoning.

Serum methanol

Definitive diagnosis of methanol toxicity requires a confirmed increase in the serum methanol level with gas chromatography. Peak levels are achieved 60-90 minutes after ingestion, but they do not correlate with the level of toxicity and thus are not a good indicator of prognosis.

Electroretinography/visual evoked response

Two cases of methanol toxicity were evaluated using these studies. Characteristic findings correlated well with pathologic results and postulated toxicity. Loss of retinal sensitivity was coupled with scotomata in both patients evaluated. In addition, decreased amplitudes were found on visual evoked-response testing, although latencies were normal.[19]

Methanol appears to affect the basal ganglia, primarily the putamen. Because of the availability of advanced neuroimaging techniques, the putaminal damage tends to be detected much earlier in current practice than it was in the past.

CT scanning

Computed tomography (CT) scanning may reveal the characteristic changes of bilateral putaminal necrosis with varying degrees of hemorrhage, in addition to involvement of the cerebral white matter. However, the lesions may not be well localized when compared with magnetic resonance imaging (MRI) findings.

Moreover, often the initial CT scan is normal and several days may elapse before lesions become evident.

MRI

A characteristic finding is bilateral putaminal necrosis with or without hemorrhage, probably as a result of the direct toxic effects of methanol metabolites. This finding is certainly not specific for methanol toxicity, because it can be seen with other diseases, such as Wilson disease, Leigh disease, and stroke.[20]

Other findings that have been described include cerebral and intraventricular hemorrhage, diffuse cerebral edema, cerebellar necrosis, subcortical white matter necrosis, optic nerve necrosis, and even enhancement of necrotic lesions.[20]

In a series of 4 patients, MRI performed within 2 weeks of methanol intoxication demonstrated changes in the putamen of all 4 patients.[21] Three of these patients had white matter lesions within the occipital/frontal lobes. Interestingly, in patients who recovered without extrapyramidal symptoms, the lesions regressed within several weeks. The authors recommend MRI as a prognostic tool and as a means of differentiating methanol intoxication from other conditions, such as hypoglycemia and carbon monoxide poisoning.

Prompt medical care is key to avoiding complications secondary to methanol intoxication. Supportive therapy is aimed at initiating airway management, correcting electrolyte disturbances, and providing adequate hydration.

Metabolic acidosis in methanol poisoning may necessitate the administration of bicarbonate and assisted ventilation. Bicarbonate potentially may reverse visual deficits. In addition, bicarbonate may help to decrease the amount of active formic acid.

Antidote therapy, often using ethanol or fomepizole, is directed towards delaying methanol metabolism until the methanol is eliminated from the patient’s system either naturally or via dialysis. Like methanol, ethanol is metabolized by ADH, but the enzyme’s affinity for ethanol is 10-20 times higher than it is for methanol. Fomepizole is also metabolized by ADH; however, its use is limited because of high cost and lack of availability.[10, 22, 23]

Hemodialysis can easily remove methanol and formic acid. Indications for this procedure include (1) greater than 30mL of methanol ingested, (2) serum methanol level greater than 20 mg/dL, (3) observation of visual complications, and (4) no improvement in acidosis despite repeated sodium bicarbonate infusions.

Consultations

Consultation with the following specialists can be beneficial:

• Nephrologist - Consultation with a nephrologist is advisable to aid in the correction of the metabolic disturbance; the nephrologist can also help to arrange dialysis, respiratory care, or both

• Ophthalmologist - Consultation with an ophthalmologist is recommended for assessment of ocular damage

• Neurologist - Consultation with a neurologist is arranged to assist with the management of seizures in the acute setting or with the treatment of any subsequent movement disorders that may develop

Ethanol and fomepizole can be administered to delay methanol metabolism until the methanol is eliminated from the patient’s system (either naturally or with dialysis). These antidotes work via competitive inhibition; ethanol and fomepizole are metabolized by ADH, just as methanol is, but the enzyme has a higher affinity for both antidotes than it does for methanol. For example, the affinity of ADH for ethanol is 10-20 times greater than it is for methanol. The use of fomepizole is limited because of its high cost and lack of availability.[10]

Class Summary

These agents inhibit the toxic effects of methanol via competitive inhibition.

Ethanol

Ethanol is believed to compete with methanol for ADH, thus preventing metabolism of methanol to its toxic by-products. ADH has a 10- to 20-fold greater affinity for ethanol than for methanol. By slowing the degradation of methanol, ethanol is assumed to prevent the accumulation of high levels of formic acid.

The goal of ethanol therapy is to achieve an ethanol blood concentration of 100 mg/dL. At this level, ethanol is thought to become a competitive substrate for ADH and to be sufficient to block methanol metabolism.

Fomepizole/4-methylpyrazole (Antizol)

Fomepizole acts similarly to ethanol. It is a stronger competitive inhibitor of ADH and, in addition, does not cause hypoglycemia or sedation. Fomepizole is relatively easier to administer than ethanol. It does not require monitoring of serum concentrations.