Idiopathic narcolepsy: a disease sui generis; with remarks on the mechanisms of sleep. By WJ Adie, MD, FRCP. Physician to Out-patients, the National Hospital, Queen Square, (London). (From a Thesis submitted for the Degree of MD in the University of Edinburgh, on February 26, 1926). Brain 1926: 49; 257–306 and The narcolepsies. By S.A. Kinnier Wilson. Brain 1928: 51; 63–109.
Cambridge
‘The disease I am about to describe is characterized by ... attacks of irresistible sleep without apparent cause, and curious attacks on emotion in which the muscles relax suddenly so that the victim sinks to the ground fully conscious but unable to move’. Concerned that the original descriptions of Westphal (1877) and Gélineau (1880) have become confused with all sorts of other sleep disorders, and quoting Sir Clifford Allbutt on ‘sticking a label’ on a new disease entity, Dr Adie (Fig. 1) describes five personal cases and summarizes those reported by Gélineau (1880), Löwenfeld (1902), Redlich (1915), Hennenberg (1916), Jolly (1916), Mendel (1916), Singer (1917), Stöcker (1918), Stiefler (1918), Noack (1918), Somer (1921, two examples) and Goldflam (1924, with two others having uncontrollable sleep but without falling attacks).
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Mis-diagnosed with petit mal epilepsy at Queen Square, Olive P, aged 14, complains that ‘when I laugh I cannot stand’ ... and she ‘sleeps at inconvenient times’; by chance, Dr Adie comes across Gélineau's description when looking up his preferred diagnosis of ‘Lachschlag’. Freda W, aged 19, under the care of Dr James Taylor, has fallen from her bicycle and slept in the middle of the road’ ... and with laughter ... ‘the limbs crumple[d] up’. On learning that a boy cycling from London to visit her home has been killed, Mrs C, aged 42, fell and lay powerless on a couch; now any unpleasant emotion provokes these episodes and she has a morbid fear of being thought dead if found in an attack; ‘London consultants’ have diagnosed hysteria and epilepsy without convulsions. Captain X, aged 35, sleeps through one of Dr Adie's lectures, as host at his Corps’ Mess dinner, and whilst driving his car; unaffected either by danger or excitement during the Great War, with laughter he goes ‘floppy all over’. Leslie W, aged 16, sleeps whilst talking to the Matron of the National Hospital.
What can be said of this mysterious disorder usually affecting otherwise healthy males in their teens or as young adults who cannot resist the urge to nod off for a few seconds or longer, sometimes in circumstances conducive to sleep but typically also at inappropriate times? Two soldiers describe sleeping whilst on listening-post duty—an offence carrying the death-penalty—and others have been saved by medical intervention prior to courts-martial. Falling attacks precipitated by emotion, usually laughter but also anger and annoyance and often associated with grimacing, protrusion of the tongue and stammering, usually start later. These also may end in sleep. As the head lolls, the patient may jerk upright a few times so that the unwary diagnose epilepsy or chorea. Gélineau's patient fell down at the prospect of a good business deal or finding that he had been dealt a winning hand at cards; Redlich's patient weakened and became flaccid during coitus.
The terms ‘hypnolepsy’ and ‘Einschlafsucht’ have been proposed but Dr Adie favours ‘narcolepsy’ for the sleep attacks. Rejecting all foreign suggestions (‘chute ou astasie’ [Gélineau], ‘kataleptische Starre’ [Löwenfeld], ‘kataleptische Hemmung’ [Henneberg], ‘plötzlicher Tonusverlust’ or ‘affektiver Tonusverlust’ [Redlich] and ‘Tonusblockade’ [Stern]) and noting that translating Lowenfeld's term as catalepsy will not work (already having meaning in Anglophone medicine), Dr Adie suggests the term cataplexy for the falling attacks. In short, ‘two kinds of sudden attack occur, sleep ... with cause and cataplexy on emotion ... [such that] anyone possessing this knowledge would be able to recognize a typical case’, although transitional states do exist. It follows that sleep attacks and cataplexy have the same mechanism. Apart from non-convulsive epilepsy, the differential diagnosis might include pyknolepsy (originally described, unhelpfully, as ‘short narcoleptic attacks’ by Friedmann, 1906), hysteria, ‘Lachschlag’ (Oppenheim, 1902: in which the patient is deeply unconscious during the emotion-induced episode and without sleep attacks), Pickwickian ‘Fat Boy’ disorder, encephalitis lethargica and cerebral tumour; but the absence of co-existent symptoms and the benign natural history of narcolepsy usually serve to distinguish these conditions.
