In memoriam of Dr. Yutaka Honda (1929-2009), A Pioneer in Sleep Medicine and Narcolepsy Research

Dr. Yutaka Honda

(1929–2009)

DR. YUTAKA HONDA, A PIONEER IN NARCOLEPSY AND SLEEP MEDICINE, PASSED AWAY SEPTEMBER 1ST, 2009, AGE 79. HIS CONTRIBUTIONS TO NARCOLEPSY research have been immense. He will be sorely missed.

Yutaka Honda was born in Shinjyuku, Tokyo. He graduated from the Tokyo University of Medicine in 1954. Dr. Honda trained as a Psychiatrist, joined the Department of Psychiatry of Tokyo University, and spent two years in Albany, New York as a visiting physician (1961–1963). Dr. Honda became quickly interested by sleep research and sleep disorders. He was among the first to report the now well-established surge in growth hormone in association with slow wave sleep.¹ He also pursued his interest in narcolepsy. He can be credited for starting the first and oldest narcolepsy support group (1967), “Narco-kai,” an association that included 71 patients at its inception. Together with Dr. Yasuro Takahashi, he was the first to report on the efficacy of antidepressant therapies on cataplexy.²

Dr. Honda was first and foremost an astute clinician-scientist. His careful clinical observations led him to rapidly conclude that cataplexy was the most specific symptom to define a homogenous disease entity. This seminal concept has been supported by recent biological observations that almost all patients with clear cataplexy have hypocretin deficiency and are HLA positive.

A major achievement was his report of a tight human leukocyte antigen (HLA)-DR and DQ association in human narcolepsy-cataplexy. What is less well known is that the story was not just a chance finding, but the result of persistence and good science. In 1980, Dr. Honda, together with Dr. Akio Asaka, decided to explore whether narcolepsy was HLA-associated, a study performed in conjunction with the study of many other genetic markers. At the time, most of the HLA studies were performed in the class I region (HLA-A, B, C), as HLA- DR/DQ antigens (also called HLA class II molecules) were poorly characterized. HLA molecules were primarily known as polymorphic proteins involved in transplant rejection, although in 1973 the strong HLA-B27 association with ankylosing spondylitis had been reported, leading to further exploration of the role of HLA in other diseases. Several hundred diseases, autoimmune or infectious, are now known to be HLA associated.

As a result of this first HLA Class I analysis in 58 narcoleptic patients, a striking increase in HLA-Bw35 (χ²=15.6) was found in 1981, suggesting a strong association with the HLA region. A follow-up study with Dr. Takeo Juji in May 1983 (Director of the Tokyo blood transfusion services and HLA specialist) then found that all patients (100%) were HLA DR2, a finding first reported as an abstract³ and later published in a landmark paper with Dr. Juji.⁴ Other investigators, alerted to the finding, quickly discovered a weak HLA-B7 association in Caucasian patients, and an almost 100% association with HLA DR2 in Caucasians. In 1984, multiple groups reported the exact same finding in Canada, England, France, Germany, and USA. Less noted at the time was the observation by Dr. Honda and others that not only were all patients DR2 positive versus 25% of controls, but all patients were also DQ1 positive, an antigen also found in 70% of controls. Subsequent studies found that DQB1*0602, a subtype of DQ1, tightly associated with DR2 in Caucasians and Asians and was the main culprit behind the association.

In 1983 Dr. Honda published one of the finest family studies ever performed in narcolepsy,⁵ suggesting familial clustering in narcolepsy and providing an insightful and still unmatched characterization of the clinical picture of narcolepsy with and without cataplexy. He also introduced the notion of “Essential Hypersomnia Syndrome,” a condition related to both narcolepsy without cataplexy and idiopathic hypersomnia, insisting on the importance of frequent and refreshing naps as one of the major characteristics of narcolepsy and its extended clinical spectrum. As in narcolepsy without cataplexy cases defined per multiple sleep latency testing (MSLT), Dr. Honda found increased HLA-DR2 positivity (40%) in these cases when compared to controls (25%) suggesting heterogeneity, but some pathophysiological overlap.⁶ All these findings have been confirmed, as approximately 15% of cases without cataplexy are now suggested to have hypocretin abnormalities, raising the HLA frequency from 25% in controls to 40% in these borderline cases.

Yutaka Honda never shied away from controversy. Taking care of several hundred narcoleptic patients at the Seiwa Hospital, he become convinced that in his population, DR2 was a prerequisite to define an etiologically homogenous group of patients, most commonly also having cataplexy. In his opinion, narcolepsy should thus be redefined by the presence of HLA-DR2. This led to a clash with the Stanford group, who after testing 13 of their own patients found a clear case with cataplexy, SOREMPs but without DR2.⁷ A decade late, I had the opportunity to take over the care of this particular DR2 negative patient, and like Dr. Honda, I started to doubt the diagnosis. Indeed, the patient had taken on weight, now had severe sleep apnea and was asking for sodium oxybate. Cataplexy was atypical and had not improved significantly with antidepressant therapy. A lumbar puncture was duly performed, revealing undetectable CSF hypocretin-1. Sodium oxybate was used in combination with CPAP with extremely good results. To the best of my knowledge, no Japanese HLA-DR2/DQB1*0602 negative subject has ever been reported with undetectable CSF hypocretin-1. Thus, both Dr. Honda and Dr. Guilleminault, who first reported on this DR2 negative patient, were right. Amazingly, only 5 subjects with low CSF hypocretin, narcolepsy-cataplexy and DQB1*0602 negativity have ever being described worldwide. This indicates that less than 0.5% of cases with narcolepsy/hypocretin deficiency are DQB1*0602 negative. That this particular exceptionally rare patient was identified in a small patient sample at Stanford still baffles me.

Like many great men, Dr. Honda continued to work tirelessly until his death. He leaves behind his wife, 4 children and 6 grandchildren. Researchers worldwide and in Japan will continue his work. Dr. Makoto Honda, his son, is pursuing research on narcolepsy and his clinical work at Seiwa Hospital. Dr. Katsushi Tokunaga, Professor of Human Genetics at the University of Tokyo, is also working with Dr. Honda and others to further our understanding of narcolepsy through genetic association studies.^8,9 Together with Dr. Takashi Kanbayashi and Tetsuo Shimizu in Akita, among others, narcolepsy research is vibrant in Japan, and it still reaches to Stanford, where the essential contributions of Dr. Seji Nishino, a native Japanese now at Stanford, who first reported low CSF hypocretin in human narcolepsy.¹⁰

Much of the work of Dr. Yutaka Honda is summarized in his 1988 book, HLA and narcolepsy.¹¹ It is telling that he passed away only 3 months after Jean Dausset, who received the Nobel Prize in Physiology or Medicine in 1980 along with Baruj Benacerraf and George Davis Snell for the discovery and characterization of the genes making the major histocompatibility complex, also called HLA. Farewell, Dr. Honda, and thank you for the many contributions and inspirations'