Methanol Poisoning:
A Clinical and Pathological Study
Donald R. McLean, MD, Harold Jacobs, MB, and Bruce W. Mielke, MD

We report 2 survivors of severe methanol poisoning who developed, apart from blindness, a Parkinson-like extrapyramidal syndrome characterized by reduced initiative, poor voice volume, masked facies, mild tremor, rigidity, and bradykinesia. Both patients were mildly demented and 1 had hyperreflexia and bilateral Babinski responses.
Computed tomographic scans in both patients demonstrated bilateral symmetrical infarction of the frontocentral
white matter and putamen. Electromyography in 1 patient showed extensive denervation, mainly involving the
legs, but normal motor conduction velocities. L-Dopa administered to the more severely affected patient had n o
effect o n the parkinsonian features.
Autopsy revealed cystic resorption of the putamen and the frontocentral subcortical white matter i n addition to
widespread neuronal damage throughout the cerebrum, cerebellum, brainstem, and spinal cord.
McLean DR, Jacobs H, Mielke BW: Methanol poisoning: a clinical and pathological study.
Ann Neurol 8:161-167, 1980

Recovery from severe methanol intoxication is now
possible, thanks to the development of sophisticated
cardiopulmonary support equipment, hemodialysis,
and better understanding of acid-base imbalance. We
report 2 cases which illustrate the characteristic neurological sequelae in the unfortunate survivors. T h e
findings o n computerized axial tomography (CT scan)
were corroborated by autopsy in 1 patient and
identified the cerebral lesions causing the neurological disability. T h e spinal cord lesions, suggested
electromyographically and confirmed at autopsy,
have not been reported previously.

versity of Alberta Hospital on November 24, 1974, with a
history, related by his wife, of nausea, abdominal pain, and
gradually failing vision. He was in great distress and was
hyperventilating, with a pulse of 120 per minute and blood
pressure of 160/120 tom. (He was known to be hypertensive.) H e was severely confused. The pupils were dilated
and sluggishly reactive to light. The optic fundi were normal, and no localizing neurological signs were noted. He
had severe metabolic acidosis (pH 7.1, Pco~, 11 torr), and
the blood methanol level was 80 mg/dl. Within 2 hours he
was deeply comatose, requiring intubation and respiratory
support. H e was given 18.75 gm of sodium bicarbonate
intravenously and was hemodialyzed for 9 hours. Despite

substantial intravenous electrolyte solution and plasma, peripheral perfusion remained clinically deficient for several
hours although central blood pressure was well maintained.
During the next two days he required 8 units of blood to
maintain his hemoglobin level. He was continuously nionitored in the intensive care unit, and no episode of
hypotension or hypoxia was observed.
On November 25 the pupils were 8 mm and unresponsive to light. The retinas were opaque, and there was
peripapillary edema with a small hemorrhage on the left
optic disc. The next day, in response to command, he nodded, gripped, and moved his arms but was unable to move
his legs. By November 28 h e had developed cogwheel
rigidity of the arms. His voice was poor in volume and tremulous. He picked at the bed clothes. A positive grasp and
suck reflex were present. The legs were held rigidly extended, with no voluntary movement. Although reflexes in
the arms were normal, those in the legs were absent, and
both plantar responses were extensor. About three weeks
after admission, a reliable sensory examination was possible
and revealed loss of light touch and pinprick sensation from
midcalf distally, where firmer pinprick caused hyperpathia. Vibration sense was impaired at the toes and ankles
but was normal above the midshin. Proprioception was
normal.
Electromyography performed on January 7, 1975, revealed normal motor conduction velocity and distal latency
in the right median, right ulnar, both peroneal, and both
posterior tibia1 nerves. The combined muscle action potential was low in both extensor digitorum brevus (0.1 niv
right, 0.3 mv left) and abductor hallucis muscles (0.6 rnv

From the Departments of Medicine (Neurology) and Pathology
(Neuropathology), University of Alberta, Edmonton, Aha,
Canada.

