pii: jc-00436-13 http://dx.doi.org/10.5664/jcsm.4210
Levothyroxine Improves Subjective Sleepiness in a Euthyroid Patient with Narcolepsy without Cataplexy Danielle L. Sobol; Andrew R. Spector, M.D.
CASE REPORTS
Duke University School of Medicine, Durham, NC
Objective: We discuss the use of levothyroxine for excessive daytime sleepiness (EDS) and prolonged nocturnal sleep time in a euthyroid patient with narcolepsy. Methods: After failure of fi rst-line narcolepsy treatments, a 48-year-old female began levothyroxine (25 mcg/day). After 12 weeks of treatment, the patient was evaluated for improvement in total sleep time and subjective daytime sleepiness assessed by Epworth Sleepiness Scale (ESS). Results: At baseline, ESS score was 16 and total sleep time
T
he primary goal in treating narcolepsy without cataplexy is improving excessive daytime sleepiness (EDS). Current narcolepsy medications include amphetamines, methylphenidate, modafinil/armodafinil, and sodium oxybate.1 Some patients do not tolerate these medications due to side effects, including increased blood pressure, gastrointestinal disturbance, headaches, and anxiety. A potential new treatment for EDS due to narcolepsy is levothyroxine (Synthroid, Levothroid). Levothyroxine is a synthetic form of thyroxine, T4, an active thyroid hormone. While thyroid medications are common management for fatigue in hypothyroid patients, their role in euthyroid patients with EDS due to narcolepsy is unknown. Studies in narcoleptic canines show thyroid releasing hormone analogs to significantly increase wakefulness, reduce sleep time, and decrease cataplexy.2,3 To our knowledge, no study has examined levothyroxine for narcolepsy; however, levothyroxine has been shown to significantly decrease EDS and mean sleep time in idiopathic hypersomnia (IH).4 The proposed mechanisms include hypothalamic-pituitary-thyroid axis alteration and/or activation of TSH, TRH, or T3 receptors in the brain’s arousal-promoting system.4
REPORT OF CASE We present a 48-year-old female with an 11-year history of prolonged nocturnal sleep time and severe daytime somnolence requiring multiple naps. She denied cataplectic symptoms such as head drop and atonia. Her initial evaluation took place in another state, and she came to our attention to establish care with a sleep clinic. Her records indicated an initial multiple sleep latency test (MSLT) with mean sleep latency of 6 min without sleep onset REM periods (SOREMPs). She was diagnosed with IH with long sleep time. She tried multiple stimulants including methylphenidate, modafinil, armodafinil, lisdexamfetamine dimesylate, and dextroamphetamine/amphetamine. All stimulants exacerbated 1231
averaged 16 h/day. After 12 weeks, ESS was 13 and reported total sleep time was 13 h/day. Conclusions: Levothyroxine improved EDS and total sleep time in a euthyroid patient with narcolepsy without cataplexy after 12 weeks without side effects. Keywords: narcolepsy, levothyroxine, excessive daytime sleepiness Citation: Sobol DL, Spector AR. Levothyroxine improves subjective sleepiness in a euthyroid patient with narcolepsy without cataplexy. J Clin Sleep Med 2014;10(11):1231-1232.
