The New England Journal of Medicine -- April 13, 2000 -- Vol. 342, No. 15

The Neurologic Illness of Eugene O'Neill -- A Clinicopathological Report

Eugene O'Neill, the only native-born American playwright awarded a Nobel
prize for literature, winner of four Pulitzer prizes, and widely regarded as
the nation's first and most distinguished dramatist, suffered from an
ultimately lethal neurodegenerative disease during the last 12 years of his
life. Yet existing biographies of O'Neill have displayed considerable
uncertainty about the details of this disease and its crippling impact on
his life and art. (1,2)

After his death on November 27, 1953, at the age of 65 -- and reflecting the
desire of his wife, Carlotta, to identify the fatal disease "because I
wanted to know what in the name of God was the matter with this man I had
nursed so long" (2) -- an autopsy was performed at Massachusetts General
Hospital under the direction of one of us, Dr. E.P. Richardson, Jr. The
family's request for confidentiality was honored, and the results of the
autopsy were not released. Recently, however, we asked the surviving
grandchildren to permit the public release of the autopsy results. The
family agreed, making this report possible.

During his lifetime, O'Neill was generally thought to have Parkinson's
disease, but this diagnosis -- along with the assumption that alcoholism
also contributed to his decline -- can now be refuted on the basis of
clinical and anatomical findings. We here trace his clinical course over a
12-year period, during which his mind remained intact while his ability to
write, to walk, and eventually, to talk disintegrated. Using his own words
and those of his wife, we have reconstructed his struggle with his disease
and their attempts to cope with it.

Medical History
A review of the O'Neill family's medical and psychological history reveals
their profound effects on his literary characters and themes. (1,2) Born in
New York City on October 16, 1888, Eugene O'Neill was raised as a Catholic.
He lost his faith at the age of 13, however, when he discovered his mother's
morphine addiction. Feeling increasingly alienated from their parents,
Eugene, who was 15, and his older brother Jamie began drinking, smoking, and
frequenting brothels. Eugene contracted syphilis but was treated and did not
relapse. He continued to smoke throughout his lifetime. At the age of 17, he
entered Princeton University. At 21, he was hastily and secretly married to
a young woman who had become pregnant by him. Since neither his parents nor
the woman's parents approved of the match, he was sent on a gold-prospecting
expedition to Honduras. The trip was short, since O'Neill contracted malaria
and returned to the United States. No relapses were described. His first
marriage lasted three years.

The years 1910 to 1912 were among the darkest of O'Neill's life. A
tormented, drunken dropout from his first year at Princeton, living on
remittances from his father, he drank heavily and socialized only with
sailors and down-and-outs. He attempted suicide in 1912 at the age of 24,
using cheap whiskey and tablets of veronal (a barbiturate readily available
at that time without prescription). His drunken companions delivered him to
a nearby hospital, preventing the successful completion of his suicide
attempt. (1,2) Shortly thereafter, he contracted tuberculosis. But six
months of isolation in a Connecticut sanitarium forced O'Neill to take stock
of himself. Having survived malaria, a drug overdose, and tuberculosis, he
concluded that he was destined to live. For the first time he began reading
extensively. Soon he committed himself with almost obsessive self-discipline
to becoming a playwright, completing his first play in 1914 at the age of
26. (1)

O'Neill had numerous depressive episodes, often in conjunction with the
completion of a play or its production. In 1925, his work diary describes a
period during which he stayed in bed and had no appetite for many days. (3)
In 1934 he had a recurrence of depression and was prescribed six months of
compulsory rest. (2) In 1936 and 1937, he had relapses that required
hospitalization for several months. Depression and alcohol abuse often
coexisted. Although O'Neill was prone to alcohol excess -- at times he drank
a quart of Scotch per day -- he was an intermittent drinker, with long
periods of sobriety between binges. The binges themselves were accompanied
by blackout spells, which were sometimes followed by delirium tremens. These
occurred primarily from his teens until the age of 40. Despite occasional
loss of appetite, his nutritional intake appears to have been adequate. In
the last 25 years of his life, he did not use alcohol in excess; for the
last 8 years, he abstained entirely. (1,2)

