Cleveland Clinic Journal of Medicine 1990 Suit 464 71

8/10/2019 Cleveland Clinic Journal of Medicine 1990 Suit 464 71

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R EVI EW

Methanol intoxication: clinical features and

differential diagnosis

P AU LA F. S UIT , MD AND M ELIND A L . ES TES , MD

M eth an o l into xic a t io n c aus es s ev ere me tabo l ic ac ido sis and c an lead to per m ane nt v isual dam ag e o r

. M eth an o l , readi ly av ai lable in c o m m o n p ro duc ts l ike ant i f reeze , is ing es ted ac c iden tal ly o r

y as a s ubs t i tute fo r e than o l an d in s uicide a t temp ts . Bec a us e i t may bec o m e a ma jo r fuel s o urc e

kely to inc re as e . R apid diag no s is is es s ent ia l so tha t appro p r ia te t rea t m en t c a n be ins t i tuted quic kly . T h e

eth an o l in to xi c a t io n . In addit io n , they dis cus s the dif ferent ia l diag no s is and t rea tm ent o f ac ut e i nto x -

ing the use o f 4 -meth y lpy razo le in prev e nt ing th e c o n v ers i o n o f m eth an o l to fo rma te .

T E R M S : P O I S O N I N G , M E T H Y L A L C O H O L C L E V E C L I N J M E D 1 9 9 0 ; 5 7 : 4 6 4 - 4 7 1

ETHA NO L (w ood sp i r i t , w ood a l cohol ,

Colu mb ian sp irit) ingestion causes a severe

metabolic acidosis and visual disturbances

that may become permanent despite ag-

readily obtained, and tox ic am ounts are pre-

1

its availability, and thus the incidence of acute

F r o m t h e D e p a r t m e n t o f P a t h ol o g y, T h e C l e v e l a n d C l i n i c F o u n d a -

Address repr ints requests to M. L . E . , Depar tm ent o f P atho lo gy, T he

i n t ox i ca t i onw he t he r acc i de nt a l or de l i b e ra t e w i l l

l ikely increase. With methanol intoxication, rapid diag-

nosis and treatment is essential to prevent death and

minimize the neurologic sequelae of poisoning.

In this review we describe the clinical and laboratory

features of methanol poisoning, discuss the differential di-

agnosis and treatment of acute intoxication, and review

the pathology and pathophysiology of the central nervous

system (CNS) lesions associated with methanol ingestion.

H I S T O R Y

Poisoning with methanol was practically unheard of

in the Uni ted States unt i l 1890 when an inexpensive

method of producing pure methanol was discovered.

2

Before that t ime, methanol produced by the dry disti l la-

tion of wood had a bad taste and smell that made it un-

p a l a t a b l e . W i t h t h e n e w m e t h o d o f p r o d u c t i o n ,

methanol was touted as a harmless and excellent substi-

tute for the more expensive ethanol.

2

Although several

hundred cases of intoxication were reported by the turn

of the century, the toxicity of methanol continued to be

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METHANOL INTOXICATION SUIT AND ESTES

debated in the medical l i terature for the next 40 years.

2

Many investigators during this t ime believed that poi-

soning was due to impurities and not to me than ol i tself.

Supporting this belief was the apparent fai lure of several

researchers to induce toxic changes in laboratory ani-

mals by giving them pure methanol.

2

R e i f p r e s e n t e d c o n v i n c i n g e v i d e n c e t h a t p u r e

me than ol was indeed tox ic in his analysis of the fluid re-

sponsible for a large outbreak of poisoning in Hamburg,

Germany, in 1923.

3

He showed that the fluid contained

less than 0.1% aldehydes, acetone, acids, and esters

concentrations too small to be toxic.

3

In addition, Reif

found no cyanides and arsenics, which others had sug-

gested were the offending compounds in so-cal led

methanol poisoning.

