Bedřich Roth, His Life’s Work and the 35th anniversary of the book “Narcolepsy and Hypersomnia”

*First published September 2015

I would like to take this opportunity during Idiopathic Hypersomnia Awareness Week 2015 to acknowledge the 35th anniversary of the classic text Narcolepsy and Hypersomnia (1980 S. Karger; NY, NY) and to pay tribute to the extraordinary contribution to neurological sleep research by renowned neurologist Bedřich Roth.

The book Narcolepsy and Hypersomnia was published in English in 1980 and is an accumulation of Roth’s work spanning more than 30 years. In fact, it is officially Roth’s second monograph on narcolepsy and hypersomnia. The first volume was published 23 years earlier in 1957 - 'Narcolepsy and hypersomnia from the aspect of physiology of sleep' [1] making Roth’s work the first in the area of modern day era Narcolepsy and Hypersomnia research. So, it is difficult to celebrate the 35th anniversary of the publication of the book Narcolepsy and Hypersomnia without documenting the history that led up to the writing of it including the many significant contributions that Bedřich Roth made to sleep research.

Bedřich Roth Roth was a renowned neurologist responsible for identifying and naming Idiopathic Hypersomnia. His seminal works over many years on narcolepsy and idiopathic hypersomnia have left an indelible mark on the history of sleep medicine. Roth was born in Slovakia into a Jewish family on 23rd March 1919. In 1937 he started studying medicine in Prague Czechoslovakia. After the outbreak of World War II, he was detained for some time in a concentration camp in Slovakia where he was forced to do hard labour. Roth, fortunately, escaped the camp and fled to Switzerland where he resumed his medical studies. After the liberation of France, he made his way to Paris where he completed his medical degree in 1946. After a short time working in Paris, he returned to Czechoslovakia. Roth first worked in the neurology department at the hospital of Hradec Králové and then in 1949 he moved on to the Department of Neurology at Charles University. Despite the adversities of the political and economic situation at the time not experienced by western countries, Roth successfully developed the world’s first sleep laboratory. This is where he spent the next 40 years working as a physician, teacher and scientist until his death in 1989.

Early years 1950-59

Life in Communist-ruled Czechoslovakia during this time meant every aspect of Roth's work was made difficult. He received little funding, had few resources and even required permission from the Soviet-controlled government to attend congresses and meetings to present his findings and to participate in discussions with regards to his own work and that of others. Yet despite these extreme adversaries Roth is credited as being a true pioneer in the area of narcolepsy and hypersomnia due to the valuable epidemiological data he compiled on these disorders [2] Many of his peers regard the book Narcolepsy and Hypersomnia as a true “classic” [2,3]. Accomplished narcolepsy researcher Dr Mignot acknowledges that Roth is responsible for the first careful epidemiological studies of narcolepsy and idiopathic hypersomnia and that Roth's work led to the classic diagnostic "narcoleptic tetrad" ie: cataplexy, sleep paralysis, hypnagogic hallucinations, and excessive daytime sleepiness that is still used today [4].

In a discussion with Dr Roger Broughton while researching for this tribute he said that the book Narcolepsy and Hypersomnia “included not only his remarkable progress having worked on the topic for over a quarter of a century but also citation of the world-wide publications on these interesting diseases. Indeed, it made clear that Professor Roth was the first neurologist to specialise more or less exclusively in the area of narcolepsy and hypersomnia. The earliest contributors elsewhere came mainly from Stanford, California, Montpellier France and Bologna, Italy whose first publications were not until the early to mid-1960 ’s. Moreover, Professor Roth clinical experience in the field was vastly greater than that in these other centres. His case series of persons with narcolepsy and cataplexy and of others with symptomatic hypersomnia each ran into the many hundreds of patients a significant proportion of whom he had followed, often with Professor Nevismalova, for several decades. He also had a significant series of patients with idiopathic hypersomnia and a good number of others with recurrent hypersomnia (Klein-Levin syndrome, bipolar disorder and menstrual hypersomnia) which was also unique at the time of his book”.

