The poor insane Ophelia: reconsidering Ophelia syndrome

“To be, or not to be, that is the question: Whether ’tis nobler in the mind to suffer The slings and arrows of outrageous fortune, Or to take arms against a sea of troubles, And by opposing, end them. To die, to sleep— No more, and by a sleep to say we end The heart-ache and the thousand natural shocks That flesh is heir to; ’tis a consummation Devoutly to be wish’d. To die, to sleep— To sleep, perchance to dream” — Hamlet, Act 3, Scene 1, Lines 56-65. In 1982, the pathologist Ian Carr wrote one of the most eloquent descriptions of disease during the suffering of his daughter Jane, as she gradually lost her memory and was eventually diagnosed with Hodgkin’s disease1. Two remarkable things can be derived from Carr’s article: his presaging of neuronal autoantibodies before the first association between autoantibodies and limbic encephalitis had been made2, and giving memory loss secondary to Hodgkin’s disease, the eponym “Ophelia syndrome”, in reminiscence of Shakespeare’s character, Ophelia, in Hamlet. The Bard’s plays have captivated neurologists and psychiatrists, with a recent review suggesting he was a Renaissance

neurologist 3 . However, the different outcomes of Carr' s description and Shakespeare' s character cast doubt about the appropriateness of the eponym, which led us to review the origins of this eponym.

HAMLET'S OPHELIA
In The Tragedy of Hamlet, Prince of Denmark 4 , William Shakespeare presents us with a distracted Ophelia, "divided from herself and her fair judgement" (Act 4, Scene 5, Line 84; from here on 4.5.84). Previously sound of mind, gentle and loving, Ophelia obeys her father Polonius's orders of rejecting Hamlet's proposals (3.1.117), a situation that paradoxically sets in motion the very circumstances that will conclude with the slaying of Polonius by Hamlet's sword (3.4.24; Figure 1). As a consequence of "the poison of deep grief ", originated from her father's death (4.5.74-75), Ophelia gets lost in a singing madness: "He is dead and gone, lady, He is dead and gone, At his head a grass-green turf, At his heels a stone. " (4.5.29-32) This madness leads to her death after falling in the mourning river, while "she chaunted snatches of old lauds, as one incapable of her own distress" (4.7.175-78). Until her water-filled clothing "pull'd the poor wretch from her melodies lay to muddy death" (4.7.181-83; Figure 2). Thus, the bard offers us one of the eeriest suicides in literature, as the poor insane Ophelia dies by her own hand, albeit unknowingly.

CARR'S OPHELIA AND ITS IMPACT
While Dr Carr narrates his daughter's journey and is reminded of Shakespeare's Ophelia, he suggests that "there is perhaps a circulating neurotransmitter-like molecule produced by the neoplasm", thus presaging the presence of autoantibodies, which were reported four years later 2 , and related to the Ophelia syndrome eight years after Carr's article 5 . Since then, the association between memory loss and Hodgkin's disease, which we now call paraneoplastic limbic encephalitis, has been widely acknowledged as the Ophelia syndrome 6 .

OPHELIA'S COMPLEX
Another occurrence of Ophelia's name was described by French philosopher Gaston Bachelard, as the Ophelia complex in his book L'Eau et les rêves 7 , as a symbol of feminine suicide, destined to end her life in the water. In this complex, the water plays a fundamental role, as Bachelard's writes: "L'eau est l'élément de la mort jeune et belle, de la mort fleurie, et, dans les drames de la vie et de la littérature, elle est l'élément de la mort sans orgueil ni vengeance, du suicide masochiste" 7 [Water is the element of young and beautiful death, of blooming death, and in the dramas of life and literature, it is the element of death without pride or revenge, masochistic suicide]. Although quite poetic, we could not find any references to the Ophelia complex in the medical literature.  Legend: "There on the pendant boughs her crownet weeds Clamb'ring to gang, an envious silver broke, When down her weedy trophies and herself Fell in the weeping brook. Her clothes spread wide, And mermaid-like awhile they bore her up, Which time she chaunted snatches of old lauds, As one incapable of her own distress, Or like a creature native and indued Unto that element. But long it could not be Till that her garments, heavy with their drink, Pull'd the poor wretch from her melodius lay To muddy death". Act 4, Scene 7, Lines 172-183.

DISCUSSION
Dr Carr's daughter never committed suicide, nor was she involved in an event related to water (Bachelard's Ophelia complex); a situation that made one of the authors (CASR) wonder about the appropriateness of the name, having found a blog entry under the provoking title "When Shakespeare meets neurology", which briefly addressed the topic 8 ; while another author (SACT) re-explored Hamlet in search of clues that might reinforce the association. While we could not find a direct relationship between Carr's daughter and Ophelia, because of the different outcomes, Dr Carr concluded: "In summary, recent memory loss may rarely be due to Hodgkin's disease, probably as a paraneoplastic event. It may be reversible and can be remembered as the Ophelia syndrome 1 ".
What did Dr Carr see in his daughter that reminded him of Ophelia? We suggest her innocence made mad by an external factor (lymphoma, in this case), with him watching from afar-through a glass-as Ophelia was seen through the waters in which her life ended, by an external factor (her father's death). We can picture him wondering-as Laertes did-if "is't possible a young maid's wits should be mortal as an old man's life" (4.5.159-60), having to endure such a difficult test. In the end, Dr Carr decides-as Hamlet declares-to "take arms against a sea of troubles, and by opposing, end them" (3.1.59-60). It can be concluded that, in both cases-however divergent the outcomes-mental soundness is lost because of an external agent set in motion by themselves: Ophelia's rejection of Hamlet leads to him killing her father, and Carr's daughter's lymphoma leads her immune system to produce autoantibodies. Amidst all the "sea of troubles", Dr Carr manages, as described by the great Argentinian writer Jorge Luis Borges, "to make of the miserable circumstance of our life, things eternal or that aspire to be 9 ".
As Carr predicted, a number of "circulating neurotransmitter-like molecules"-which we now call antineuronal autoantibodies-have been identified in patients with limbic encephalitis and Hodgkin's disease: anti-mGluR5 10-12 ; anti-Hu 13,14 ; anti-NMDAr 15 ; anti-SOX1 and anti-PCA2 16 (detailed in Table). Although in many other patients they have not been found, in almost all patients, tumor-directed therapy improves the neurologic syndrome.
Although initially we intended to propose changing the eponym to Carr's syndrome, to praise his accurate observations and prediction of autoantibodies; yet, as it correlates with the pathophysiology of the syndrome, perhaps it should still be remembered as the Ophelia syndrome.