Beyond his clinical interest, Dr Adie wants to understand the nature of sleep. He has been reading Ivan Pavlov, but not yet ‘Conditioned reflexes: an investigation of the physiological activity of the cerebral cortex’ based on lectures given in 1924 to the Military Medical Academy in Petrograd (1926), and translated into English by GV Anrep (1927). Here is an exposition of reflexes that are innate to any nervous system, and those that are learned by association between a neutral stimulus and a primitive response; conditioned reflexes fade if not actively habituated and through internal inhibition when the conditioning stimulus is no longer followed by the expected ‘reward’. But Pavlov's research has been thwarted by his dogs falling asleep during training or on repetition of the conditioned reflex, although they became alert in response to something new—the orientation reflex. Pavlov considers sleep and internal inhibition as one and the same. Simply stated, the cortex finds any repetitive stimulus dull and so switches off until something novel crops up. The Pavlovian dog, subjected to a familiar routine, shows increasingly long intervals between the sight of food and reflex salivation, and eventually takes a nap in response to stimulation. Internal inhibition has spread throughout the cerebral hemispheres. But a novel stimulus wakes the cortex and restores responsiveness to conditioned reflexes—old and new alike. Sleep and inhibition are one; narcolepsy and cataplexy are part of the same process. At first, attacks are favoured by the lack of extraneous stimuli (... ‘sitting before the fire, after a heavy meal, in a warm room, during the rest hour’) and then by monotonous challenges. But the patient with narcolepsy who cannot resist sleep in the context of repetitive but familiar stimulation soon wakens when the eyelids are raised, the skin is pinched, or an unexpected sound is heard.
Now, Dr Adie advances the idea that narcolepsy–cataplexy is an ‘endocrine–nervous’ disorder. The pituitary is reciprocally connected to the ‘tween–brain’ and, together, these structures regulate temperature, fat, water and sugar metabolism, and sexual activity. ‘In symptomatic narcolepsy, I surmise, the primary disturbance is in the [pituitary] gland; in idiopathic and post-encephalitic narcolepsy the nucleus hypophyseus and adjoining structures are at fault’. But why are only certain individuals affected? Much depends on their constitutional state of alertness. Lively Pavlovian dogs sleep more readily than easy-going animals because the former—once restrained in a cage—experience fewer and more monotonous stimuli by comparison with their natural habitat. Narcolepsy is an expression of fatigue in individuals with a constitution that favours the spread of normal inhibitions throughout pathways of the endocrine–nervous system. Sleep is controlled by sub-cortical centres that ultimately inhibit the cortex. Trömner has it that this lies in the optic thalamus, turning off the ascending sensory lights that illuminate the drowsy cortex, and simultaneously inhibit muscle tone down below. Hence, narcolepsy is thalamic. Whilst accepting that thalamic activity may set in motion an inhibitory mechanism, Dr Adie does not see this as related to sensory volleys. Rather, he prefers the evidence—from examples of von Economo's encephalitis lethargica—that the crucial region is restricted to ‘the floor of the tween brain in and around the vegetative centres that form a part of the pituitary tween-brain system’. Reflecting that the pendulum of opinion on how the nervous system works has swung from a doctrine of medieval humours to the neural concept of brain function and back to discoveries of the ductless glands ... ‘it is almost certain that hormones play a part ... my study of narcolepsy has taught me that ... nervous and endocrine organs work together as equivalent parts of an intimate system’.