Address reprint requests to D. R. McLean, MD, 9-lOt Clinical
Sciences Bldg, University of Alberta, Edmonton, Alta, Canada
T6G 2G3.

Case Histories
Patient 1
A 4 1-year-old alcoholic physician was admitted to the Uni-

Received Apr 23, 1979, and in revised form Nov 9. Accepted for
publication Nov 28, 1979.

0364-5134/80/080161-07$01.25 @ 1979 by Donald R. McLean

161

right, 0.6 mv left). Distal sensory latency in the right median nerve was normal in amplitude and latency. A sensory
response could not be recorded on distal stimulation of the
right or left sural nerve. Needle electrode examination revealed widespread fibrillation potentials and positive sharp
waves in leg, lumbar paraspinal, right first dorsal interosseous, and several forearm muscles. A moderate to marked
reduction in interference pattern was noted in all muscles
examined. The signs of denervation were greatest in the
legs.
A CT scan on March 25 (Fig 1)showed slight, symmetrical enlargement of the lateral and third ventricles. In addition, well-defined oval radiolucencies were present in the
region of the putamen bilaterally, suggesting cyst formation
at these sites. Similar lesions were present in the white
matter of the frontal lobes. A repeat C T scan on August 27
showed only minimal increase in the size of the ventricles
with apparent diminution of the radiolucent areas in the
frontal lobes.
When the patient was examined several months following the intoxication, the striking behavioral feature was a
lack of initiative, particularly in conversation. Formal
psychometric assessment revealed mild intellectual deterioration. H e was blind, with optic atrophy, but there was
minimal pupillary response to light. H e spoke in a quiet,
tremulous voice. Arm strength was normal with mild cogwheel rigidity at the elbows and wrists. H e had weakness of
dorsiflexion of the ankles, right more than left, and marked
rigidity of the legs without cogwheeling. There was right
ankle clonus and a bilateral Babinski response. Pinprick
sensation was reduced below the knees, and touch sensation was diminished in the feet. Proprioception and vibratory sense were normal. H e walked with the trunk, arms,
legs, and toes flexed, the forefoot scraping the floor with
each small, slow step. Walking and turning, done “en bloc,”
was interrupted by brief bouts of akinesia.
The patient died on October 25, 1975, 12 hours after
hanging himself.

Patient 2
A 38-year-old alcoholic window washer was taken to
another hospital by his wife in the afternoon of September
23, 2977. H e admitted drinking methanol and complained
of nausea. Blood gas determinations revealed severe metabolic acidosis ( p H 6.78, PCoz 20 torr). Following gastric
lavage, 130 ml of whiskey was placed in his stomach and
400 ml of 0.5% ethanol and 3.6 gm of sodium bicarbonate
were given intravenously. Repeat blood gas determinations
~ torr), but despite
showed improvement (pH 7.11, P C O25
this the patient became comatose and required respiratory
support. H e was transferred to the intensive care unit at the
University of Alberta Hospital.
At this time his pulse was 100 per minute, blood pressure was 130/80 tom, and respirations were 40 per minute.
The pupils were fixed at midposition. Doll’s eye movements as well as ciliospinal and tendon reflexes were absent. He was given 15 gm of sodium bicarbonate over 4
hours. Hemodialysis was started and maintained continuously for 17y2 hours. H e developed seizures, which were
initially treated with Valium followed by Dilantin and phenobarbitone. No hypotensive or hypoxic events occurred, but a

162 Annals of Neurology

Vol 8 No 2 August 1980

F i g 1 . (Patient 1) CT scan shows radiolucencies bilaterally in
frontal white matter and putamen suggesting cystic resorption.

