Toxic Alcohols

Methanol

Methanol is a colorless, volatile, slightly sweet-tasting alcohol. It is a product of natural fermentation and originally was manufactured from the distillation of wood, but currently, methanol is almost all synthetically produced. Certain products found in the home may contain high concentrations of methanol; these include antifreeze, windshield washer fluid, carburetor fluid, duplicator fluid, hobby engine fuel, gasohol, dry gas, Sterno, glass cleaners, cleaning agents, and thinners for shellacs, lacquers, adhesives, and inks. Methanol is a precursor in the manufacture of plastics, films, and dyes. Methanol is also found in formalin and embalming fluid. Illicit alcohol production remains a global source of methanol poisoning from products such as chang’aa (Kenya), raki (Turkey), and tuica (Romania).

Although epidemic poisonings from methanol are reported occasionally, most exposures are sporadic. In 2009, of the 2162 cases of methanol poisoning reported to American poison centers, 77% were unintentional, 6% had moderate to major complications, and 10 were fatalities. Treatment delay is associated with increased morbidity, making early recognition of clinical and laboratory clues crucial.

Methanol is absorbed rapidly from the gastrointestinal tract, and blood levels peak 30 to 60 minutes after ingestion.¹ Transdermal and respiratory tract absorption also has resulted in toxicity, especially in infants. Certain occupations, including painting, glazing, varnishing, lithography, and printing, are high risk for inhalational exposure to methanol. Inhalational abuse of methanol is a recent trend that can result in toxic serum levels.²

At low serum concentrations, the elimination of methanol follows first-order kinetics; but at concentrations after overdose, zero-order kinetics predominate. This produces a prolonged half-life of 24 to 30 hours, which may be extended even further by the concurrent ingestion of ethanol. First-order elimination prevails at high levels (>300 mg/dL), possibly as a result of enhanced pulmonary elimination. Small amounts of ingested methanol may be exceptionally toxic. In adults, the smallest lethal dose reported is 15 mL of 40% methanol, and 4 mL of pure methanol has led to blindness. With appropriate and timely treatment, however, survival without loss of eyesight has been reported despite extremely high levels. From a pediatric perspective, the ingestion of only 1.5 mL of 100% methanol in a toddler (0.15 mL/kg) is sufficient to produce a toxic blood level of 20 mg/dL. Any suspected pediatric methanol ingestion warrants aggressive evaluation and treatment.

Methanol itself has little toxicity, producing less central nervous system (CNS) depression and inebriation than ethanol. Metabolites of the parent alcohol are extremely toxic, however. Although small amounts of methanol are eliminated by renal and pulmonary routes, 90% is metabolized in the liver. Methanol is oxidized by alcohol dehydrogenase (ADH) to formaldehyde, which is rapidly converted by aldehyde dehydrogenase to formic acid (Fig. 155-1). Formic acid is the primary toxicant and accounts for much of the anion gap metabolic acidosis and ocular toxicity peculiar to methanol ingestion.³ Through a folate-dependent pathway, formic acid is degraded to carbon dioxide and water.

Figure 155-1 Metabolism of methanol. NAD, nicotinamide adenine dinucleotide; NADH, reduced form of nicotinamide adenine dinucleotide.

Pathophysiology

Optic neuropathy and putaminal necrosis are the two main complications of severe methanol poisoning. Long-term morbidity takes the form of visual impairment, including blindness, and parkinsonian motor dysfunction, characterized by hypokinesis and rigidity. Formic acid has a high affinity for iron and inhibits mitochondrial cytochrome oxidase, halting cellular respiration.⁴ Methanol metabolism in the cytosol and mitochondria may account for a second mechanism of adenosine triphosphate depletion.⁵ Lactate accumulation resulting from hypotension or seizures further compounds the metabolic acidosis predominantly caused by formate. Other mechanisms of toxicity involve increased lipid peroxidation, free radical formation, and impaired protective antioxidant reactions.^4,6 Severe dysfunction of subcellular metabolism from methanol also has been linked to significant disturbance in proteolytic-antiproteolytic balance.⁷

The primary sites of ocular injury are the retrolaminar optic nerve and retina. Selective myelin damage to the retrolaminar optic nerve has been seen at autopsy after methanol toxicity. Müller cells, the principal glial cells of retinal neurons and photoreceptors, have been proposed as the initial target in methanol-induced visual toxicity. It seems that they alone harbor the enzymes necessary to metabolize methanol to formate. Histopathologic correlates suggest that retinal cells develop intra-axonal swelling, calcium influx, mitochondrial destruction, and microtubular disruption. Ultimately, this interferes with transport of essential proteins from the retinal neuron cell body to the nerve fiber axoplasm. Oligodendrocyte involvement causes myelin degeneration and leads to visual decrements. Acidosis may accelerate this process by enhancing nonionic diffusion of formic acid into neurons and further increasing lactate production.⁴ This self-perpetuating cycle of acidosis, termed circulus hypoxicus,⁸ underscores the need for aggressive correction of pH to accomplish ion trapping of formate outside the CNS.