O'Neill's family history suggests essential tremor in his mother, one
brother, and his older son. (1,2) His father, the actor James O'Neill, who
also drank to excess, died of intestinal cancer at about the age of 70. (2)
His mother, Ella, died two years later, in 1922, after a series of strokes.
(2) His brother Jamie died of delirium tremens in 1923 at the age of 49. (2)
Affective disorders, perhaps bipolar in nature, were probably present in his
mother, his father, his surviving brother, and his two sons. Eugene O'Neill,
Jr., O'Neill's son by his first marriage, also had a tendency to alcoholism
and committed suicide in 1950. (2) O'Neill's daughter, Oona, became the
fourth wife of Charlie Chaplin and subsequently bore eight children. She had
alcoholic tendencies and died of pancreatic cancer at the age of 66. (4) In
1948, O'Neill's son Shane was arrested on a charge of heroin possession. In
1977, he also committed suicide. (2)

O'Neill's Neurologic Course
While a freshman at Princeton in 1906, O'Neill first noted a mild tremor of
his hands, but it did not seriously interfere with his writing or other
activities for many years (Figure 1A). It is unclear whether he observed
that alcohol could temporarily suppress his tremors, as it does in most
persons with essential tremor. By 1939, however, his tremors had noticeably
increased. (2) A review of O'Neill's daily work diaries from 1924 to 1943
documents his first mention of difficulty in controlling a pencil while
writing, in May 1941, 12 1/2 years before his death. (3) Soon thereafter, he
insisted on a definitive diagnosis. Just as he had feared, Parkinson's
disease was diagnosed. (1,2) In July 1941 an entry in his work diary read,
"Trying new vitamin shot for Parkinson's disease." From February 1942
onward, he mentioned his affliction with increasing frequency, describing
his Parkinson's disease as "bad... terrible... rotten... super lousy." In
October 1942, he wrote "Parkinson's. Too bad to write a.m." His last entry
was on May 4, 1943. (3) He discontinued the work diary because of
progressive difficulty with handwriting.

In 1943, when someone commented on the narrowed size of his handwriting in
recent letters, he explained, "I did not wish it on myself, God knows,
because it made it so hard to get my scripts typed.... Of late years, I
can't write anything but minute, but there is a physical reason for that --
the curse of Parkinson's disease -- it's easier to control tremor in minute
writing." The "worst part" was the "fits of extreme melancholia that go with
it. God knows I have had enough of Celtic Twilight in my makeup without
needing any more of the same. And this isn't the same. It isn't sadness.
It's an exhausted horrible apathy." (2) In 1943, his wife, Carlotta,
described days when he could produce no more than a tremulous, illegible
scrawl. "No one could read it but me and I would type his manuscripts over
and over for him. He would change a few words, and make me type the whole
page over. I nearly went blind." (1) O'Neill commented, "I've always had
[the tremor] more or less, but it was not bad in the period in which the
Princeton scripts were written. Now, Mrs. O'Neill, who has typed all my
plays for years, has to operate with a magnifying glass and a book on
Egyptology. There are the times when she wonders if, after all, our marriage
was not a grave mistake." (1)

In 1943, at the age of 55, he first noted unsteadiness of gait. Shortly
thereafter, he began experiencing increasing difficulty coordinating the use
of his arms. It was hard for him to convey food to his mouth. Impairment in
articulation soon followed, so that his speech became increasingly difficult
to understand. (2) On July 9, 1944, he wrote to his son, Eugene, Jr.,

The other day my hands without warning jerked a cup of coffee all over the
surrounding landscape, and as suddenly I burst into weeping, not because I'd
spilt the coffee but impelled by the same nervous impulse, as it were. As
I've never been addicted to nervous weeps, no matter what the strain or (in
the old days) how much booze was in me -- I am terribly upset by such
exuberant blues, and if the docs didn't say these things were all part of
the game, I would feel more than slightly nuts. As it is, I try to be merely
disgusted with myself. (2)
Evidence of his deteriorating handwriting as of 1945 can be seen in Figure
1B. In 1948, as his neurologic disease progressed, he relocated to the
Boston area to be near its medical community. (1,2)

Vitamin injections, bromides, mephenytoin, and chloral hydrate were tried
without benefit during the course of O'Neill's disease. The combination of
bromide and chloral hydrate at times induced delirium, with disorientation,
hallucinations, and agitation. "All the drugs tried on me [for Parkinson's]
had made me feel worse instead of better," he stated. (2) He required daily
barbiturates for anxiety.