brief episode of hypertension (blood pressure 230/130
tom) was recorded during hemodialysis. Blood ethanol
measured before dialysis was 100 mgjdl, and methanol, 346
mg/dl.
By September 25 he was arousable to pain, and the following day he responded to simple commands. A computerized scan performed on October 4 (Fig 2A) showed
well-defined lucent areas in the frontal white matter, probably representing infarction. Larger, less well defined areas
were identified in the region of the putamen. By October
15 the patient was able to walk, but he was confused and
disoriented and spoke in a whisper. Severe rigidity did not
occur. When examined on December 12 he had a bland
expression, was alert and able to follow simple commands,
but perseverated frequently. He had no idea of the date,
month, or season. He was able to add 2 2 but not 8 8.
H e made no spontaneous conversation. His responses
were appropriate but often incorrect. He was able to see
hand movements and large objects in the peripheral fields
of each eye. The pupils were dilated and reacted very sluggishly to light. There was tremor of his tongue, a fine
tremor of the fingers, and mild generalized rigidity with
cogwheel characteristics at the elbows and wrists. Tendon
reflexes were symmetrical and the plantar response was
flexor. Rapid alternating finger movements were poorly
performed. H e walked with a slightly flexed posture and
normal-sized steps but with a reduced arm swing. Cerebellar and sensory testing was normal.
A C T scan performed on June 19, 1978 (Fig 2B) showed
bilateral radiolucent areas involving the frontal subcortical

+

+

F i g 3. (A) Frontal lobes, showing large areas of cystic white
matter infarction exclusive of subcortical association fiber layer.
( B ) Coronal section of cerebrum, showing continuation of white
matter infarction and bilateral resorbed necrosis of putamen.

white matter and putamen that were virtually identical to
those in Patient 1. Electromyography was unremarkable.

F i g 2. (Palient 2) Early {A)and late ( B ) C T scans. Welldefined lacent area5 are seen bilaterally i n frontal white matter
and putamen.

Pathological Findings
Gross Examination
The brain of Patient 1 weighed 1,494 gm after fixation and showed mild herniation of the cerebellar
tonsils. There was no evidence of atherosclerosis or
thrombosis within the major vessels composing the
circle of Willis. The leptomeninges were grossly
normal.
O n coronal sections, bilaterally symmetrical cystic
areas of old, resorbed necrosis extended continuOuslY throughout the subcortical white matter from
the frontal poles to the anterior portions of the occipital lobes (Fig 3A). These lesions were most extensive within the anterior thirds of the frontal lobe,
McLean et al: Methanol Poisoning

163

where they were positioned through the superior and
middle convolutions. At many points they were continuous peripherally through the entire white matter
with the exception of an intact subcortical U-fiber
layer. N o infarction was demonstrable within the
deep white matter, and there was no evidence of
periventricular softening. The white matter of the cerebral hemispheres otherwise showed moderate
rarefaction with widening of perivascular spaces.
Mild compensatory dilatation was present throughout the ventricular system. The cerebral cortex was
grossly unremarkable throughout.
Symmetrical areas of cystic, resorbed infarction
extended throughout the substance of the putamen
(Fig 3B). Posteriorly, only a narrow margin of the
medial inferior aspects of these nuclei remained intact. The lesions were less extensive in their anterior
extent, where they terminated in the superolateral
poles of the putamen. The remainder of the central
gray matter, including the globus pallidus, hypothalamus, and thalamus bilaterally, was unremarkable. The substantia nigra and locus ceruleus were
normally pigmented.
The midbrain, pons, medulla oblongata, spinal
cord, and dorsal root ganglia appeared normal
grossly.
MicroJcopic Examination
For microscopic examination, sections prepared from
paraffin blocks were stained routinely with hemotoxylin and eosin. Special stains employed included
Nissl, Weil, myelin, Bodian silver, and Holzer preparations.
Swelling, pallor of staining, and eccentric pyknotic
nuclei involved occasional large pyramidal neurons in
the lower third layer of the occipital, parietal, posterior frontal, and insular cerebral cortex. Typical recent ischemic neuronal change was present within the
second zone of the Ammon horns. Mild depletion of
neurons with accompanying astrocytosis was present
in the deeper layers of the cortex within occasional
sulci. Betz cells of the anterior central gyri showed
prominent central chromatolysis, some containing
fine vacuolization of the cytoplasm.
The cavities within the white matter showed typical histological features of resorbed infarction and
were partially traversed by glial vascular strands containing small numbers of phagocytes. A narrow zone
of adjacent white matter revealed mild gliosis with
myelin pallor. The remaining cerebral white matter
showed mild astroglial hyperplasia.
In the central gray matter the areas of resorbed infarction within the putamen contained occasional
phagocytes filled with lipid and hemosiderin. Intact
portions of these nuclei showed mild astroglial

