eMedicine Specialties > Neurology > Neurotoxicology

Methanol

Kalyani Korabathina, MD, Department of Neurology, University of South Florida College of Medicine
Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital; David Likosky, MD, Clinical Instructor, Department of Neurology, University of Washington

Updated: Mar 15, 2007

Introduction

Background

Methanol, also known as wood alcohol, is a commonly used organic solvent, the ingestion of which has severe potential ramifications. It is a constituent in many commercially available industrial solvents and in poorly adulterated alcoholic beverages. Toxicity usually occurs from intentional overdose or accidental ingestion and results in metabolic acidosis, neurologic sequelae, and even death. Methanol toxicity remains a common problem in many parts of the developing world, especially among members of lower socioeconomic classes.

Sophisticated imaging techniques have enabled a better understanding of the clinical manifestations of methanol toxicity. Additionally, with the improvement in medical therapy, neurological 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 improvements.

Pathophysiology

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 to formaldehyde via the enzyme alcohol dehydrogenase (ADH). This reaction is slower than the next step, the transformation of formaldehyde to 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 (Rathi, 2006).

Formic acid is further oxidized to carbon dioxide and water in the presence of tetrahydrofolate. The metabolism of formic acid is very slow; thus, it often accumulates in the body, which results in metabolic acidosis (Rathi, 2006).

The eye damage caused by methanol has been well described; however, the mechanism behind this phenomenon is not well understood. 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 (Casarett, 1996).

Methanol also affects the basal ganglia. With severe intoxication, common problems are hemorrhagic and nonhemorrhagic damage of the putamen. This was described initially in 1953, although the clinical syndrome associated with this lesion was not described until more recently (Phang, 1988). As a result, patients can develop parkinsonism or other dystonic/hypokinetic clinical pictures.

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 (LeWitt, 1988).

In addition, cases of axonal polyneuropathy in association with chronic exposure have been reported (Hageman, 1999). Further, motor neuron disease resembling amyotrophic lateral sclerosis has been documented in 1 case report (Chio, 2004).

Mortality/Morbidity

• Exact rates of morbidity and mortality from intoxication are not available.
• Prognosis is correlated with the degree of metabolic acidosis (and the quantity of methanol ingested); more severe acidosis confers a poorer prognosis.
• Direct correlation exists between the formic acid concentration and the morbidity and mortality.

Clinical

History

• Time course
  • Initial symptoms generally occur 12-24 hours after ingestion.
  • The interval between ingestion and the appearance of symptoms is correlated with the volume of methanol ingested and the amount of ethanol concomitantly ingested; competitive inhibition exists between the two (Rathi, 2006). Methanol blood levels peak at 30-90 minutes following ingestion and are often not correlated with time to symptom appearance. The minimal lethal dose in adults is believed to be 1 mg/kg of body weight.
  • In cases of altered mental status and intentional overdose, the diagnosis may be difficult without a high clinical index of suspicion.
• Neurological manifestations
  • Initially, the symptoms from 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.
  • Methanol appears to affect the basal ganglia, primarily the putamen. With advanced neuroimaging techniques, the putaminal damage is detected much earlier in current practice than in the past.
• Vision loss
  • Blindness from methanol inhalation was described as early as 1910.
  • Formic acid accumulates within the optic nerve, which results in classic visual symptoms of flashes of light and blurring. Subsequently, this may progress to scotomas and scintillations.
  • 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 also been reported to be due to formic acid destruction of myelin.
  • 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

Physical examination helps to rule out other causes of altered mental status and visual dysfunction, the 2 most common presenting signs of methanol intoxication.

• General physical examination
  • During the initial phase, individuals may experience effects similar to inebriation with alcohol and thus do not seek medical attention. As symptoms develop, most signs are related to metabolic acidosis manifested as tachycardia, tachypnea, hypertension, and altered mental status.
  • Pulmonary edema and acute respiratory distress may ensue, requiring intubation.
  • With large ingestions, depressed cardiac contractility heralds circulatory collapse and leads to signs of heart failure, cardiac arrhythmias, or both.
• Neurologic examination
  • In addition to the progression from drowsiness to stupor to coma, ocular findings 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 the methanol intoxication.
  • Pupillary response to light is compromised and, subsequently, is lost. Little to no retinal damage is observed.