3

Even with Rei f 's documentat ion, many cont inued to

doubt the toxic properties of methanol, mainly because

of the marked variabil i ty in tolerance . Th ere have been

reports of some persons ingesting large amounts of

methanol with no apparent i l l effects, whereas others

suffered permanent blindness after ingesting only a few

teaspoonfuls.

2,4-7

Al though the toxici ty of methanol i s

now well accepted, this variabil i ty is sti l l unexplained.

PHARMACOLOGY

Pure methanol is a colorless liquid that is easily ab-

sorbed through the gastrointestinal tract, skin, and res-

piratory tract.

4

'

8

The minimum lethal dose is about 80 g

in untreated patients and visual defects can be expected

with ingestion o f half of this dose.

9

Methanol distributes

readily in body water and may be concentrated in vit-

reous hum or and cerebrospinal fluid.

10

A sm all amou nt is

excreted unchanged by the lungs and by the kidneys.

8

Methanol is oxidized by hepatic alcohol dehydro-

genase at a rate about one-fifth that of ethanol.

11

T h e

product of this oxidation is formaldehyde which is

rapidly converted to formate.

12-14

The accumulat ion of

formate corresponds to the development of metabolic

acidosis and accounts for 50% to 100% of the observed

drop in the bicarbonate ion.

15-17

Formate directly inhib-

its cytochrome oxidase; and as aerobic respiration is

depressed, lactic acid accumulates, exacerbating the me-

tabolic acidosis.

7

'

1819

I t is formic acid and not methanol that is responsible

for the acidosis and ocular damage in methanol intox-

ication.

12-14

Th e oxidat ion of methanol can be prevented

by giving 4-methylpyrazole, an alcohol dehydrogenase

inhibitor. In monkeys given 4-methylpyrazole, no acido-

sis or signs of toxicity develop despite toxic blood levels

of methanol.

14

'

20

Formate infused into monkeys main-

T A B L E 1

C L I N I C A L F E A T U R E S O F M E T H A N O L I N T O X I C A T I O N

Mild ce ntral nervous system depression

Visual d isturbances

Severe epigastric pain

Weakness

General feeling of ill being

Memo ry loss

Confusion

Agitat ion

Stupor

Coma

tained at normal pH produces ocular lesions similar to

those seen in methanol poisoning.

13

The metabolism of formate in man is sti l l unclear. In

some animals, such as the rat, formate is rapidly con-

verted to carbon dioxide via a folate-dependent one-

carbon pathway.

21

Because this pathway is efficient,

these animals do not develop acidosis after ingesting

methanol. However, i f rats are made folate-deficient,

they are unable to use this pathway. Formate accumu-

lates, and a toxic state develops that is identical to that

in man.

22

Hepatic tetrahydrofolate levels are 40% lower

in monkeys than in rats, corresponding to the 50 % lower

rate of formate oxidation observed in monkeys.

23

Thu s ,

the susceptibility of monkeys and possibly humans to

methanol toxicity may be related to a relatively low

level of hepa tic tetrahydrofolate.

23

Noker and associates reversed the toxic effects of

methanol in monkeys by administering folinic acid, a fo-

late derivative. Folinic acid decreased or prevented accu-

mulation o f formic acid and was effective when given both

at the same time methanol was given and after toxicity

developed.

24

This study suggests that folinic acid may be

useful in treating methanol intoxication in humans.

24

CLINICAL FEATURES OF METHANOL POISONING

The cl inical features of acute methanol poisoning

have been thoroughly described by Bennett and co-

workers, who reviewed an outbreak in Atlan ta involving

323 people.

4

Typical features are listed in Table 1.

Symptoms

Methanol has a central nervous system depressant ef-

fect similar to ethanol. There is a characteristic latent

period which corresponds to the slow conversion of

methanol to formate . Symptoms usual ly develop 24

hours after ingestion, but may appear as soon as 12

hours. Initially there is a general feeling of ill being with

weakness, headache, and nausea. There may be severe

JULY AUGUST 1990

CLEVELAND CLINIC JOURNAL OF MEDICINE 465



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IG U R E 1. C T scan left) and corresponding brain section right) from 25-yea r-old male who died 17 days after ingesting

ion arrow s). Also, the areas of subcortical white matter necrosis are apparent on the C T scan arrow s).

