With this background, Economo in 1917 described seven patients in a first paper, an additional four in a second, with common features of lethargy and restricted eye movement [15, 16]. The onset was acute, in a matter of hours or days with malaise, fever, headache and neck stiffness, ‘subalertness’, ‘reduced attention’, ‘mental dazing’, ‘somnolence’, persistent sleep bordering ‘stupor’ and then ‘unrousable’ coma. One subject was a somnambulist, another fell asleep ‘whenever…standing or walking’. Yet another ‘when aroused…(was)…not alert’…with ‘attention only possible for short periods’. In contrast, another subject, a boy of 12, ‘lay awake in bed day and night’. One patient was deluded, and another hallucinated. There was partial or complete paralysis of eye movement, reduced or absent voluntary up-gaze and ‘dull, half closed eyes’. The disease was severe, ending in the death of four subjects although three made an initial complete recovery over the next 3–16 weeks. Of the 11 patients, 10 were young, aged from 12 to 38 and one was aged 56.

After Economo’s descriptions, many similar cases were reported, and the disease spread worldwide over the next decade, although the presentation was very variable from case to case and from year to year. In addition to lethargy and involvement of the third, fourth, fifth and sixth nerves, Vilenski and Gilman (2011) recorded well over 50 different signs and symptoms that might be present [17]. Both sexes were equally affected. Hall (1924) considered that of each 100 cases, 25 died in the acute phase, 25 recovered practically completely, and 50 went on to develop secondary symptoms after days, weeks or months of apparent recovery. The most serious and frequent of these included motor disorders, change of personality and mental defect, whilst ‘lethargy’ or sleep disturbances were less pronounced than at initial presentation. The pattern of late disease depended largely on the age of initial infection. Infants went on to develop mental defects, and children personality disorders that were sometimes accompanied by disturbed sleep—nocturnal restless behaviour continuing from the primary illness was more common or possibly more disruptive in children than in adults. The severity of secondary symptoms was largely unrelated to the severity of the initial attack, and with late so-called hypersomnia , narcolepsy and insomnia, it was often difficult or impossible to establish a causal relationship with previous encephalitis. In contrast, Parkinsonism eventually developed in most if not all adults who survived the initial illness, and had a uniformly bad prognosis.

Cruchet first reported cases of possible encephalitis lethargica amongst French World War troops in Verdun at the end of 1916 and 1917 [18]. Previous sporadic outbreaks of influenza had occurred in these soldiers from 1915, and it was difficult at first to separate the two illnesses. A great influenza pandemic, later named the Spanish flu, then broke out in Europe between 1918 and 1921. Both diseases went on to spread over all continents. Many physicians, like Cruchet, first saw encephalitis lethargica during or after flu, and it was natural to assume a connection. However, von Economo held from the start that influenza did not cause or lead on to encephalitis lethargica. The name ‘Spanish’ flu derived from the facts that the Spanish press—Spain not being involved in the Great War—was amongst the first to report extensively on the severity of the pandemic. Three major waves of influenza occurred over the next 10 years, and up to a billion people, quarter to half the world population of 1.86 billion at that time, were affected. The total loss of life worldwide from Spanish flu was estimated at perhaps 50–100 million, greater than that due to the 1914–1918 war and surpassing even the Black Death of medieval Europe. This compared with the half- to one-million deaths from encephalitis lethargica.

The influenza virus may have predisposed to but did not cause encephalitis lethargica. Influenza, but not encephalitis lethargica, was highly contagious with a high rate of case-to-case, school and family transmission. The peaks of the natural frequency curves of the two conditions did not match, although as with encephalitis lethargica, most cases of influenza occurred in winter. The clinical features of the two conditions were usually quite distinct, and in most cases the tracheitis, upper respiratory infection, malaise, fever, lethargy and muscle aching of influenza recovered within a week following bed rest, although a few subjects died within 24 h of infection. Influenza does sometimes lead to brain inflammation, although this is very uncommon, occurring in perhaps 1 in 100,000 cases who go on to develop headache , vomiting, delirium and coma during influenza outbreaks.

Encephalitis lethargica may be more relevant to the study of wakefulness than to that of sleep: in as much as these can be separated. The defining sleep disturbance of encephalitis lethargica was described by von Economo as the inability to maintain wakefulness rather than the occurrence of sleep. His name for the illness was based on the striking lethargy of the initial meningeal and brain involvement of the first phase. Subsequent popular use of the term ‘sleeping sickness’ in place of ‘encephalitis lethargica’ may have over-stressed the sleep component in a multifaceted disease. In practice, signs and symptoms of extrapyramidal motor disorder and of mental disturbance were more persistent, troublesome, prominent and frequent in the late illness than were lethargy, too much or too little sleep.