Prior to Roth’s first monograph in 1957 his work included a number of studies

where he recognised and recorded the clinical differences between narcolepsy and hypersomnia [5,6,7,8,9,10]. This included an early very detailed article on the EEG in narcolepsy published in 1952 [5]. Sleep drunkenness, a typical feature of idiopathic hypersomnia was first recorded in his 1956 paper Sleep Drunkenness and Sleep Paralysis [9]. It was during this time that Roth started to realise that patients with hypersomnia but without the classic clinical features of narcolepsy and without any other explanation for their symptoms were suffering from an independent clinical entity.

Narkolepsie a Hypersomnie S. Hlediska Fysiologie Spanku – 1957

Years of careful and meticulous study of a large number of patients led to Roth’s first monograph; Narcolepsy and hypersomnia from the aspect of physiology of sleep (Narkolepsie a Hypersomnie S. Hlediska Fysiologie Spanku – 1957). This monograph was described in the book Sleepiness: Causes, Consequences and Treatment as “a master book” [11]. It is very significant as it documented the early work Roth had been doing almost exclusively over the previous six years identifying the very distinct differences between patients with narcolepsy and those with hypersomnia. The 1957 monograph was based upon a large number of personally observed cases. The series included 248 patients and proposed to differentiate patients with narcolepsy (155) from patients with hypersomnia (93). Roth identified several subgroups of patients. Among the narcoleptic patients, he distinguished patients with essential narcolepsy (194), including patients with narcolepsy with cataplexy (70) and patients with narcolepsy without cataplexy (34), from patients with symptomatic narcolepsy (51). Among the patients with hypersomnia, he separated those with functional hypersomnia including patients with neuroses (27) and patients with vegetative dystonia (23), patients with organic basis (29), and patients with independent post-dormital drunkenness (14) later referred to as the polysymptomatic form of idiopathic hypersomnia (1976).

1960’s and beyond

By now it was clear to Roth that the subgroups of hypersomnia patients including those with idiopathic hypersomnia did not have narcolepsy. This identification was later confirmed by other researchers including Dement in the 1966 paper “The nature of the narcoleptic sleep attack“ [12] “Subjects with excessive daytime sleepiness but no cataplexy, sleep paralysis or sleep onset REM periods do not have narcolepsy and should be relegated to another diagnostic category”.

Roth’s work during the 1960’s and 70’s included many great professional achievements and collaborations. In 1965 Roth presented one of the first papers written on the polygraphic study of narcolepsy and hypersomnia [13]. In 1969 Roth with Bruhova published a study on REM and NREM sleep in these disorders [14] and in the same year they published one of the first papers using polysomnogram focusing on dreams in narcolepsy and hypersomnia [15,16]. Another important study during this time was Roth’s first collaboration with Allan Rechtschaffen, Nocturnal sleep of hypersomniacs [17].

In 1967 Roth was invited to join a committee of investigators with experience in scoring sleep, led by Allan Rechtschaffen and Anthony Kales. The aim of the committee was to develop a terminology and scoring system to be universally used by sleep specialists. They developed the first consensus-based guidelines for staging and scoring sleep in human subjects, “A manual of standardised terminology, techniques and scoring system for sleep stages of human subjects” commonly called R&K or Rechtschaffen and Kales [18].

Roth continued to make significant contributions to sleep research throughout the 70’s and 80’s right up until the time of his death in 1989. In 1972 the European Sleep Research Society was established in Basel Switzerland where Roth was one of the founding members. Collaborations in 1972 and 73 with Nevšímalová resulted in papers on the familial tendency of narcolepsy and idiopathic hypersomnia. These papers were significant because up until this time a genetic connection had not been explored in these disorders [19,20]. Another collaboration with Allan Rechtschaffen, Hypersomnia with Sleep Drunkenness was published in 1972 [21]. Other collaborations resulted in further studies with PSG in narcolepsy and idiopathic hypersomnia [22] and investigations into the psychological and socioeconomic impact of idiopathic hypersomnia on the life of the patient were written with Broughton and Nevšímalová and published in 1975 and 1978 [23,24]. Roth’s most cited paper “Narcolepsy and hypersomnia: review and classification of 642 personally observed cases” was published in 1976 [25] and Idiopathic Hypersomnia: a study of 187 personally observed cases was published in 1978 [26]. Roth’s years of extensive research that led to his description of idiopathic hypersomnia as a separate disease entity was accepted and included in the first ICSD, Diagnostic Classification of Sleep and Arousal Disorders in 1979 [27]. As the world authority on idiopathic hypersomnia, Roth's work through the 70's and early 80's included writing papers, book chapters, collaborations, presenting papers and chairing workshops at international congresses with a particular focus on educating others on the clinical picture and definition of idiopathic hypersomnia [28,29,30].

