The Disappearing Story: Recapping Sleep Research
The biggest news in sleep this year may have been the story that wasn’t
What were the biggest stories in sleep care this year?
Erik K. St. Louis, MD: In sleep neurology in 2014, the biggest or at least most provocative story may have actually been a paper retraction. The Mellins/Mignot lab at Stanford had reported in December 20131 that narcolepsy appeared to be associated with a T-cell mediated autoimmune response involving molecular mimicry between the pandemic H1N1 virus and hypocretin, but then later retracted this report when the labs could not reproduce some original results.2,3 Nonetheless, the strong epidemiologic links between H1N1 infection and vaccination as potential narcolepsy triggering factors from Europe and Asia saw further expanded evidence last year.
Sabater and the Barcelona group also reported a novel parasomnia and neurological disorder associated with the autoantibody IgLON5, characterized by prominently disturbed NREM sleep architecture, prominent sleep disordered breathing including inspiratory stridor and sleep apnea, abnormal rapid periodic limb movements, oneric behaviors, and REM sleep behavior disorder, that suggested a possible link with neurodegeneration by evidence of abnormal tau deposits in the brainstem and hypothalamus in autopsied cases.4
Another important clinical advance in the field was the publication of a pivotal clinical trial demonstrating the efficacy of pregabalin, an alpha-2-delta ligand agonist, with superior clinical efficacy and lower tendency toward augmentation at one-year follow-up in restless legs syndrome/ Willis-Ekbom disease.5
What were some of the important overlooked stories?
Dr. St. Louis: Of the above, the IgLON5 paper is perhaps not as widely known, despite its impact for the field; subspecialists are aware of it, but the general sleep clinician and neurologist may not be. Another crucial paper from the same group also further established the growing recognition between REM sleep behavior disorder (RBD) and synucleinopathy neurodegeneration (with risk of evolving conditions, such as Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy). Alex Iranzo and colleagues from Barcelona found during longitudinal follow-up of their cohort of patients with idopathic RBD presenting to their sleep clinic that the risk of evolving a synucleinopathy was 33 percent at five years, 75 percent at 10 years, and 91 percent at 15-year follow-up.6
What do you think 2015 has in store for sleep care?
Dr. St. Louis: About the biggest trend in our field right now is the growing transition from in-laboratory polysomnography to home-based studies, at least for the indication of sleep-disordered breathing. This trend started on the coasts, driven by cost and reimbursement forces, but is now spreading across the country gradually. Accommodating to this trend will require further research to ensure best practices for determining which patients need to still be studied in a sleep lab environment. It will likely impact the field by an increasing (rather than decreasing) need for well-trained sleep specialists (and especially neurologists!) to interpret more complex studies as reimbursement forces increasingly limit application of sleep laboratory studies. This is because in-lab polysomnography will increasingly involve sicker and more complex patients with more neurological, cardiovascular, and pulmonary co-morbidities.
Another trend of particular interest and relevance to neurologists is the growing recognition of the association between REM sleep behavior disorder and synucleinopathy neurodegeneration. This should interest neurologists and motivate them to acquire familiarity and training in sleep medicine to provide optimal diagnostic and prognostic information to their patients, and hopefully one day, to help with the timely application of neuroprotective therapies.
Carl Bazil, MD: There is a new drug approved—suvorexant— but I understand it won’t be in pharmacies until early 2015. It’s much anticipated in the sleep community. What we are really looking forward to in sleep medicine from my perspective is awareness of sleep disorders; too many people (and doctors!) don’t take sleep seriously. It’s especially important in neurology, where the brain can’t function well without sleep, particularly when there are other problems interfering with cognition.
Suvorexant makes a lot of sense in terms of its mechanism: it seems to act directly on the waking center of the brain to encourage sleep, and therefore could have fewer side effects. But mechanism doesn’t necessarily translate into a better treatment. Although the studies do show it promotes sleep, there are no comparisons to existing drugs like zolpidem (Ambien). I suspect it will initially be used where existing treatments don’t work or have problems; as we get more real world experience it may become more popular.
The FDA is, I think, rather nervous about a new sleep drug, given the recent reports of residual drowsiness in women on zolpidem, and possibly some other areas such as mood disorders and memory problems linked to some sleep drugs. I have questions about the latter, but I think that’s why the FDA is being more cautious about warnings, not necessarily that this is a more powerful (or dangerous) drug.
Erik K. St. Louis, MD is Head of Sleep Neurology at the Mayo Clinic and Foundation and Associate Professor of Neurology at the Mayo Clinic College of Medicine.
Carl Bazil, MD, PhD is Director of Division of Epilepsy and Sleep and Caitlin Tynan Doyle Professor of Neurology at Columbia.
- De la Herrán-Arita AK, Kornum BR, Mahlios J, et al. CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy. Sci Transl Med. 2013 Dec 18;5(216):216ra176.
- De la Herrán-Arita AK, Kornum BR, Mahlios J, Jiang W, Lin L, Hou T, Macaubas C, Einen M, Plazzi G, Crowe C, Newell EW, Davis MM, Mellins ED, Mignot E. Retraction of the research article: “CD4⁺ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy”. Sci Transl Med. 2014 Jul 30;6(247):247rt1.
- Underwood E. Immunology. Key narcolepsy-influenza vaccine findings retracted. Science. 2014 Aug 1;345(6196):498.
- Sabater L, Gaig C, Gelpi E, Bataller L, Lewerenz J, Torres-Vega E, Contreras A, Giometto B, Compta Y, Embid C, Vilaseca I, Iranzo A, Santamaría J, Dalmau J, Graus F. A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study. Lancet Neurol. 2014 Jun;13(6):575-86.
- Allen RP, Chen C, Garcia-Borreguero D, Polo O, DuBrava S, Miceli J, Knapp L, Winkelman JW. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med. 2014 Feb 13;370(7):621-31.
- Iranzo A, Fernández-Arcos A, Tolosa E, et al. Neurodegenerative disorder risk in idiopathic REM sleep behavior disorder: study in 174 patients. PLoS One. 2014 Feb 26;9(2):e89741.