Causes

Methanol intoxication occurs in several discrete populations.

• 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.
• Alcoholic persons commonly consume methanol as a substitute for ethanol. The excessive consumption of methanol then leads to intoxication.
• 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 those in lower socioeconomic classes.
• In the industrial setting, inhalation of methanol fumes is a risk. It is used in the production of formaldehyde and shellac processing. In addition, it is used as an extractant in chemical processes and as a denaturant in ethanol (Rosenstock, 1994).
• Suicide attempts using methanol are uncommon (Jacobsen, 1997).

Differential Diagnoses

Other Problems to Be Considered

Ethylene glycol intoxication
Carbon monoxide poisoning
Pseudoseizure
Any cause of altered mental status with acidosis and potential cardiovascular collapse

Workup

Laboratory Studies

• 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 (Jacobsen, 1986).
• Serum osmolality: Methanol ingestion results in an elevated osmolar gap. This 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.
  • A serum glucose measurement is required to calculate the expected plasma osmolality. Calculated osmolality requires a serum glucose measurement (calculated osmolality (mOsm/kg) = 2[Na⁺] + [glucose/18] + [BUN/2.8]).
  • 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.
• Serum amylase: Hemorrhagic pancreatitis has been described in as many as two thirds of the patients.
• Serum methanol level: 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.

Imaging Studies

• CT scanning
  • 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 MRI findings.
  • Moreover, often the initial CT scan is normal and several days may elapse before lesions become evident.
• Magnetic resonance imaging
  • Characteristic findings are 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 (Blanco, 2006).
  • 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 (Blanco, 2006).
  • In a series of 4 patients, MRI performed within 2 weeks of methanol intoxication demonstrated changes in the putamen of all 4 patients (Hantson, 1997). 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 both a prognostic tool and to differentiate methanol intoxication from other conditions, such as hypoglycemia and carbon monoxide poisoning.

Other Tests

• 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 (McKellar, 1997).

Treatment

Medical Care

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.
• The metabolic acidosis may necessitate 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 is directed towards delaying methanol metabolism until the methanol is eliminated from the system either naturally or via dialysis. This is often accomplished in 2 ways: ethanol or fomepizole. Ethanol is also metabolized by ADH, and the enzyme has 10-20 times higher affinity for ethanol compared with methanol. Fomepizole is also metabolized by ADH; however, its use is limited because of high costs and lack of availability (Rathi, 2006).
  • Hemodialysis can easily remove methanol and formic acid. Indications include (1) greater than 30 mL 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 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.
• Consultation with an ophthalmologist is recommended to assess ocular damage.
• Consultation with a neurologist is arranged to assist with the management of seizures in the acute setting or the treatment of any subsequent movement disorders that may develop.

Medication

For a number of years, only one treatment was available for methanol toxicity. Recently, advances have been made with potential for more effective therapy.

Antidotal treatment

Inhibit the toxic effects of methanol via competitive inhibition.

Ethanol

Believed to compete with methanol for ADH, thus preventing metabolism of methanol to its toxic by-products. ADH has 10- to 20-fold increased affinity for ethanol compared with methanol. By slowing degradation, assumed to prevent accumulation of high levels of formic acid.
Goal of therapy is to achieve ethanol blood concentration of 100 mg/dL (Brown, 2001). At this level, ethanol is thought to become a competitive substrate for ADH and be sufficient to block methanol metabolism.