In a fitting end to an outstanding body of work in 1986, Roth's group in collaboration with the Max Planck Institute in Germany was one of the first to discover an association between HLA DR2 and Narcolepsy [31].

After many requests from his peers to translate his 1957 monograph into English Roth spent a considerable amount of time with Roger Broughton writing Narcolepsy and Hypersomnia. The “blue book” as it was sometimes known was published in 1980 [32].

Narcolepsy and Hypersomnia (1980 S. Karger; NY, NY)

“Pathological states of inappropriate or excessive sleep – narcolepsy and hypersomnia – are very frequent and cause the afflicted subjects considerable inconvenience and distress. The study of these hitherto inadequately elucidated conditions can help us to a better understanding of them and thus lead to more accurate diagnosis and to more effective treatment. The clinical, electroencephalographic and polygraphic investigation of these syndromes can also furnish valuable information concerning the physiology of both sleep and wakefulness” Bedřich Roth – Preface, Narcolepsy and Hypersomnia 1980.

Roth also explains in the preface of Narcolepsy and Hypersomnia that “findings obtained in the initial 251 patients studied over a period of six years were summarized in a monograph entitled “Narcolepsy and hypersomnia from the aspect of physiology of sleep”, published in Czech in 1957, which contained extensive Russian and English summaries. A German translation was published in 1962. Although widely cited in international literature, the full text of this book was unfortunately inaccessible to readers not knowing Czech or German. Consequently, I was frequently asked by many colleagues to publish an English translation. During the past 20 years, however, there have been such scientific advances in the fields of the physiology and the pathology of sleep that it has proven necessary to rewrite the book in its entirety, I hesitated for a long time before deciding to do so, as I was well aware of the many difficulties involved. But I believe that the clinical experience acquired and the findings obtained during 26 years of systematic study of these problems could be of value to the medical and scientific public and so decided to proceed…”

The book Narcolepsy and Hypersomnia is based on 30 years of Roth’s work on these disorders including the data from his study published in 1976 [25]. This study included patients with either narcolepsy (368) or hypersomnia (274) that Roth personally examined and observed at the Charles University Neurology Clinic in Prague between 1949 and 1975. Many patients were studied for 15 to 20 years, some for as much as 25 years or more, all with meticulous follow up. Each patient was examined clinically and by EEG, many of them repeatedly and as of 1966 each of the patients was also examined via polysomnograph (PSG). This series of narcolepsy and hypersomnia patients remains the largest ever studied making Roth’s epidemiological studies on narcolepsy and idiopathic hypersomnia unsurpassed. It contributed to the literature the largest most meticulously followed series of all of the then known neurological sleep disorders and provided new information on the pathophysiology and genetics of these disorders [33].

Roth made significant contributions to the advancement of the modern day identification of narcolepsy. This is documented in various papers and publications including both of his monographs. For this tribute, we will be focusing primarily on the hypersomnias, in particular, idiopathic hypersomnia.