O'Neill's deterioration forced him to stop writing plays and most personal
correspondence by the age of 55. He completed his last play, A Moon for the
Misbegotten, in 1943, 10 years before his death. (1) Eight years before his
death, he gave up handwriting entirely because "my hands would almost fly
off the page" (Figure 1C). (1,2) His wife, Carlotta, felt that the "real"
O'Neill died in the early 1940s when the tremor forced him to quit writing.
"Writing was his life," she repeatedly said. "Nothing else really mattered
to him." (2) On February 4, 1949, he wrote to his agent "I will never write
another play and there is no use kidding myself that I will. As to
production, I do not want anything produced. I mean anything new. These
Hollywood directors would distort everything I intended -- and cheapen my
work. And I am too tired, too ill, to go through a production myself." In
1949, he formally and publicly joined the Euthanasia Society of America. (1)

Neurologic Examination
Neurologic examinations of O'Neill were recorded on several occasions in the
last two years of his life. (5) His speech was poorly articulated, low
pitched, and nasal; "words died in the back of his teeth." Hypotonia was
noted. His head and trunk swayed even while he was seated, unless he
supported himself with his arms. There were coarse tremors of wide excursion
when the arms were outstretched, most marked at the shoulders.
Incoordination of the arms and legs was evident. He was able to stand with
difficulty in the Romberg position with variable titubation of his head. His
gait was wide-based with irregular placement of his feet. His posture
remained erect. The deep tendon reflexes were normal, the plantar reflexes
remained flexor, and there was no recorded disturbance of sensory,
autonomic, or sphincteric functions. Several years before his death, the
diagnosis of cerebellar degeneration of unknown cause was suggested. During
recurrent respiratory infections, he became delirious, with temperatures of
102 degrees to 103°F (38.8 degrees to 39.4°C). However, no serious prolonged
confusional or psychotic episodes occurred. There was no evidence of
dementia.

The Final Months
All of O'Neill's symptoms worsened considerably in the last year of his
life. He had increasing difficulty in swallowing, resulting in frequent
choking on morsels of food. He became sullen and reclusive and was no longer
interested in what went on around him. Several months before his death, his
condition rapidly worsened. Except for a few assisted steps once or twice a
day, he was confined to bed. (2) Because of difficulties clearing his own
secretions, he repeatedly aspirated and developed a recurrent cough and
fever. Three days before his death, his temperature rose to 104°F (40°C),
and rales at the right posterior base were noted. Antibiotics afforded no
improvement. Born in a New York hotel room, he lived the last several years
of his life in the Shelton Hotel, now a Boston University dormitory. Soon
after he uttered, "I knew it! I knew it! Born in a god damn hotel room, and
dying in a hotel room!" his eloquence was forever silenced at 4:39 p.m. on
November 27, 1953. (2)

Postmortem Findings
The postmortem examination, performed 16 hours after death, revealed
bronchopneumonia; fibrous adhesions of the right pleural cavity due to
healed tuberculosis; emphysema with patchy fibrosis in the left upper lobe,
probably due to smoking; diverticulosis of the sigmoid colon; chronic
cholecystitis; marked benign prostatic hypertrophy; a normal liver (weight,
1850 g) except for a small hamartoma; and normal heart and testes. (5)

The brain weighed 1330 g, a normal weight. The large, medium, and small
blood vessels were free of disease. The cerebral hemispheres were
unremarkable except for slight dilatation of the lateral and third
ventricles. The cerebellum was atrophic with striking shrinkage of the folia
and widening of the sulci of the superior vermis. The basis pontis had its
usual rounded contour. Celloidin sections of brain samples were stained with
Nissl, Loyez, and modified Weigert stains. (5)