4,25,26

As acidosis develops, most patients com-

4,27

Other central

4

Patients may be apprehensive or com bative. T he vital

are uncommon despite severe acidosis.

4

Patients with

severe abdominal pain may have rigidity of the abdomi-

nal wall but rebound tenderness is not seen.

4,22

T he op ht ha l m ol og i c e xam is ab norm a l in m ost

patients. Even patients without visual impairment will

exhibit dilated and sluggish or nonreactive pupils.

27,28

These ophthalmoscopic changes are characterist ic , and

their severity correlates with th e degree of acidosis. O c-

casionally, retinal changes are present in nonacidotic

patients.

4,27

The earl iest finding is hyperemia of the

optic disc which may be striking and lasts up to 3

days.

4,27,28

Peripapil lary retinal edema and optic disc

edema develop more slowly and may persist for up to 2

weeks.

4,27

In cases of severe toxicity, optic atrophy may

develop.

4,28

V O L U M E 5 7 N U M B E R 5



4/8


T A B L E 2

LABORAT ORY FINDINGS OF MET HANOL INT OXICAT ION

Increased methanol level

Increased formic acid

Metabolic acidosis

Increased anion gap

Increased osmolal gap

Increased lactic acid

Increased amylase

Increased mean corpuscular volume

Laboratory f indings

The laboratory findings are summarized in Table 2. A

definitive diagnosis depends on identifying methanol

and formic acid in blood or urine. A severe metabolic

acidosis is present with a high anion gap and elevated

osmolal gap.

29

Lactic acid may be elevated. Sodium and

potassium are initially normal. Urinalysis is normal and

no crystals are present in the sediment.

4

The he m og l o-

bin, hematocrit , and white blood cell count are normal,

but the mean corpuscular volume may be elevated. This

finding is probably a reflection of general cellular swel-

ling and has been used as an indication of more severe

toxicity.

26

Serum amylase may be elevated, indicating

acute pancreatit is.

4,25

C o m p u t e d t o m o g r a p h i c s c a n

Sym metrical putaminal necrosis is a comm on finding at

autopsy in patients with methanol intoxication.

9,30

The se

lesions can be detected on computed tomographic (CT)

scan as early as 3 days after ing estion, and appear as areas o f

low attenuation which may extend into the surrounding

white matter (Figure I).

31

33

Aquilonius and associates

correlated C T findings with prognosis in six patients w ith

methanol poisoning and suggested that the diagnosis be

considered wh en putaminal lesions are identified on C T

even if blood me thano l is undetectable.

31,32

PATHOLOGY

At autopsy, the most common finding is cerebral

edema, which is often marked.

4,34

Other common f ind-

i ng s i nc l u de p u l m onary e de m a and he m orrhag i c

gastritis.

34

Acute hemorrhagic pancreatit is is common in

those patients w ho had epigastric pain.

4

In patients with

prolonged survival , complications of coma and intuba-

tion, including pneumonia and pulmonary emboli , are

not unexpected.

Extensive central nervous system abnormalities have

been described in methanol poisoning.

35,36

Methanol i s

selectively toxic to the optic nerve and basal ganglia and

JULY

AUGUST 1990

FI G U R E 2. Cross-section of optic nerve stained with Lux ol

fast blue) from patient who died of methanol intoxication. There

is a central core of pallor corresponding to the area of

demyelination, with a surrounding rim of spared myelin.

causes characteristic lesions in these areas. In the optic

nerve, there is selective demyelination of the retrolami-

nar segment, consisting of central demyelination begin-

ning directly behind the lamina cribrosa and extending

proximally for several millimeters.

36

On cross section, a

rim of spared myelin is present around the demyelinated

core (Figure 2). Axons are preserved, although axonal

swelling is often significant.