Methanol adversely affects other areas of the CNS, specifically the basal ganglia. Bilateral, symmetrical putaminal hypodensities, hemorrhages, or cystic lesions are characteristic, occurring in 13.5% of patients. Necrosis is described in the subcortical white matter, spinal cord anterior horn cells, and cerebellum.⁹ Acute signs and symptoms may be lacking or may take several days to develop despite the presence of these radiographic findings. The cellular mechanisms of injury may be similar to the mechanisms of the ophthalmologic injury, but the reason for localization of neurologic damage to the basal ganglia is unknown. Quantitative neuropathologic studies conflict as to whether concentrations of formic acid within the putamen are higher than levels in the blood or other tissues. Massive edema adjacent to the putamen shown by magnetic resonance imaging (MRI) suggests a possible localized disruption of the blood-brain barrier. Other proposed mechanisms for the vulnerability of this region include the unique pattern of arterial blood supply and venous drainage and greater metabolic activity.

Clinical Features

With individual cases of methanol poisoning, the history may be unobtainable or unreliable. The diagnosis should be considered in patients with altered mental status, visual complaints, or metabolic acidosis and in patients with occupations that put them at high risk for exposure. Because methanol is a poor substrate for ADH, a latency period exists between the time of ingestion and metabolism to the formate that causes visual or metabolic disturbance. The typical 12- to 24-hour latency may be shorter when large amounts are consumed or longer when ethanol is coingested (range, 40 minutes to 72 hours).¹ Formic acid accumulation may be ongoing, with risk for significant toxicity, in patients who present early despite being initially asymptomatic. When symptoms are manifested, they are primarily neurologic, gastrointestinal, or ocular.

Although methanol is less inebriating than ethanol, early symptoms of methanol poisoning include depressed mental status, confusion, and ataxia. Nonspecific complaints of weakness, dizziness, anorexia, headache, and nausea develop; in severe cases, coma and seizures may be seen. Although vomiting and abdominal pain commonly result from mucosal irritation, the absence of gastrointestinal complaints does not rule out a serious ingestion.¹ Abdominal tenderness, however, may be so severe that it suggests an acute surgical abdomen.¹ This may result from pancreatitis, and elevation of serum amylase is relatively common, but increased salivary amylase isoenzyme can occur without pancreatic inflammation.

Visual disturbances are seen in 50% of patients, and their development may precede or parallel that of other symptoms.⁸ Patients may complain of cloudy, blurred, indistinct, or misty vision or may note yellow spots or, rarely, photophobia. The most common acute field defect is a dense central scotoma.¹⁰ Some patients compare their visual symptoms with “stepping out into a snowstorm,” a complaint unique to methanol ingestion. Patients can have a complete lack of light perception and total loss of vision. Visual acuity should be determined. On examination, optic disc hyperemia is seen at 18 to 48 hours after ingestion. Peripapillary retinal edema follows, is most striking in the nerve fiber layer along the vascular arcades, and only rarely involves the macula.^5,10 Sluggishly reactive or fixed and dilated pupils indicate a poor prognosis. Pallor and cupping, indicative of optic atrophy, are late findings suggesting a poor prognosis for visual recovery. On occasion, the fundus may appear normal, even in patients with visual symptoms.

Compensatory tachypnea heralds the onset of metabolic acidosis, which often may be severe, with reported serum bicarbonate concentrations of less than 5 mEq/L and an arterial pH less than 7.0. Early tachycardia has been noted, but in general, cardiovascular abnormalities are rare.¹ Hypotension and bradycardia, when present, are preterminal findings.¹¹ Historically, death is associated with a peculiar, abrupt cessation of respiration rather than with cardiovascular collapse.¹ Multiple organ failure is rare.¹¹

Prognosis after methanol ingestion seems to correlate with the degree of acidosis, time to presentation, and initiation of treatment within 8 hours of exposure.1,12 Poor prognosis is associated with coma, seizures, or arterial pH less than 7.0.¹¹ A large outbreak was associated with a fatality rate of 44%.¹³ Patients surviving the acute phase of toxicity may be left with permanent blindness or neurologic deficits, such as parkinsonism, toxic encephalopathy, polyneuropathy, cognitive dysfunction, transverse myelitis, primitive reflexes, or seizures.¹⁴