368 narcolepsy cases were classified according to their aetiology, clinical form and path physiological mechanisms of origin. The 274 hypersomnia cases were divided into symptomatic and functional groups and then further distinguished by "short cycle hypersomnia" and "long cycle hypersomnia”. Roth’s first task was “to distinguish the symptomatic hypersomnias determined by some known underlying disease or organic brain condition, or metabolic affection or intoxication from the functional hypersomnias, in which pathological sleep is not induced by other known disease” SYMPTOMATIC HYPERSOMNIA:

Of the 274 patients with hypersomnia 61 patients were identified as having hypersomnia caused by a known disease or medical condition. Roth noted that organic brain conditions including head trauma, bacterial and viral infections, vascular diseases and tumour were the most frequent causes of hypersomnia. And “amongst metabolic conditions, hepatic and renal diseases” were also common causes. Drugs and medications also “represented another frequent aetiology”. The clinical picture including the severity and intensity of the sleepiness in symptomatic hypersomnia varies depending on the underlying cause. “Sometimes sleepiness can be mild and the patient can easily be awakened…at other times his sleep may be very deep so that it is very difficult to wake him.” The course of hypersomnia also depends on the evolution of the underlying condition. “In favourable cases, the patient may recover and all the symptoms may disappear… Sometimes the underlying condition regresses, but irreversible changes have occurred in the brain which causes the hypersomnia to become chronic”.