The microscopical slides that are still available were reviewed by both of
us. Our observations were in agreement with those of a previous report in
which O'Neill was 1 of 50 patients described anonymously. (6) The chief
abnormality was found in the cerebellar cortex. The neuronal loss of
Purkinje cells in the region of the vermis exceeded 90 percent (Figure 2A).
There was also a reduction in the number of granule cells in the vermis, but
Golgi type II cells were present in normal numbers, and there was mild
proliferation of astrocytes. The fastigial nuclei were not visualized, but
myelin pallor and gliosis were described in the superior portions of the
medial fastigiobulbar tract. (6) The remaining cerebellar cortex and the
emboliform, globose, and dentate nuclei were unremarkable (Figure 2B).
Cerebellar structures including the arcuate nuclei and nuclei of the basis
pontis were entirely normal, as were the spinocerebellar tracts.

Severe neuronal loss was seen symmetrically in the lingula, central lobule,
culmen, the portion of the declive bordering on the primary fissure, and in
the most anterior folia of the anterior cerebellar lobes (Figure 3). (6) The
inferior olivary nuclei were severely depleted, with gliosis in the dorsal
laminae, most intense in the dorsal laminae of the medial portions. The
dorsal accessory olives were almost completely devoid of nerve cells and
were gliotic, although the gliosis was not prominent. The dorsal portions of
the medial accessory olives contained fewer neurons than usual. The fleece
and hilum of the olives were normal, as were the external cuneate, lateral
medullary nuclei, and vestibular nuclei of the brain stem. (6) The
corticopontine, corticobulbar, and pontocerebellar tracts were normal, as
were the neurons of the pontine nuclei.

The cerebral cortex was unremarkable, including the nucleus basalis of
Meynert and medial temporal structures. The neurons of the substantia nigra
(pars compacta) on each side were intact, well pigmented, and without Lewy
bodies. The spinal cord had normal posterior columns and spinocerebellar
tracts. Given the age and small number of the remaining slides,
quantification of cortical neurons was not possible.

Clinical Significance of the Pathological Findings
The neuropathological findings indicate that Eugene O'Neill suffered from an
idiopathic form of late-onset cerebellar cortical atrophy. The primary
abnormalities involved the superior vermis of the cerebellum, with extension
into the anterior parts of the anterior lobe and secondary lesions in the
inferior olives. There was no evidence of Parkinson's disease.

In 1893, Pierre Marie described a group of families who suffered from a form
of hereditary ataxia clinically distinct from that previously described by
Nikolaus Friedreich. (7) However, a later review of Marie's cases disclosed
that several of the patients had no disease of the cerebellum. (8) Gordon
Holmes's observations in 1907 formed the accepted histologic prototype for
familial cerebellar cortical degeneration with secondary olivary atrophy.
(9) Although a familial pattern could not be established in O'Neill's case,
the topography of the cerebellar degeneration and the secondary olivary
changes were strikingly similar to those described by Holmes.

When one compares the typography and histologic findings of Holmes's
cerebello-olivary atrophy with those described by Victor et al. in 1959 as a
"restricted form of cerebellar cortical degeneration occurring in alcoholic
patients," (6) the changes are virtually indistinguishable. Chronic
alcoholism is one of the most common causes of cerebellar degeneration in
adults. (10) Cerebellar degeneration usually evolves subacutely or
insidiously after many years of poor nutrition and heavy drinking. (10) It
can occur alone or in conjunction with other alcohol-induced brain
syndromes, especially Wernicke's encephalopathy. (10,11) Alcoholic
cerebellar degeneration is characterized by stance and gait ataxia. (10) It
may be accompanied by nystagmus and dysarthria. Pathological examination
reveals midline atrophy of the cerebellum, most notably of the anterior and
superior vermis, with varying degrees of involvement of the anterior lobes
and a particularly marked loss of Purkinje cells. (10,11) The
flocculonodular lobe and inferior olivary nuclei may be involved. (6,10)
Similar histopathological abnormalities in the midline have been reported in
patients with paraneoplastic cerebellar degeneration. (12)

