Diagnosis and Reasoning
This young girl has presented with an alarming constellation of symptoms: headache, blurring of vision, obtundation, dyspnea, wheezing, nausea and vomiting, and abdominal pain; all of these are of acute onset, and appear to be progressing rapidly.
At first, it is hard to make heads or tails of this complex presentation; however, her examination throws up a clue: Kussmaul breathing. Could there be a metabolic acidosis?
An urgent arterial blood gas (ABG) assay confirms this, by demonstrating a severe mixed acidosis in association with a high anion gap.
Thus, key differentials to consider include diabetic ketoacidosis, severe uremia, lactic acidosis, and ingestion of toxins such as salicylates, ethylene glycol, or methanol.
Her random plasma glucose levels are normal, making diabetic ketoacidosis unlikely, while serum lactate is also within normal parameters. In addition, the innocuous renal profile excludes uremia.
However, transaminase levels are seen to be elevated, favoring ingestion of a hepatotoxic agent; an urgent toxicological screen is essential next step.
This in turn reveals elevated levels of methanol, confirming the diagnosis to be methanol intoxication.
Fomepizole is the antidote of choice, and should be administered as soon as possible. In addition, given the presence of visual disturbances and serum methanol levels >20 mg/dL, urgent hemodialysis is a must.
Correction of the severe metabolic acidosis with sodium bicarbonate should also be considered.
Note that insulin is indicated in the management of diabetic ketoacidosis and is not required here.
Following the acute management, the child in this case was found to have ingested a perfume containing methanol about 10 hours prior to development of symptoms, after mistaking it for a soft drink.
Methanol is a clear, colorless, volatile organic solvent used in the industrial production of certain synthetic organic compounds.
Methanol ingestion is an uncommon form of poisoning; in most cases, this occurs following ingestion of beverages contaminated with methanol (for example, adulterated liquor, or perfume).
Note that doses of over 100 mg/kg are considered to be toxic (i.e. ~10 to 30 mL of 40% methanol for most persons), while 340 mg/kg and above (~60 to 240 mL of 40% methanol) is potentially lethal.
Following ingestion, methanol (which itself is non-toxic) is dehydrogenated into formaldehyde, and then to formic acid, both of which are highly reactive and bind into tissue proteins; these in turn interfere with oxidative metabolism via inhibition of cytochrome oxidase system.
The formic acid is further metabolised into carbon dioxide and water in the presence of tetrahydrofolate. However, this metabolic process is rather slow, resulting in accumulation of formic acid in the body, with a subsequent metabolic acidosis.
While the pathophysiology of the eye damage observed in these patients is uncertain, possibilities include interruption of mitochondrial function in the optic nerve and/or optic nerve demyelination due to formic acid mediated destruction of myelin.
Methanol also affects the basal ganglia resulting in hemorrhagic and nonhemorrhagic damage to putamen in severe intoxication; this results in parkinsonism and a dystonic/hypokinetic clinical picture.
The initial symptoms of intoxication are typically observed 12 to 24 hours after ingestion, with the exact time period depending on the volume of methanol and the amount of ethanol concomitantly ingested (in patients with accidental poisoning). This is due to competitive inhibition of these 2 compounds.
The initial symptoms of methanol intoxication are similar to those of ethanol intoxication, i.e. disinhibition and ataxia; however, these patients then proceed to develop dizziness, headache, nausea, vomiting and epigastric pain; they may progress on to develop drowsiness, obtundation or a coma.
Seizures may occur, due to the metabolic derangement and brain parenchymal damage; other neurological manifestations include axonal polyneuropathy and motor neuronal disease resembling amyotrophic lateral sclerosis.
Formic acid accumulation in optic nerve often results in flashes of light and blurring of visual fields; this often progresses into complete loss of vision.
Examination may reveal a fruity odor of the breath (due to the methanol); Kussmaul breathing, tachycardia, hypertension, and signs of pulmonary edema (due to the metabolic acidosis); features of heart failure and cardiac arrhythmias may be seen in individuals who have ingested large amounts of methanol.
The diagnosis of methanol poisoning is based on the suspicion of ingestion, and the presence of visual disturbances, and metabolic acidosis with increased anion gap and markedly increased liver enzyme levels; confirmation is by assessment of plasma methanol levels.
Note that plasma methanol concentrations >0.2 g/L are considered toxic while concentrations >0.9 g/L are potentially deadly.
Other laboratory findings seen in patients with methanol toxicity include an elevated osmolar gap, high anion gap and marked metabolic acidosis; therefore, an arterial blood gas assay, serum electrolytes, renal functions, and blood glucose levels are mandatory.
Imaging studies such as computed tomography (CT) and magnetic resonance imaging (MRI) are approaching investigations may help detect damage to the basal ganglia. Visual evoked responses are helpful in patients presenting with scotomas and loss of retinal sensitivity; these will show decreased amplitudes but normal latencies.
Administration of an antidote such as ethanol or 4-methylpyrazole (fomepizole) is the mainstay of therapy; these agents competitively inhibit the action of methanol, thus slowing down the production of toxic metabolites..