Economo suggested that lesions causing insomnia were mainly situated in the basal forebrain, those causing hypersomnia in the midbrain tegmentum and posterior hypothalamus: but this division may have been more apparent than real and has little value as to the exact localisation of sleep–wake systems in the brain. Encephalitis lethargica was rarely if ever a cause of persistent true hypersomnia as opposed to stupor, of the narcoleptic syndrome, of the complaint of difficulty in falling asleep or in maintaining sleep; although it seems probable that it sometimes might have led to symptomatic central sleep apnoea.

What is lethargy? The Greek term ‘lethargos’ dates from the medical school of Hippocrates, and describes forgetfulness which, when accompanied by fever, could lead to rapid death. To drink from Lethe, the river of Hades in mythology, led to forgetfulness of the past. In the middle ages , ‘lethargic’ came to indicate morbid torpor as well as prolonged unresponsiveness, and in this sense was used by von Economo. ‘Lethargy’ implies physical ‘tiredness’ but although we all know what ‘tiredness’ means, it varies over time and setting, is not quite in the same category as ‘fatigue’ , ‘arousal’ , ‘awareness’ or ‘vigilance’ , and carries the mental burden of disinclination. Economo did not use the term ‘lethargy’ in any of his first eleven case descriptions but rather somnolence, delirium, confusion, stupor, tendency to sleep, mental diminution, continually dazzlement, long reaction time, reduced consciousness, falling asleep standing, walking and sitting; drowsiness, hypersomnolence.

Lethargy , merging with stupor, may be a disorder of arousal , rather than of sleep. Arousal from stupor demands a stronger stimulus than arousal from sleep. Lethargy, unlike sleep has no definite circadian rhythm , distinction or division into various behavioural stages, and can last days, months or sometimes, years. In lethargy, there is no periodic dream mentation, no regular postural shifts nor intervallic atonia. Muscle tone in patients with post-encephalitic lethargy was sometimes described as increased rather than diminished, with ‘catatonic’ resistance to the movement and preservation of enforced posture: this observation may, however, have been biased by extrapyramidal damage in patients with encephalitis lethargica.

Hypersomnolence implies definite sleep, and may be misleading if applied retrospectively to encephalitic lethargy. ‘Pseudosleep’, popular terminology in the pandemic period to describe stupor, does not totally get away with the problem. To further confuse the issue, Economo observed that in three subjects ‘somnolence’ was independent of the severity of all other conditions, as well as ‘not connected with diminished consciousness’. The word ‘consciousness’ defined as the ‘knowledge of what goes on in one’s own mind’ might today not be used, but the meaning is clear. Subjects with hypersomnolence had an intense desire for sleep, reporting that ‘it was impossible… or near-impossible…to stay awake’. The emphasis is on the preservation of vigilance , motor response, and with intact cortical functions of cognition, memory, personality and intellect when aroused despite ‘pressure’ for sleep or the near inability to remain awake. Several observers stressed that the ‘sleep’ itself in encephalitis lethargica could be normal, with normal eye closure, meiosis, atonia, and dream report. Any abnormality of sleep lay only in its long duration and considerable depth, a large stimulus being required for arousal . The subject might then be immediately alert.

‘Unrousable’ sleep was sometimes associated with encephalitis as well as head injury , brain tumours and many other metabolic and cerebral disorders. No clear nomenclature was possible in a pre-encephalographic era, and without careful behavioural studies. This could last days, months, or even in the fabled case of the seven sleepers of Ephesus, for many years. Often likened to hibernation, this is journalistic, not scientific.

One EEG recording in a recent post-encephalitic subject who developed Parkinsonism , during ‘stupor’ from which the patient could be aroused only by deep painful stimuli, showed diffuse high-voltage delta and theta activity [19]. Perhaps other electroencephalographic parallels to encephalitis lethargica today come from patients with ‘idiopathic’ hypersomnolence or the Kleine–Levin syndrome, who complain of lethargy and tiredness and go on to develop prolonged sleep episodes lasting up to 20 out of 24 h, usually persisting a few days to several weeks. Here, the EEG between attacks is usually completely normal. During episodes of periodic lethargy or stupor, there may be decrease in stage 3–4 non-rapid eye movement (NREM) and also in REM sleep, interrupted by alpha activity; with occasional early-onset REM sleep and a very short sleep latency.

The term ‘narcolepsy’ continues to be one of the most widely misused in journalism if not in medicine. A typical misconception is shown by reports such as that in 2011, when an English burglar was let off from his full sentence when the defence claimed he had ‘Attention Deficit Hyperactivity Disorder—which can cause disruption to sleep patterns and narcolepsy, a chronic sleep disorder characterised by an excessive urge to sleep at inappropriate times’. The 20-year-old had stolen DVDs, computer games, sandpaper, toiletries and elastic bands. The court was told that he had a ‘sleeping disorder that meant he was awake for up to two weeks at a time and then could be out like a light for one or two days’. As 24-h supervision in the community might prove difficult, health and safety concerns for his attendants combined with powerful medical advocacy and a lenient judge led to a ruling that he could not be sentenced to unpaid work [20].