164 Annals of Neurology Vol 8 No 2 August 1980

hyperplasia bordering the infarcts. Large and small
neurons of normal appearance were demonstrable at
these sites. Moderate focal neuron depletion with
astrocytosis was present in the superior poles of the
caudate heads. The globus pallidus bilaterally showed
mild neuron depletion and astrocytic hyperplasia,
particularly through the posterior two-thirds of its
substance.
Many neurons within the medial nuclei of the
thalamus exhibited cytoplasmic swelling with nuclear
eccentricity and pyknosis, comparable to the focal
neuronal changes within the depth of the cerebral
cortex. Scattered neuronophagocytosis was demonstrable through the lateral nuclei (Fig 4A). Moderately intense astrocytic hyperplasia was present
throughout the thalamus. Similar neuronal swelling
was seen through all layers of the lateral geniculate
bodies and was also encountered within the amygdala, subthalamic nuclei, and mammillary bodies, although no astrocytosis was present at these sites.
The third and fourth nuclei were intact. Scattered
neurons within the midbrain tegmentum were
swollen, with predominantly central dissolution of
Nissl substance and eccentrically positioned nuclei.
The substantia nigra showed comparable alteration,
occasionally accompanied by perinuclear aggregations of pigment.
In the pons, neurons of each locus ceruleus
showed changes similar to those in the substantia
nigra. Neuronal swelling and rare neuronophagocytosis were demonstrable within scattered
neurons of the tegmentum and basis pontis.
Similar changes in the medulla oblongata involved
reticular neurons of the medullary tegmentum and
inferior olivary nuclei. Several neurons within the
twelfth nerve nuclei exhibited well-defined peripheral chromatolysis.
Mild neuronal depletion of the granule cell layer of
the cerebellum was evident in the upper vermis. Purkinje cells in this location and in crests of convolutions laterally within the hemispheres showed swelling, chromatolysis, nuclear pyknosis, and occasional
neuronophagocytosis.
Swelling and chromatolysis occurred in neurons
within the anterior horns and Clarke’s columns at all
levels of the spinal cord. Occasional anterior horn
cells at all levels showed neuronophagia (Fig 4B),
which was most extensive within the cervical segments. Myelin preparations revealed descending degeneration extending through the lateral columns.
Sections of the posterior portions of the eyes
showed marked diminution of retinal ganglion cells
accompanied by gliosis. The optic nerves were virtually devoid of myelin and axons and had intense astrocytic hyperplasia throughout.

F i g 4. (A1 Thalamus, showing neuronophgocytosis and mild
astroglial hyperplasia. (B) Section of anterior born of the midthoracic spinal cord, showing neuronophagia. (Both Nissl;
X300.1

Discussion
Neurological sequelae of methanol intoxication
other than the well-recognized optic atrophy is decidedly unusual [3]. Riegel and Wolf [ 2 2 ] described a
60-year-old man seen 20 years after methanol intoxication who had a Parkinson-like extrapyramidal
syndrome, optic atrophy, and focal cranial nerve
deficits. Similar case reports appear in older litera-

ture referred to by Orthner [19]. More recently,
Guggenheim et al [13] reported a 13-year-old girl
with delayed-onset parkinsonian symptoms who, in
contrast to our Patient 1, responded to L-dopa.
Aquilonius et a1 [l]described a patient who survived
methanol intoxication with bilateral infarction of the
putamen demonstrated by CT scan. While the patient
had a “moderate peripheral neuropathy,” he had no
extrapyramidal signs, although blindness, right facial
weakness, and bilateral Babinski responses were
present.
Our 2 cases demonstrated the rare motor complications of methanol intoxication. The clinical features