Hemodialysis is of use in removing methanol and formic acid; this is indicated in patients who have ingested >30 mL of methanol, in those with serum methanol levels >20 mg/dL, if visual complications are present, and in individuals who fail to demonstrate improvement of acidosis despite sodium bicarbonate infusions.
Good supportive therapy is also essential; this should include maintenance of adequate hydration, initiation of airway management, correction of electrolyte imbalances.
Severe metabolic acidosis may necessitate administration of bicarbonate; note that this has been reported to also cause reversal of visual deficits and reduction of the concentration of active formic acid.
The mortality rate of methanol poisoning appears to solely depend on the amount of toxin absorbed; it is reported to be 19% and 50% in patients with serum CO2 levels < 20 mmol/L and < 10 mmol/L respectively.
In addition, the majority of survivors demonstrate complete recovery from visual impairment.
Take home messages
1. Methanol itself is nontoxic; symptoms of intoxication are due to its metabolites - particularly formic acid.
2. The metabolic acidosis observed in methanol poisoning is associated with a high anion gap and high osmolar gap.
3. Administration of ethanol is the mainstay of treatment.
4. The mortality rate of methanol toxicity depends solely on the amount of toxin ingested.
1. LIISANANTTI JANNE HENRIK, ALA-KOKKO TERO ILMARI, DUNDER TEIJA SINIKKA, EBELING HANNA ELINA. Contributing Factors in Self-Poisoning Leading to Hospital Admission in Adolescents in Northern Finland. Subst Use Misuse [online] 2010 May, 45(9):1340-1350 [viewed 03 October 2014] Available from: doi:10.3109/10826081003682859
2. KRAUT JA, KURTZ I. Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin J Am Soc Nephrol [online] 2008 Jan, 3(1):208-25 [viewed 07 October 2014] Available from: doi:10.2215/CJN.03220807
3. REESE E, KIMBROUGH RD. Acute toxicity of gasoline and some additives. Environ Health Perspect [online] 1993 Dec:115-31 [viewed 07 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/8020435
4. PRABHAKARAN V, ETTLER H, MILLS A. Methanol poisoning: two cases with similar plasma methanol concentrations but different outcomes. CMAJ [online] 1993 Mar 15, 148(6):981-4 [viewed 07 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/8383577
5. RIETJENS SJ, DE LANGE DW, MEULENBELT J. Ethylene glycol or methanol intoxication: which antidote should be used, fomepizole or ethanol? Neth J Med [online] 2014 Feb, 72(2):73-9 [viewed 07 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/24659589
6. ZAKHAROV S, PELCLOVA D, NAVRATIL T, BELACEK J, KURCOVA I, KOMZAK O, SALEK T, LATTA J, TUREK R, BOCEK R, KUCERA C, HUBACEK JA, FENCLOVA Z, PETRIK V, CERMAK M, HOVDA KE. Intermittent hemodialysis is superior to continuous veno-venous hemodialysis/hemodiafiltration to eliminate methanol and formate during treatment for methanol poisoning. Kidney Int [online] 2014 Jul, 86(1):199-207 [viewed 07 October 2014] Available from: doi:10.1038/ki.2014.60
7. SHADNIA S, RAHIMI M, SOLTANINEJAD K, NILLI A. Role of clinical and paraclinical manifestations of methanol poisoning in outcome prediction. J Res Med Sci [online] 2013 Oct, 18(10):865-9 [viewed 07 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/24497857
8. SANAEI-ZADEH H. Magnetic resonance imaging and computed tomography scan findings in methanol poisoning. Ann Indian Acad Neurol [online] 2013 Oct, 16(4):738-9 [viewed 07 October 2014] Available from: doi:10.4103/0972-2327.120446
9. PORHOMAYON J. What's new in Emergencies, Trauma and Shock? Studying the clinical and biochemical correlates in methanol poisoning. J Emerg Trauma Shock [online] 2013 Apr, 6(2):71-2 [viewed 07 October 2014] Available from: doi:10.4103/0974-2700.110744
10. MINGUELA JI, LANZAGORTA MJ, HERNANDO A, AUDICANA J. Methanol poisoning. Evolution of blood levels with high-flux haemodialysis. Nefrologia [online] 2011, 31(1):120-1 [viewed 07 October 2014] Available from: doi:10.3265/Nefrologia.pre2010.Oct.10653
11. PAASMA R, HOVDA KE, JACOBSEN D. Methanol poisoning and long term sequelae - a six years follow-up after a large methanol outbreak. BMC Clin Pharmacol [online] 2009 Mar 27:5 [viewed 07 October 2014] Available from: doi:10.1186/1472-6904-9-5
12. AL ASERI Z, ALTAMIMI S. Keeping a high index of suspicion: lessons learned in the management of methanol ingestion. BMJ Case Rep [online] 2009 [viewed 07 October 2014] Available from: doi:10.1136/bcr.09.2008.1013