Dear Editor,

We have read with great interest the paper by Brigo and colleagues, “You Are Older, although You Do Not Know That”: Time, Consciousness, and Memory in “A Kind of Alaska” by Harold Pinter (1930–2008) [1].

In this comment, Brigo and colleagues analyzed how the clinical effects of the encephalitis lethargica (EL) pandemic (1915–1926) have been portrayed in Oliver Sack’s “Awakenings” and in the derived stage-play by Harold Pinter, “A Kind of Alaska.” These works had the merit to present a complex clinical condition to the general audience; however, Brigo and colleagues raised some cautionary doubt about the wording used in these literary translations.

Both works described extreme consciousness impairment and its unexpected dramatic, although temporary, recovery after the use of levodopa with a restoration of motor and verbal functions. In both literary works, the term “awakening” is used to describe this event. Brigo and colleagues pointed out that this re-emergence of responsiveness should not be compared to a real awakening within a global alteration of consciousness but rather to the recovery of voluntary motor function in patients with a post-encephalitic parkinsonism in the context of EL, described by von Economo [2]; EL is currently interpreted as an auto-immune post-infectious encephalitis, mainly affecting basal ganglia [3, 4].

In EL chronic phase, the amyostatic-akinetic form (comparable to an extreme form of parkinsonism) is more prevalent. According to Brigo and colleagues, patients affected by EL in chronic phase were not actually asleep but rather severely slowed down by dopaminergic depletion. Thus, they hypothesized that severe akinesia with a preserved awareness of the passage of time, rather than a real sleep, could better explain the pathogenesis of the condition. However, some data showed that time perception is impaired in PD patients [5], supporting the hypothesis that in akinetic parkinsonism, time could appear to slow down or remain still. In this comment, we would like to briefly discuss (i) the fundamental contribution of von Economo to the understanding of neuronal mechanisms for sleep/wake regulation, (ii) the close relationship between impairment of consciousness and post-encephalitic parkinsonism, and (iii) a possible role of local sleep as responsible for alterations of consciousness in the chronic phase of EL.

Around 100 years ago, the outbreak of EL promoted fundamental knowledge advancement regarding sleep regulation and movement disorders. After having observed hundreds of patients, von Economo first described the clinical presentation of EL in three possible variants: somnolent-ophthalmoplegic, hyperkinetic, and amyostatic-akinetic. Von Economo also defined the specific neuropathological associated changes that included involvement in the midbrain and substantia nigra, as well as the basal ganglia and hypothalamus. More specifically, based on clinical and anatomopathological correlations, von Economo first recognized distinct centers for promoting sleep, in the rostral hypothalamus, and wakefulness, in the posterior hypothalamus and rostral midbrain. Of particular note, the passage from acute to chronic phase of EL reflected an overlap of movement, psychiatric, and sleep disorders demonstrating, besides a clinical polymorphism, close anatomo-functional interconnections. For example, the chronic amyostatic-akinetic form was characterized by the presence of rigid akinetic parkinsonism but also by psychiatric symptoms, such as catatonia, and sleep inversion with hypersomnolence.

Besides, another paradigmatic example of the fluid boundaries between consciousness disorders and parkinsonism is the syndrome known as akinetic mutism [6]. In akinetic mutism, a failure to initiate spontaneous and voluntary responses with an absence of speech is present, but there is also an overlap with consciousness disorders due to a variable impairment of vigilance and awareness [7]. The original description of akinetic mutism by Cairns et al. [8] closely resembles the hyporesponsive conditions reported by von Economo and Sacks. Akinetic mutism was first described as follows: “the patient sleeps more than normally, but is easily roused. In the fully developed state he makes no sound and lies inert, except that his eyes regard the observer steadily or follow the movement, and they may be diverted by sound. Despite his steady gaze, which seems to give promise of speech, the patient is quite mute, or he answers only in whispered monosyllables. Often repeated commands may be carried out in a feeble, slow, and incomplete manner, but usually there are no movements of a voluntary character.” Recently, significant advances have been made in defining neurocircuits involved in the akinetic mutism and the crucial role of the three main dopaminergic projections such as mesolimbic, mesocortical, and nigrostriatal pathways, particularly the last one [9].

Notably, when looking at EEG in akinetic mutism, high-amplitude fronto-central slow waves resembling a functional local sleep-like activity have been reported [10, 11]. Similarly, a growing body of evidence suggested that sleep disorders are common in synucleinopathies with parkinsonism. In particular, recent studies found that an impairment of arousal (taking the form of intermittent sleep intrusions) was one of the most specific features of cognitive fluctuations and daytime sleepiness observed in dementia with Lewy bodies [12].

These data suggested that in parkinsonism syndromes, clinical and neurophysiological features could be related to a sleep disorder, affecting only limited portions of the brain. Sleep is a physiological condition, whose role is not fully understood yet, which is strongly preserved in different animal evolutionary lines [13]. Local sleep has been described in some stroke patients [14] and in a murine model of PD [15].

We could speculate that global vigilance, time perception distortion, and motor impairment experienced by severely akinetic patients in the chronic phase of EL could be related to local sleep functional phenomena. If things were in this way, Sacks and Pinter might have been right talking about “an awakening,” not only at the poetic level but also from a pathogenetic point of view. It would be interesting to consider this subject as a possible matter of investigation in the future to demonstrate or disprove whether patients described by Sacks were really asleep, at least locally, when they were somehow “awaken” by the treatment.

The authors have no conflicts of interest to declare.

No funding was received for this study.

Alessandro Viganò e Angela Comanducci conceptualized the paper. Alessandro Viganò, Angela Comanducci, and Mario Meloni drafted the manuscript.

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