Dosing

Adult

10% ethanol solution typically administered as 600-mg/kg bolus followed by continuous infusion

Pediatric

Administer as in adults

Interactions

May increase toxicity of benzodiazepines or barbiturates and result in death; additive toxicity may occur with other CNS depressants; cimetidine may increase toxicity; disulfiram and other drugs (eg, ketoconazole, metronidazole) cause alcohol intolerance (eg, facial flushing, nausea, vomiting); may increase serum levels of drugs metabolized by ADH (eg, abacavir)

Contraindications

Ingestion of other CNS depressants

Precautions

Pregnancy

D - Unsafe in pregnancy

Precautions

IV administration may cause thrombophlebitis; oral administration may cause severe gastritis

Fomepizole/4-methylpyrazole (Antizol)

Acts similarly to ethanol. Stronger competitive inhibitor of ADH. In addition, does not cause hypoglycemia or sedation. Relatively easier to administer than ethanol. Does not require monitoring of serum concentrations.

Dosing

Adult

Clinical dose not established; however, 20 mg/kg/d used in small series (Jacobsen, 1997)

Pediatric

Not established

Interactions

Inhibitory effects on ADH increased in presence of ethanol

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Do not give as bolus; caution in breastfeeding because no information available on excretion in breast milk; caution in renal impairment

Follow-up

Complications

• Vision loss
  • The mechanism by which the methanol causes toxicity to the visual system is not well understood. Formic acid, the toxic metabolite, is responsible for ocular toxicity in animal models and is rightly presumed to be responsible in human studies.
  • 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 is 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.
• Movement disorders
  • Parkinsonian motor impairment has been described in some long-term survivors of methanol poisoning. This is thought to be due to the predilection for high concentrations of formic acid to accumulate within the putamen, but the reasons for this are unclear. One proposed reason is that formic acid has the ability to impair dopaminergic pathways and increase enzymatic activity of dopa-B-hydroxylase (Finkelstein, 2002).
  • 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, dystonia and corticospinal tract signs have been established.
  • Several case reports have indicated symptom response with standard antiparkinsonian agents, particularly levodopa, amantadine, and bromocriptine (Bitar, 2004).
• Muscle spasms have also been reported. As expected, these symptoms respond poorly to traditional therapy (LeWitt, 1988).

Prognosis

• Prognosis correlates with amount of methanol consumed and the subsequent degree of metabolic acidosis. This is further dependent on the amount of formic acid that has accumulated in the blood. Little long-term improvement can be expected in patients with neurologic complications.

Miscellaneous

Medicolegal Pitfalls

• Diagnosis is the most important part of treating methanol poisoning.
• In cases of stupor of unknown cause, testing for an osmolar gap should be routine. This enables early recognition and treatment of methanol intoxication.
• In addition, a careful history should be taken in high-risk patients who report typical symptoms.

References

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Keywords

organic solvent, formaldehyde, formate, alcohol dehydrogenase, ADH, methanol ingestion, methanol toxicity, methanol intoxication, antifreeze ingestion, perfume ingestion, paint solvent ingestion, photocopying fluid ingestion, windshield washing fluid ingestion, shellac ingestion, inhalation of methanol, methanol fumes, methanol poisoning

Contributor Information and Disclosures

Author

Kalyani Korabathina, MD, Department of Neurology, University of South Florida College of Medicine
Kalyani Korabathina, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Coauthor(s)

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

David Likosky, MD, Clinical Instructor, Department of Neurology, University of Washington
David Likosky, MD is a member of the following medical societies: American Academy of Neurology, American College of Physicians-American Society of Internal Medicine, and American Heart Association
Disclosure: Nothing to disclose.

Medical Editor

Jonathan S Rutchik, MD, MPH, Assistant Professor, Department of Occupational and Environmental Medicine, University of California at San Francisco
Jonathan S Rutchik, MD, MPH is a member of the following medical societies: American Academy of Neurology and Association of American Physicians and Surgeons
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Nestor Galvez-Jimenez, MD, Program Director of Movement Disorders, Department of Neurology, Division of Medicine, Director of Neurology Residency Training Program, Cleveland Clinic Florida
Nestor Galvez-Jimenez, MD is a member of the following medical societies: American Academy of Neurology, American College of Physicians, and Movement Disorders Society
Disclosure: Nothing to disclose.

CME Editor

Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital
Matthew J Baker, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

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