Liza Ashbrook, MD February 10, 2017 Recent Advances in Neurology Patient 1 This 70-year-old man has restless leg syndrome (RLS), a clinical diagnosis. RLS affects 5-10% of the adult population of European ancestry, though likely only 2-3% come to clinical attention. The cause of RLS is not clear but it is associated with low central iron stores. This is supported by evidence from autopsy studies, CSF analysis, gradient echo MRI and transcranial ultrasound. A family history of RLS is reported in 63-92% of individuals suggesting a strong genetic component as well. RLS is typically separated into intermittent symptoms, defined by fewer than twice/week over a year and chronic symptoms. When symptoms are only bothersome intermittently, such as a long plane flight, medications such as carbidopa/levodopa 25/100 can be very effective, however use more than twice weekly can lead to augmentation. Benzodiazepines and hypnotics are also recommended only for as needed use. Periodic limb movements (PLMs) occur in up to 80% of patients with RLS and are diagnosed by polysomnography. These are stereotyped kicking movements and patients are usually unaware of their presence though bed partners may complain. A small subset of those with PLMs are thought to have periodic leg movement disorder (PLMD), defined by PLMs causing either night time or daytime impairment. Other causes of insomnia and hypersomnia must be ruled out and those with RLS cannot have a diagnosis of PLMD. PLMs are of unclear clinical significance and may be a part of normal aging or an epiphenomenon. RLS and PLMs are commonly confused. RLS is a sensation during wake in contrast to PLMs which are a movement during sleep. References 1. 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. New England Journal of Medicine. 2014 Feb 13;370(7):621-31. 2. American Academy of Sleep Medicine. International classification of sleep disorders, 3rd ed. Darien, IL: American Academy of Sleep Medicine, 2014. 3. Aurora RN, Kristo DA, Bista SR, Rowley JA. Zak RS; Casey KR; Lamm CI; Tracy SL; Rosenberg RS. The treatment of restless legs syndrome and periodic limb movement disorder in adults—an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses. Sleep. 2012;35(8):1039-62. 4. Cho YW, Allen RP, Earley CJ. Lower molecular weight intravenous iron dextran for restless legs syndrome. Sleep medicine. 2013 Mar 31;14(3):274-7. 5. Garcia-Borreguero D, Silber MH, Winkelman JW, Högl B, Bainbridge J, Buchfuhrer M, Hadjigeorgiou G, Inoue Y, Manconi M, Oertel W, Ondo W. Guidelines for the first- line treatment of restless legs syndrome/Willis–Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Medicine. 2016 May 31;21:1-1. 6. Howell MJ, Schenck CH. Restless nocturnal eating: a common feature of Willis- Ekbom Syndrome (RLS). J Clin Sleep Med. 2012;8(4):413-419.
7. Silver N, Allen RP, Senerth J, Earley CJ. A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome. Sleep medicine. 2011 May 31;12(5):440-4. 8. Trenkwalder C, Beneš H, Grote L, García-Borreguero D, Högl B, Hopp M, Bosse B, Oksche A, Reimer K, Winkelmann J, Allen RP. Prolonged release oxycodone– naloxone for treatment of severe restless legs syndrome after failure of previous treatment: a double-blind, randomised, placebo-controlled trial with an open-label extension. The Lancet Neurology. 2013 Dec 31;12(12):1141-50. Patient 2: This 20-year-old woman has delayed sleep-wake phase disorder (DSPD). DSPD is far more common in adolescents but can last throughout life. This patient reports daytime sleepiness which may be due to not sleeping aligned with her internal clock, but can also be related to several other factors including excessive time in bed, mood disorder, or another sleep disorder such as obstructive sleep apnea. We focused in the case presentation on how to use melatonin and light as treatment. Other interventions that are important for this patient include using the bed for sleep and sex only, going to bed only when tired, maintaining a consistent wake time (unless actively working with tools discussed to change sleep schedule) and getting out of bed when not sleeping for about 20 minutes. Management of co-morbid considers such