But not everyone is impressed. Within a year Samuel Kinnier Wilson (Fig. 2), Adie's senior colleague at Queen Square, publishes his account of the narcolepsies: ‘recent communications dealing with the subject are reduced in value by ignorance or neglect of previous work ... hypotheses are evolved which suffer ... fatally ... from failure to take all the germane data into consideration ... to describe ... narcolepsy as a "morbus sui generis" is a nosological error, yet in the communication of ... Adie ... this regrettably occurs "passim"’. Narcolepsy is no more a single disorder than epilepsy: both are syndromes with idiopathic and secondary causes. The ‘vicissitudes that [Gélineau's] conception has undergone’ make it proper only to refer to "the narcolepsies" ’; and Dr Adie is wrong in allowing the diagnosis in individuals who do not also have falling attacks ... ‘experience should surely have convinced the neurologist that no good purpose is served by a hard-and-fast schematization of a clinical syndrome—which is all that narcolepsy can possibly be—to fit a conception based solely on an original description’. Kinnier Wilson describes four cases that although having the combination of sleep, or sometimes reveries, and falling attacks ‘... have nothing else than a purely symptomatic and non-committal significance, and under no circumstances can be used for a "disease" ’. POR (aged 24, railway porter), EC (aged 26, bricklayer), TT (aged 41, boilerman), ABCD (aged 18, schoolboy) and HGB (aged 32, business-man) describe their sleep attacks and falling with emotion (Fig. 3). In a famous passage Dr Kinnier Wilson relates how ... ‘I was able to observe an (emotional attack) from beginning to end and to examine the patient's neurological condition during it. Dr Macdonald Critchley, the present Registrar at the National Hospital, was with me at the time ... testing the knee-jerks I found them completely abolished and ... Dr Critchley ... obtained a slight but definite left extensor [plantar] response ... which I corroborated ... just as we were finishing ... the patient said "I’m all right, sir" ... testing his knee jerks again, I found them active’. Arguing that all examples are symptomatic, Kinnier Wilson considers narcolepsy to consist of recurring diurnal episodes of sleep, with or without toneless attacks, or sleeps of longer duration that straddle day and night and may be continuous (as in encephalitis lethargica and trypanosomiasis). He accepts that, very occasionally, larval or incomplete varieties either of sleep or cataplexy may occur without the other. Transitional variants are seen in which emotion triggers sleep: cataplexy may occur if sleep is prevented; sleep may follow cataplexy; and cataplexy may occur without an emotional trigger. Agreeing for once with Dr Adie, Kinnier Wilson concludes that a common factor must underlie all the clinical phenomena—a not as-yet fully understood inhibitory mechanism responsible both for the sleeping and falling attacks, and both for the narcolepsies and conditions with which they may be confused or indeed overlap. He lists periodic familial paralysis, catalepsy, nocturnal or sleep paralysis (described by Silas Weir Mitchell), epilepsy (especially reflex forms) and Lachschlag—described on hearsay by Oppenheim and which Kinnier Wilson considers to be cataplexy without narcolepsy, thus scoring another point over Dr Adie who judges these to be different conditions.
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In defence of his emerging ideas, Dr Kinnier Wilson identifies the several causes of narcolepsy—traumatic, psychopathological, endocrine, epileptic, toxi-infective, circulatory, tumour-related and those in which no ‘Grundkrankheit’ is found. People do not die of narcolepsy unless there is an underlying cause. In those situations, pathology in the floor of the third ventricle is usually found; and experimental work (for example by Harvey Cushing on hibernating wood-chucks) also directs attention to a sleep centre in that region although it is obvious that sleep involves alteration in many other distributed physiological functions that cannot be ‘localised to grey matter around the back end of one ventricle’. Jabbing again at Dr Adie, Kinnier Wilson politely dismisses Pavlov's work on conditioned reflexes as irrelevant to any understanding of narcolepsy and cataplexy. So what is going on?
The narcolepsies occur only in the daytime, unrelated to nocturnal sleep, and the falling aspect is close to the normal experience of being made ‘helpless with laughter’. The tonelessness is reminiscent of the Sherringtonian ‘knock-out’ blow in which ‘... the lower jaw conveys concussion to the otocyst [and] reduces in a moment a vigorous athlete to an unstrung bulk of flesh whose weight alone determines its attitude’. Dr Kinnier Wilson therefore considers that labyrinthine stimulation may explain the generalized inhibition of muscle-tone in narcolepsy and cataplexy. More generally, any group of nerve-cells can be activated or inhibited by several categories of ascending or descending impulse, any combination of which may result in the same outcome such that one narcoleptic state may closely resemble another although differing markedly in its exciting elements: ‘only in some such way as this can we find a possible interpretation for the diverse narcoleptic symptoms of the psychoneurotic, the post-encephalitic, or the sufferer from cerebral tumour, as well as of the patient whose case is classed as spontaneous or idiopathic’.
Neither Dr Adie nor Kinnier Wilson mention hyposmia in their account of the narcolepsy–cataplexy disorder nor could they predict that a peptide product of the hypothalamus—hypocretin-1 or orexin-A—would emerge as a strong candidate for direct involvement in the pathogenesis. But their struggles with definition and classification, and ideas on mechanism and anatomy, clearly did anticipate contemporary understanding of this curious disorder to which Paul Baier and colleagues now add new details (page 2734).
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