her underlying anxiety and were intolerable. She was also prescribed fluoxetine, citalopram, bupropion, and desvenlafaxine for concerns that underlying depression caused her sleepiness, but these had no effect on her sleep. Her past medical history was significant for elevated Epstein-Barr virus antibody titers, anxiety, B12 deficiency, GERD, asthma, and hypertension. Medications upon presentation included albuterol-ipratropium, vitamin B12, desogestrel-ethinyl estradiol, dicyclomine, montelukast, and omeprazole. Physical exam demonstrated no focal neurological deficits and no cataplectic symptoms. A repeat polysomnogram with MSLT (Table 1) performed prior to her first visit demonstrated an apnea-hypopnea index of 2/h, total sleep time of 400 min, 85% sleep efficiency, and no SOREMP. Her MSLT showed a mean sleep latency of 3.4 min and 3 SOREMPs in 4 naps without notable sleep paralysis. At the time of her initial sleep clinic consult she slept 12 h/night with 4 one-hour daytime naps. Her Epworth Sleepiness Scale (ESS)5 score was 16/24. TSH was 2.13 mIU/mL with T4 unmeasured. An MRI of the brain was normal. Her diagnosis was changed to narcolepsy without cataplexy as defined by the International Classification of Sleep Disorders, 2nd edition.6 She was not interested in trying additional stimulants or sodium oxybate for her sleepiness. We initiated levothyroxine 25 mcg/day based on its reported benefits in patients with idiopathic hypersomnia.4 After 12 weeks, her ESS was 13/24 and her mean total sleep time dropped to 10 h/night with only 3 one-hour naps. She refused TSH and T4 testing after 12 weeks, though TSH after 9 months of therapy remained within normal limits at 1.69 mIU/ mL. No clinical signs of hyperthyroidism were reported or observed. Temperature, weight, and blood pressure were unaffected. She considered levothyroxine to be the most effective treatment thus far and felt the change represented clinical success, as she gained 3 hours awake each day. The benefits were sustained over a 9-month follow-up interval with no clinically significant change in TSH (2.13 vs 1.69 mIU/mL). Journal of Clinical Sleep Medicine, Vol. 10, No. 11, 2014
DL Sobol and AR Spector
IH, idiopathic hypersomnia MSLT, multiple sleep latency test SOREMPs, sleep onset REM periods TRH, thyroid releasing hormone TSH, thyroid-stimulating hormone
Table 1—Baseline sleep study results. Nocturnal Polysomnography Sleep latency Sleep efficiency Total sleep time Apnea-hypopnea index Periodic limb movement index
9 min 85% 400 min 2/h 12/h (no arousals)
Multiple sleep latency test Sleep latency - test 1 Sleep latency - test 2 Sleep latency - test 3 Sleep latency - test 4 Mean sleep latency Sleep onset REMs
4.5 min 4.0 min 3.5 min 1.5 min 3.4 min 3 of 4 naps
REFERENCES
DISCUSSION This is the first report of levothyroxine improving total sleep time and excessive daytime sleepiness in narcolepsy. Lowdose levothyroxine treatment was well tolerated, produced no side effects, reduced total daily sleep time, and improved EDS. Long-term follow-up is needed to determine if the patient becomes clinically hyperthyroid, continues to improve, or develops tolerance to this dose. While this patient benefited by sleeping fewer hours per day, many narcoleptics do not have long sleep times. It is unknown how levothyroxine would affect such patients. Side effects including osteoporosis and tachyarrythmias during chronic hyperthyroidism and high-dose levothyroxine use are potential side effects to monitor during low-dose treatment as well. Further research is needed to assess the efficacy and tolerability of levothyroxine on EDS and total sleep time in euthyroid narcoleptic patients.
ABBREVIATIONS
ACKNOWLEDGMENTS The authors thank Dr. Craig Jaffe for providing clinical expertise in endocrinology.
SUBMISSION & CORRESPONDENCE INFORMATION Submitted for publication January, 2014 Submitted in final revised form June, 2014 Accepted for publication June, 2014 Address correspondence to: Andrew R. Spector, M.D., Duke University School of Medicine, 3116 North Duke Street, Durham, NC 27704; Tel: (919) 660-8237; Fax: (919) 660-8569; E-mail: [email protected]
DISCLOSURE STATEMENT This was not an industry supported study. The authors have indicated no financial conflicts of interest. Off label use: Levothyroxine was given for excessive daytime sleepiness in a patient diagnosed with narcolepsy without cataplexy. The patient failed standard narcolepsy treatments and understood that levothyroxine was not approved for her condition.
EDS, excessive daytime sleepiness ESS, Epworth Sleepiness Scale GERD, gastroesophageal reflux disease
Journal of Clinical Sleep Medicine, Vol. 10, No. 11, 2014
1. Morgenthaler T, Kapur VK, Brown T, et al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin: an American Academy of Sleep Medicine Report. Sleep 2007;30:1705-11. 2. Riehl J, Honda K, Kwan M, Hong J, Mignot E, Nishino S. Chronic oral administration of CG-3703, a thyrotropin releasing hormone analog, increases wake and decreases cataplexy in canine narcolepsy. Neuropsychopharmacology 2000;23:34-45. 3. Nishino S, Arrigoni J, Shelton J, Kanbayashi T, Dement WC, Mignot E. Effects of thyrotropin-releasing hormone and its analogs on daytime sleepiness and cataplexy in canine narcolepsy. J Neurosci 1997;17:6401-8. 4. Shinno H, Ishikawa I, Yamanaka M, et al. Effect of levothyroxine on prolonged nocturnal sleep time and excessive daytime somnolence in patients with idiopathic hypersomnia. Sleep Med 2011;12:578-83. 5. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540-5. 6. American Academy of Sleep Medicine. International classification of sleep disorders, 2nd edition: diagnostic and coding manual. Westchester, IL: American Academy of Sleep Medicine, 2005.