FUNCTIONAL HYPERSOMNIA: The term “functional hypersomnia” includes the hypersomnias not caused by other sleep disorders or medical or mental disorders. Of the 213 patients with functional hypersomnia Roth further divided them into short cycle (191) and long cycle (22) functional hypersomnia. The difference in these cycles is the length of the sleep periods and the time between episodes. Long Cycle Functional Hypersomnia (periodic hypersomnia): Long cycle hypersomnia also referred to as periodic hypersomnia is comparably rare to the short cycle hypersomnias. Roth distinguished two forms of long cycle functional hypersomnia, monosymptomatic (15) and polysymptomatic (6). In both forms “..the condition is characterised by states of excessive sleep lasting from one day to several weeks” patients then usually experience periods where they are completely symptom free “lasting from one to several months or even years As a rule, the longer the duration of the attacks, the longer the intervals between them.” In the polysymptomatic form (Kleine- Levin Syndrome) periods of hypersomnia can also be “accompanied by polyphagia (excessive eating/increased appetite) and mental disturbances”. Various degrees of behavioural or cognitive disturbances and hypersexuality are also associated with this form of recurrent hypersomnia. Short Cycle Functional Hypersomnia: Short cycle functional hypersomnia is more common than long cycle. In Roth’s series, it included idiopathic hypersomnia (monosymptomatic 71 and polysymptomatic 103), neurotic hypersomnia (5) and hypersomnia associated with sleep apnea (12). Hypersomnia with sleep apnea: Unlike in patients with idiopathic hypersomnia where patients tend to have a greater capacity to stay awake despite usually constant excessive sleepiness Roth noted that patients with sleep apnea are usually unable to overcome sleepiness and as a result typically nod off frequently, often in inappropriate circumstances throughout the day. “Most patients are sleepy for a large portion of the day, and, in severe cases, for virtually the entire day. They are often unable to overcome their sleepiness and will fall asleep against their will, even in the most unsuitable situations. Patients in my own series have stated that they fell asleep while standing and walking, while eating or working, during conversation, while driving a car, in the toilet, and in other inappropriate circumstances. These episodes of excessive daytime sleep are usually of short duration (the patient sleeps only a few minutes), but their frequency is high, and short periods of sleep often alternate with equally short periods of wakefulness.” It was also noted that some patients have longer daytime sleep episodes of around 30-60 minutes. Duration of sleep over a 24 hour period is greater than normal however due to constant respiratory disturbances the sleep is light and non-restorative. Patients wake up feeling unrefreshed and morning headaches are common. Roth quoted several studies including one of his own that show sleep apnea also occurs in narcolepsy with cataplexy. Sleep apnea, however, does not occur in idiopathic hypersomnia. The concept of the CPAP (Continuous Positive Airway Pressure) machine was discovered by Australian respiratory physician, Colin Sullivan in June 1980 [34]. Since then various oral devices have also become available for the treatment of sleep apnea. Unfortunately, despite full compliance and effective treatment of apnea events with either CPAP or oral device sleep apnea patients can still experience excessive daytime sleepiness, this is referred to as “residual sleepiness” [35,36,37,38,39]. There are a number of possible causes for residual sleepiness including depression, obesity which in itself is associated with sleepiness and in some patients a natural vulnerability to sleep deprivation or sleep disturbance has also been found to contribute to residual sleepiness [35,36,38]​. Therefore despite effective treatment of apnea events a number of patients with treated sleep apnea may still experience what Roth described as “hypersomnia with sleep apnea”. It should also be noted that CPAP has limited effectiveness in reducing sleepiness in milder sleep apnea [39]. More awareness of this fact and of residual sleepiness is needed to prevent misdiagnosis of idiopathic hypersomnia in these patients. Idiopathic Hypersomnia: The clinical description and neurophysiological characterisation of idiopathic hypersomnia was made by Bedrich Roth in a series of papers published over the course or more than 30 years. The book Narcolepsy and Hypersomnia is an accumulation of all of that work which is why it was considered a valuable text by clinicians and scientists.“Study of the functional hypersomnia patients showed that over 80% presented a highly uniform clinical picture. These were all short cycle hypersomnia manifested by daily diurnal sleep episodes lasting up to several hours. The condition develops most often during puberty and then remains stationary. The symptoms are permanent. A large number of these patients have now been followed for 10 to 20 years or more. With my colleague Nevsimalova (Nevsimalova and Roth 1972, Nevsimalova 1973) we have found a heredofamilial pattern in over 30% of all cases. They represent an independent nosological entity, for which I have suggested the term “Idiopathic Hypersomnia” [27]. Roth identified two variants of Idiopathic Hypersomnia, a monosymptomatic and polysymptomatic form. In his series, the monosymptomatic form manifested in daytime hypersomnia alone. However, studies have shown that patients with monosymptomatic hypersomnia can also experience long nocturnal sleep. The polysymptomatic form also includes daytime hypersomnia. However, it’s most striking features are exceptionally deep and protracted (long) nocturnal sleep and sleep drunkenness on arousal. Patients with polysymptomatic hypersomnia can find it extremely difficult to wake from sleep. Sleep drunkenness was first identified by Roth in 1956, however, the most significant paper was published in 1972 [9,21]. Clinical picture: Excessive daytime and nocturnal sleep with significant daytime sleepiness are the major symptoms of idiopathic hypersomnia with sleep drunkenness and extreme difficulty waking from sleep typical in the polysymptomatic form. “The excessive daytime sleepiness is not as irresistible as it is in narcolepsy. The patient usually does not fall asleep against his will while engaged in some activity, and especially not in circumstances inappropriate for sleep such as during a conversation, while eating or while riding a bicycle. He is obliged, however, to fight sleepiness for a large part of the day and eventually must lie down and go to sleep; subjects may even fall asleep sitting up…As a rule, these patients are able to resist sleep for the whole of their working day. When they get home, however, they simply have to lie down and sleep. The duration of the periods of daytime sleep varies from about 30 minutes to as much as 5-8 hours. If the patient goes to sleep in the afternoon, he may not wake up again before the following morning. Some patients will even sleep for a whole weekend – from Friday afternoon until Monday morning – virtually without a break. In addition to attacks of excessive sleep, patients complain of long periods of intense sleepiness, which in some cases is more or less permanent.” “Excessive daytime and nocturnal sleep with significant daytime sleepiness are the major symptoms of idiopathic hypersomnia with sleep drunkenness typical in the polysymptomatic form. The excessive daytime sleepiness is not as irresistible as it is in narcolepsy. The patient usually does not fall asleep against his will while engaged in some activity, and especially not in circumstances inappropriate for sleep such as during a conversation, while eating or while riding a bicycle. He is obliged, however, to fight sleepiness for a large part of the day and eventually must lie down and go to sleep; subjects may even fall asleep sitting up…As a rule, these patients are able to resist sleep for the whole of their working day. When they get home, however, they simply, have to lie down and sleep. The duration of the periods of daytime sleep varies from about 30 minutes to as much as 5-8 hours. If the patient goes to sleep in the afternoon, he may not wake up again before the following morning. Some patients will even sleep for a whole weekend – from Friday afternoon until Monday morning – virtually without a break.”