Clinically, a strong argument can be made against alcoholism as the cause of
Eugene O'Neill's terminal neurologic disease. Despite periods of eating
poorly during drinking binges in his earlier years, his diet was otherwise
nutritionally adequate throughout his life. A review of his personal records
and of biographies suggests that for at least 25 years before his death, he
did not use alcohol in excess and that during his last 8 years, he consumed
none at all. Yet his terminal disease, which began more than 12 years before
his death, progressed relentlessly. There was no clinical or
neuropathological evidence of any other related alcoholic-nutritional
diseases, such as polyneuropathy or Wernicke-Korsakoff syndrome. (10) Organs
frequently affected by chronic alcoholism, such as the liver and testes,
were normal in O'Neill's case. (10) There was no neuropathological evidence
of Parkinson's disease, tertiary neurosyphilis, or other multisystem
degenerative disorders such as striatonigral degeneration,
olivopontocerebellar atrophy, or dentatorubropallidoluysian atrophy. (5)

In contrast to the essential familial tremor that began in O'Neill's early
20s with mild progression over time, the tremor attributable to alcohol
alone is usually not severe or disabling. (13) The tremor may persist after
abstinence from alcohol, but typically it does not worsen over time. (13,14)
Alcohol can dramatically reduce the amplitude of the essential tremor by up
to 75 percent, usually for an hour or less after ingestion. (14,15) Although
patients with essential tremor were therefore felt to be at greater risk
than others for alcohol addiction, chronic alcoholism in patients with
essential tremor appears to be infrequent. (15) Contrary to O'Neill's own
opinion, a causal relation between his essential tremor and the development
of his degenerative cerebellar syndrome in later life has not been
described.

In 1981, Harding described 36 patients with idiopathic, late-onset
cerebellar degeneration in whom an underlying cause, including alcoholism,
was ruled out insofar as possible. (16) Most patients had sensory loss,
hyporeflexia, dementia, and pyramidal signs. In the majority of cases,
pathological changes were found outside the cerebellum in areas including
the dentate nuclei, pontine nuclei, hypoglossal nuclei, substantia nigra,
spinocerebellar tracts, posterior columns, and anterior horn cells. (16,17)
In 1993, Harding further classified autosomal dominant cerebellar ataxia on
the basis of phenotypic characteristics. (18) Beginning in 1993, genetic
studies of autosomal dominant cerebellar ataxias have identified genes for
spinocerebellar ataxia types 1, 2, 3, 6, and 7, all with a common mutational
mechanism of trinucleotide-repeat expansions in the coding regions of the
responsible genes. (19,20,21,22) Spinocerebellar ataxia types 4 and 5 have
now been identified by linkage analysis. (19) A chromosomal marker for
spinocerebellar ataxia type 8 was recently reported. (23)

These ataxic syndromes represent a clinically and genetically heterogeneous
group of neurodegenerative diseases that have varying effects on the
cerebellum, brain stem, basal ganglia, cerebellar tracts, and peripheral
nerves. Wide variations in clinical presentations and pathological features
have been observed among patients with the same genotype from the same
family. (23) The molecular basis for these dramatic clinical variations and
their neuroanatomical correlations remains incompletely understood, (24) and
inheritance patterns are not yet well defined. Any phenotype may occur
sporadically as a result of the mutation. Because of the implications of
inheritance patterns for future generations, screening tests are now
recommended for patients who present with progressive ataxia or have a
positive family history of the disorder. (24) The possibility of an
autosomal dominant or autosomal recessive inheritance pattern within
O'Neill's family cannot be entirely excluded, given the premature death of
his two brothers. Because of the age of the remaining specimens and the
paucity of tissue, as well as the celloidin preservation method used in
1953, DNA analysis for CAG repeats was not possible in his case.