McLean et al: Methanol Poisoning 165

would seem to reflect the effects of putaminal and
subcortical white matter necrosis demonstrated by
CT scan and at autopsy. O n the other hand, the widespread electromyographic signs of denervation
seemed secondary to anterior horn cell loss rather
than peripheral nerve dysfunction, and this was
confirmed by the anterior horn cell necrosis found at
autopsy.
The precise pathogenesis of methanol intoxication
remains controversial. Methanol is metabolized to
formaldehyde and formic acid by liver alcohol dehydrogenase. However, high levels of formaldehyde d o
not appear in the blood, whereas the blood formic
acid levels found in patients are consistent with levels
measured in methanol-intoxicated monkeys [ 181. In
monkeys susceptible to methanol intoxication, onset
of the clinical syndrome parallels the appearance of
acidosis, which in turn coincides with the formation
of formic acid. The syndrome develops despite correction of the acidosis, suggesting that formic acid
per se is responsible. Formic acid is variably reported
to account for all [ 5 ] or half [ l G j the anion gap during methanol acidosis. If monkeys are given 4methylpyrazole, an inhibitor of liver alcohol dehydrogenase, toxicity [ 161 is delayed because formic
acid is not produced.
The extensive cerebral abnormalities demonstrated in our cases and by others [ 7 ] appear related
to duration of survival. Of the 41 patients who died
in the outbreak of methanol poisoning reported by
Bennett et a1 [3], 22 were brought in dead or died
within 30 minutes, whereas 17 were treated for more
than 30 minutes but no longer than a few hours.
Death occurred within 7 hours of hospital arrival in
the 20 cases described by Menne [18]. By contrast,
the 3 autopsy cases reported by Erlanson et a1 [71,
with extensive bilateral putaminal hemorrhagic infarcts, had survived 77, 110, and 130 hours.
White matter degeneration and necrosis have been
reported in association with a variety of circumstances, including carbon monoxide and other drug
intoxications, postoperative and anesthetic hypotension, strangulation, hypoglycemia, cardiac arrest, and
subsequent to seizures [9]. Orthner [201 described
the unique association of white matter and putaminal
necrosis in a single case of methanol intoxication.
The identical range of pathological expression should
reasonably be expected to have a common pathogenesis. Hypoxemia appears to be the one feature
common to all cases; but coexistent circulatory depression is thought to be an important factor [9].
Several experimental models have been devised to
study physiological indices of possible relevance [9,
11, 12, 15, 21, 23,241, but controversy persists [4,6,
8, 14, 161. The pathogenetic mechanism must reconcile the morphological characteristics of the white

166 Annals of Neurology Vol 8 No 2 August 1980

matter lesions, which indicate infarction due to circulatory stasis.
Explaining the putaminal necrosis, unique to
methanol intoxication, also presents difficulties. Orthner [19] considered it to result from decreased venous outflow through the veins of Rosenthal. Others
have suggested that formic acid and formaldehyde
may achieve higher concentrations within the putamen [24],and their effect would be potentiated by
reduced venous drainage or inadequate arterial flow.
In our 2 cases, we did not document marked
hypoxemia or hypotension. The patients arrived in an
awake state, and therapy commenced along with
continuous monitoring. Granted, a brief hypotensive
o r hypoxemic episode may have been missed. Notwithstanding the emphasis on hypoxemia and
hypotension described here, the pathogenesis may be
related to a direct toxic effect of formic acid.
While anterior horn cell damage from the initial
methanol intoxication was demonstrated electromyographically, anterior horn cell necrosis
characterized pathologically by neuronophagia was
more likely related to preterminal hypoxemia. Similar recent spinal cord alterations have been reported
following systemic anoxia [2].
We wish to thank Dr J. D. R. Miller and Dr D. B. Russell for
interpreting the CT scans.

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