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.