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Levothyroxine Improves Subjective Sleepiness in a Euthyroid Patient with Narcolepsy without Cataplexy Danielle L. Sobol; Andrew R. Spector, M.D.
CASE REPORTS
Duke University School of Medicine, Durham, NC
Objective: We discuss the use of levothyroxine for excessive daytime sleepiness (EDS) and prolonged nocturnal sleep time in a euthyroid patient with narcolepsy. Methods: After failure of fi rst-line narcolepsy treatments, a 48-year-old female began levothyroxine (25 mcg/day). After 12 weeks of treatment, the patient was evaluated for improvement in total sleep time and subjective daytime sleepiness assessed by Epworth Sleepiness Scale (ESS). Results: At baseline, ESS score was 16 and total sleep time
T
he primary goal in treating narcolepsy without cataplexy is improving excessive daytime sleepiness (EDS). Current narcolepsy medications include amphetamines, methylphenidate, modafinil/armodafinil, and sodium oxybate.1 Some patients do not tolerate these medications due to side effects, including increased blood pressure, gastrointestinal disturbance, headaches, and anxiety. A potential new treatment for EDS due to narcolepsy is levothyroxine (Synthroid, Levothroid). Levothyroxine is a synthetic form of thyroxine, T4, an active thyroid hormone. While thyroid medications are common management for fatigue in hypothyroid patients, their role in euthyroid patients with EDS due to narcolepsy is unknown. Studies in narcoleptic canines show thyroid releasing hormone analogs to significantly increase wakefulness, reduce sleep time, and decrease cataplexy.2,3 To our knowledge, no study has examined levothyroxine for narcolepsy; however, levothyroxine has been shown to significantly decrease EDS and mean sleep time in idiopathic hypersomnia (IH).4 The proposed mechanisms include hypothalamic-pituitary-thyroid axis alteration and/or activation of TSH, TRH, or T3 receptors in the brain’s arousal-promoting system.4
REPORT OF CASE We present a 48-year-old female with an 11-year history of prolonged nocturnal sleep time and severe daytime somnolence requiring multiple naps. She denied cataplectic symptoms such as head drop and atonia. Her initial evaluation took place in another state, and she came to our attention to establish care with a sleep clinic. Her records indicated an initial multiple sleep latency test (MSLT) with mean sleep latency of 6 min without sleep onset REM periods (SOREMPs). She was diagnosed with IH with long sleep time. She tried multiple stimulants including methylphenidate, modafinil, armodafinil, lisdexamfetamine dimesylate, and dextroamphetamine/amphetamine. All stimulants exacerbated 1231
averaged 16 h/day. After 12 weeks, ESS was 13 and reported total sleep time was 13 h/day. Conclusions: Levothyroxine improved EDS and total sleep time in a euthyroid patient with narcolepsy without cataplexy after 12 weeks without side effects. Keywords: narcolepsy, levothyroxine, excessive daytime sleepiness Citation: Sobol DL, Spector AR. Levothyroxine improves subjective sleepiness in a euthyroid patient with narcolepsy without cataplexy. J Clin Sleep Med 2014;10(11):1231-1232.
her underlying anxiety and were intolerable. She was also prescribed fluoxetine, citalopram, bupropion, and desvenlafaxine for concerns that underlying depression caused her sleepiness, but these had no effect on her sleep. Her past medical history was significant for elevated Epstein-Barr virus antibody titers, anxiety, B12 deficiency, GERD, asthma, and hypertension. Medications upon presentation included albuterol-ipratropium, vitamin B12, desogestrel-ethinyl estradiol, dicyclomine, montelukast, and omeprazole. Physical exam demonstrated no focal neurological deficits and no cataplectic symptoms. A repeat polysomnogram with MSLT (Table 1) performed prior to her first visit demonstrated an apnea-hypopnea index of 2/h, total sleep time of 400 min, 85% sleep efficiency, and no SOREMP. Her MSLT showed a mean sleep latency of 3.4 min and 3 SOREMPs in 4 naps without notable sleep paralysis. At the time of her initial sleep clinic consult she slept 12 h/night with 4 one-hour daytime naps. Her Epworth Sleepiness Scale (ESS)5 score was 16/24. TSH was 2.13 mIU/mL with T4 unmeasured. An MRI of the brain was normal. Her diagnosis was changed to narcolepsy without cataplexy as defined by the International Classification of Sleep Disorders, 2nd edition.6 She was not interested in trying additional stimulants or