as migraine and chronic pain should be simultaneously addressed for best results. Melatonin phase response curve summary: • To advance the circadian clock (sleepier earlier) give 2-8 hours before bedtime • To maximally advance give 0.5mg 5 hours before bedtime • To delay the circadian clock (sleepier later) give at core body temperature minimum (about 2 hours before wake) to midday • To maximally delay give 0.5mg within 4 hours after habitual wake • Melatonin taken around bedtime until 3 hours after mid sleep midpoint has minimal effect on the circadian clock Light phase response curve summary: • To advance the circadian clock (sleepier earlier) use bright light shortly after the core body temperature minimum (typically two hours before awakening) until early afternoon • To delay the circadian clock (sleepier later) use bright light at time of dim light melatonin onset (typically two hours before bedtime) until two hours before wake • The most effective duration is 6.7 hours of bright white though 60 minutes will provide about 40% of the shifting power References: 1. Auger RR, Burgess HJ, Emens JS, Deriy LV, Thomas SM, Sharkey KM. Clinical practice guideline for the treatment of intrinsic circadian rhythm sleep-wake disorders: advanced sleep-wake phase disorder (ASWPD), delayed sleep-wake phase disorder (DSWPD), non-24-hour sleep-wake rhythm disorder (N24SWD), and
irregular sleep-wake rhythm disorder (ISWRD). An update for 2015: an American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2015 Oct 15;11(10):1199-236. 2. Burgess HJ, Revell VL, Molina TA, Eastman CI. Human phase response curves to three days of daily melatonin: 0.5 mg versus 3.0 mg. The Journal of Clinical Endocrinology & Metabolism. 2010 Jul;95(7):3325-31. 3. Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E, Rollag MD. Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor. Journal of Neuroscience. 2001 Aug 15;21(16):6405-12. 4. Khalsa SB, Jewett ME, Cajochen C, Czeisler CA. A phase response curve to single bright light pulses in human subjects. The Journal of physiology. 2003 Jun 1;549(3):945-52. 5. Magee M, Marbas EM, Wright KP, Rajaratnam SM, Broussard JL. Diagnosis, cause, and treatment approaches for delayed sleep-wake phase disorder. Sleep Medicine Clinics. 2016 Sep 30;11(3):389-401. 6. Saxvig IW, Wilhelmsen-Langeland A, Pallesen S, Vedaa Ø, Nordhus IH, Bjorvatn B. A randomized controlled trial with bright light and melatonin for delayed sleep phase disorder: effects on subjective and objective sleep. Chronobiology international. 2014 Feb 1;31(1):72-86. 7. St Hilaire MA, Gooley JJ, Khalsa SB, Kronauer RE, Czeisler CA, Lockley SW. Human phase response curve to a 1 h pulse of bright white light. The Journal of physiology. 2012 Jul 1;590(13):3035-45.
Jenny Clarke, MD, MPH Feb 10, 2017 Patient 1: Peri-Ictal Imaging Changes in Brain Tumor Patients With increased frequency of brain imaging in the setting of acute neurological changes, it has become increasingly appreciated within the neurology community that there can be acute peri-ictal MRI changes that can mimic other pathology 1 , including stroke 2 or recurrent tumor 3 . This can be a particular concern in patients with a known history of glioma, for whom a an abrupt increase in seizure activity may herald tumor recurrence. While a high index of suspicion should be maintained for the possibility of recurrent tumor as a trigger for breakthrough seizures, it is now recognized that a pattern of focal cortical/leptomeningeal enhancement likely represents peri-ictal changes rather than tumor progression. T2/FLAIR imaging, diffusion-weighted imaging, and perfusion imaging findings can all be variable in the peri-ictal setting, adding to the challenge of recognizing this uncommon entity. References: 1 Cole AJ: Status Epilepticus and Periictal Imaging. Epilepsia 45:72-77, 2004 2 Lansberg MG, O’Brien MW, Norbash AM, et al : MRI abnormalities associated with partial status epilepticus. Neurology 52:1021, 1999 3 Rheims S, Ricard D, van den Bent M, et al: Peri-ictal pseudoprogression in patients with brain tumor. Neuro-Oncology 13:775-782, 2011
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