36,37

Proximal to the lesion,

myelination is normal.

36

O c u l a r c h a n g e s

Electron microscopic exam inat ion of opt ic nerves

from methanol-poisoned rhesus monkeys showed gener-

alized swell ing of intra-axonal mitochondria and clear

spaces within the myelin sheath in the retrolaminar por-

tion.

37

Early reports emphasized degeneration of gan-

glion cells of the retina with sparing of the optic

nerve.

34,38

40

Most investigators now believe the ganglion

cell changes represented artifact , and that these patients

died before the optic nerve lesion had time to develop.

36

The or i e s o f t he p at hog e ne s i s o f v i su a l l oss i n

methanol poisoning must be able to explain al l of the

observed changes including optic disc edema, visual dys-

function, and selective demyelination of the retrolami-

nar optic nerve. Based on their experiments with rhesus

monkeys, Hayreh and co-workers believe that the direct

toxic effect of formate is responsible for the ocular

changes.

28,37

Since formate inhibits cytochrome oxidase,

adenosine triphosphate (ATP) production is inhibited

and ATP-dependent functions are depressed.

18,19

T h e

loss of the sodium-potassium membrane pump inhibits

electrical conduction, causing the early, but potential ly

reversible, visual disturbances.

28,37

CLEVELAND CLINIC JOURNALOFMEDICINE 467



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Anterograde axoplasmic flow is also inhibited, result-

28

'

37

S ince

36

The unique sensitivity of the retrolaminar nerve seg-

36

Th is area receives its blood supply from

41

In addition, the optic nerve is

10

Alternatively, Sh arpe and colleagues proposed that

56

This area is a vascular

41

43

m i n a l a n d w h i t e m a t t e r n e c r o s i s

Bilateral hemorrhagic putaminal necrosis appears to

igure

).

32,35

The mechanism for this se lect ive necro-

35

I t i s interest ing that carbon monoxide ,

44

A

33,45

A l t hou g h

s do not h ave symptoms attributable to this lesion, th e

45

Extensive white matter necrosis has been described in

35

and in a variety of other co ndi-

46,47

Common to al l these condi-

47

The pattern of necrosis is characteristic,

ng of the sub cortical arcua te fibers (Figure 3) .

3 5

Burger and Vogel suggested that the differences in

FI G U RE 3 . Brain section from same patient as Figure 1. There

are large areas of white matter necrosis with sparing of the

subcortical arcua te fibers arro ws).

the vasculature of the grey and white matter lead to the

selective white matter necrosis.

46

The grey matter and

the subcortical white matter are supplied by a rich,

branching capi l lary network aris ing from pial ves-

sels.

48,49

The venous drainage from these areas is exter-

nal, via the pial vessels.

50

The deeper white matter is

supplied by longer and larger caliber vessels which pass

t hrou g h t he cor t e x w i t hou t b ranchi ng .

4 8 , 4 9

V e n o u s

drainage from the white matter is internal , to the

Galenic system.

50

Diffuse cerebral edema would compress and com-

promise both the arterial supply and the venous

drainage of the deep white matter w hile the grey matter

and the subcortical arcuate fibers would continue to be

perfused via their rich anastomosing blood supply.

46

In

V O L U M E 5 7 N U M B E R 5



6/8


TABLE 3

C A U S E S O F I N C R E A S E D A N I O N G A P A C I D O S I S *

Uremia

Ketoacidosis

Lactic acidosis

Salicylate

Methanol

thylene glycol

Paraldehyde

* [Na+] - ([HC03-] + [CI-]) > 15 mmol/L

TABLE 4

C A U S E S O F I N C R E A SE D O S M O L A L G A P *

Methano l

Ethyl ether

Isopropanol

Ethylene glycol

Acetone

*Osmolal

m ea sur cd

- ( 1 . 8 6 [ N a

+

] + B UN + [Glucose] >5mOsm/kg

2 8 1 8

addition, the long penetrators supplying the deep white

matter may be more sensi t ive to hypoxia- induced va-

sospasm, further com prom ising th e blood supply.