sodium oxybate for her sleepiness. We initiated levothyroxine 25 mcg/day based on its reported benefits in patients with idiopathic hypersomnia.4 After 12 weeks, her ESS was 13/24 and her mean total sleep time dropped to 10 h/night with only 3 one-hour naps. She refused TSH and T4 testing after 12 weeks, though TSH after 9 months of therapy remained within normal limits at 1.69 mIU/ mL. No clinical signs of hyperthyroidism were reported or observed. Temperature, weight, and blood pressure were unaffected. She considered levothyroxine to be the most effective treatment thus far and felt the change represented clinical success, as she gained 3 hours awake each day. The benefits were sustained over a 9-month follow-up interval with no clinically significant change in TSH (2.13 vs 1.69 mIU/mL). Journal of Clinical Sleep Medicine, Vol. 10, No. 11, 2014
DL Sobol and AR Spector
IH, idiopathic hypersomnia MSLT, multiple sleep latency test SOREMPs, sleep onset REM periods TRH, thyroid releasing hormone TSH, thyroid-stimulating hormone
Table 1—Baseline sleep study results. Nocturnal Polysomnography Sleep latency Sleep efficiency Total sleep time Apnea-hypopnea index Periodic limb movement index
9 min 85% 400 min 2/h 12/h (no arousals)
Multiple sleep latency test Sleep latency - test 1 Sleep latency - test 2 Sleep latency - test 3 Sleep latency - test 4 Mean sleep latency Sleep onset REMs
4.5 min 4.0 min 3.5 min 1.5 min 3.4 min 3 of 4 naps
REFERENCES
DISCUSSION This is the first report of levothyroxine improving total sleep time and excessive daytime sleepiness in narcolepsy. Lowdose levothyroxine treatment was well tolerated, produced no side effects, reduced total daily sleep time, and improved EDS. Long-term follow-up is needed to determine if the patient becomes clinically hyperthyroid, continues to improve, or develops tolerance to this dose. While this patient benefited by sleeping fewer hours per day, many narcoleptics do not have long sleep times. It is unknown how levothyroxine would affect such patients. Side effects including osteoporosis and tachyarrythmias during chronic hyperthyroidism and high-dose levothyroxine use are potential side effects to monitor during low-dose treatment as well. Further research is needed to assess the efficacy and tolerability of levothyroxine on EDS and total sleep time in euthyroid narcoleptic patients.
ABBREVIATIONS
ACKNOWLEDGMENTS The authors thank Dr. Craig Jaffe for providing clinical expertise in endocrinology.
SUBMISSION & CORRESPONDENCE INFORMATION Submitted for publication January, 2014 Submitted in final revised form June, 2014 Accepted for publication June, 2014 Address correspondence to: Andrew R. Spector, M.D., Duke University School of Medicine, 3116 North Duke Street, Durham, NC 27704; Tel: (919) 660-8237; Fax: (919) 660-8569; E-mail: [email protected]
DISCLOSURE STATEMENT This was not an industry supported study. The authors have indicated no financial conflicts of interest. Off label use: Levothyroxine was given for excessive daytime sleepiness in a patient diagnosed with narcolepsy without cataplexy. The patient failed standard narcolepsy treatments and understood that levothyroxine was not approved for her condition.
EDS, excessive daytime sleepiness ESS, Epworth Sleepiness Scale GERD, gastroesophageal reflux disease
Journal of Clinical Sleep Medicine, Vol. 10, No. 11, 2014
1. Morgenthaler T, Kapur VK, Brown T, et al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin: an American Academy of Sleep Medicine Report. Sleep 2007;30:1705-11. 2. Riehl J, Honda K, Kwan M, Hong J, Mignot E, Nishino S. Chronic oral administration of CG-3703, a thyrotropin releasing hormone analog, increases wake and decreases cataplexy in canine narcolepsy. Neuropsychopharmacology 2000;23:34-45. 3. Nishino S, Arrigoni J, Shelton J, Kanbayashi T, Dement WC, Mignot E. Effects of thyrotropin-releasing hormone and its analogs on daytime sleepiness and cataplexy in canine narcolepsy. J Neurosci 1997;17:6401-8. 4. Shinno H, Ishikawa I, Yamanaka M, et al. Effect of levothyroxine on prolonged nocturnal sleep time and excessive daytime somnolence in patients with idiopathic hypersomnia. Sleep Med 2011;12:578-83. 5. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540-5. 6. American Academy of Sleep Medicine. International classification of sleep disorders, 2nd edition: diagnostic and coding manual. Westchester, IL: American Academy of Sleep Medicine, 2005.
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