Within the past 10 years, hypothesis-driven research, along with anatomical
and clinical evidence, has suggested a role of the cerebellum in emotional
and cognitive regulation. (25,26) The "limbic cerebellum" is thought to
modulate affective states and has been localized to the flocculonodular lobe
including the vermis and the fastigial and globose nuclei. (26) In O'Neill's
case, lesions in the vermis and possibly the fastigial nuclei may help
explain his self-reported emotional lability. The "cognitive cerebellum" is
postulated to modulate thinking, planning, learning, and linguistics and has
been identified as located in the lateral hemispheres, as well as the
dentate and emboliform nuclei. (26) These regions were spared in O'Neill's
case, corroborating the observation that his disease did not impair his
cognition.

In summary, Eugene O'Neill did not suffer from Parkinson's disease. Against
a background of familial essential tremor that began in his early 20s, an
unrelated idiopathic and progressive cortical cerebellar atrophy syndrome
emerged in his sixth decade. Neuropathologically, O'Neill's disorder
resembled a familial form of the disease first described by Holmes, but it
appears to have been sporadic in his case. The restriction of the cerebellar
atrophy to the anterior vermis and anterior lobes -- a pattern similar to
that of alcoholic cerebellar degeneration -- was unique, but it was not
clinically associated with poor nutrition or excessive alcohol ingestion
during the last 25 years of his life. This disease progressed relentlessly
over a 12-year course, leading to his death at the age of 65 from pneumonia.

Epilogue
In 1934, Eugene O'Neill conceived the idea of a cycle of plays that would
chronicle the fortunes of the Hartford family from the early 19th century
into the 20th century. (1,2,27) Over the next 10 years, the cycle grew in
his mind from a trilogy to 11 plays. It was intended to be his searing
critique of the split ethical and moral psyche he perceived in American
civilization -- a civilization that he believed was hopelessly caught
between its professed democratic ideals and the greed that fueled its
progress and was therefore doomed. (1,2,27,28) He explained that the main
theme of this epic, which he entitled "A Tale of Possessors,
Self-Dispossessed," was "that everlasting game of trying to possess your own
soul by the possession of something outside of it.... This was really said
much better in the Bible. We are the clearest example of 'For what shall it
profit a man if he gain the whole world but lose his own soul?'" (27)

Occupied by this cycle of plays in the final decade of his life but plagued
by his worsening disabilities, Eugene O'Neill never completed the project.
By 1942, he had finished only one play in the proposed cycle (A Touch of the
Poet). (1,2) In 1952, less than two years before his death, Eugene and
Carlotta O'Neill burned the remaining unfinished manuscripts. Carlotta
described the tragic scene: "He could only tear a few pages at a time,
because of his tremor, so I helped him. We tore up all the manuscripts
together, bit by bit. It took hours. After a pile of torn pages had
collected, I'd throw them in the fire. It was awful. It was like tearing up
children." (2) Had O'Neill's vision been fulfilled, this cycle of plays
might conceivably have become one of the most extraordinary works of
American theater. Instead, the now-defined neurologic illness robbed him of
his abilities and his life, depriving us all of further works by the writer
who has been called "America's Shakespeare." (29)

Bruce H. Price, M.D.
McLean Hospital
Belmont, MA 02478

E.P. Richardson, Jr., M.D.
Massachusetts General Hospital
Boston, MA 02114

Editor's note:

Dr. Richardson died on November 30, 1998.

We are indebted to Marsel Mesulam, M.D., who first suggested this project in
1990; to Drs. Raymond D. Adams, Maurice Victor, Tessa Hedley-Whyte, Stanley
Robbins, and Jeremy Schmahmann, as well as John Case, B.S., Louise Grant,
LICSW, and Cathy Gilmore, LICSW, for their critical reviews of the
manuscript; to Pat Willis and Donald Gallup of the Beinecke Rare Book and
Manuscript Library at Yale University; to Susan Currier, the patient and
expert transcriptionist; and to the surviving members of Eugene O'Neill's
family for their permission to release the autopsy results publicly.

Source Information
Address reprint requests to Dr. Price at the Department of Neurology, McLean
Hospital, 115 Mill St., Belmont, MA 02478, or at [log in to unmask]

Copyright © 2000 by the Massachusetts Medical Society. All rights reserved.