46

W i t h

aggressive therapy and prolonged respirator use, these

white matter lesions may dominate and lead to severe

neurologic sequelae.

35

DIFFERENTIAL DIAGNOSIS

Rapid diagnosis of methanol intoxicat ion is essen-

tial , since treatment must begin immediately. The diag-

nosis must be suspected in any patient who complains

of visual disturbances, is confused or agitated, or has an

unexplained metabolic acidosis.

29

Although a definitive diagnosis depends on identify-

ing methanol or formate in blood or urine, these assays

may not be available on a 24-hour basis. In these situa-

tions, the differential diagnosis of unexplained metabo-

l ic acidosis can be narrowed by determining the anion

and osmolal gap, thus al lowing appropriate therapeutic

intervention.

29 ,51 ,52

Anion gap

T h e an ion gap is determ ined by calculat ing the

difference between sodium and the measured serum an-

ions, chloride and b icarbonate

Table

3).

29 ,52

T h e n o r -

mal anion gap of about 14 mmol/L is accounted for by

proteins, sulfate, phosphate, and organic acids.

29,52

A n

increase in any unmeasured anion wi l l e levate the

anion gap. Table 3 l ists the differential of a high anion

gap. In methanol poisoning, the accumulation of for-

mate causes the high gap.

29

Osmolality

Osmolality is a reflection of the number of molecules

dissolved in a solute.

53

The serum osmolality can be

quickly calculated using the following formula

53

:

Osmolal = 1.86 [Na

+

] + BUN + [Glucose]

2 8 1 8

The osm ol a l g ap i s t he d i f fe re nce b e t w e e n t he

measured and calculated osmolality and normally is less

than 5 mOsm/kg.

29,53

Any substance dissolved in serum

elevates the osm olal gap; however, only tho se present in

high molar concentrations cause a significant increase.

29

Agents capable of raising the osmolal gap are listed in

Table 4. O f t he su sp e ct e d t ox i c i ng e s t i ons , onl y

me than ol and ethylen e glycol are capab le of raising bo th

the anion gap and the osmolal gaps.

29

Methanol ethylene glycol

Dist inguishing metha nol from ethylene glycol intox-

ication in a stuporous or comatose patient presenting to

the em ergency ro om may no t be possible initial ly.

51

Like

methanol, ethylene glycol is a popular substitute for

ethanol and may be ingested deliberately or acciden-

tally.

51,54,55

Ethylene glycol is metabolized to toxic pro-

ducts by alcohol dehydrogenase, and accumulation of

these products causes a me tabo lic acidosis.

51

There i s an

asymptomatic latent period as in methanol poisoning,

and neurologic symptoms may be present.

54

The p re -

sence of oxalate crystals in the urine supports a diagno-

sis of ethylene glycol ingestion but crystals may not be

present in all cases.

51,54,56

Because prognosis in both

methanol and ethylene glycol intoxicat ion depends on

prompt treatment, the osmolal and anion gap should be

determined on any pat ient present ing with a metabol ic

acidosis of unknown etiology. I f both gaps are elevated,

therapy should be initiated while awaiting blood levels

to confirm the diagnosis.

TREATMENT

Trea tme nt is aimed at reversing the m etabo lic acido-

sis, removing methanol and formate, and preventing

further oxidation of methanol to formate.

2,4,6,9,57

Rapid reversal of the me tabolic acidosis is probably the

most important measure in acute intoxication.

4

Sodium

bicarbonate should be administered intravenously to

maintain a blood pH above 7.35.

26

The correction of the

bicarbonate deficit is often associated with a dramatic im-

provem ent in visual disturbances, pain, and m ental status.

Co m a m ay be reversed as the acidosis is corrected but, un-

fortunately, th e improv ement m ay be temporary.

4

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