Case 1 Liza Ashbrook, MD Assistant Clinical Professor UCSF - - PowerPoint PPT Presentation

2/10/2017 1

Case 1

Liza Ashbrook, MD Assistant Clinical Professor UCSF Department of Neurology

Disclosures

I have no disclosures

History of Present Illness

70-year-man with obstructive sleep apnea and right hip replacement who presents for trouble falling asleep He complains of leg discomfort and an overwhelming urge to move his legs at night, feels legs will jump on their own, and he often gets up to walk around when in bed at night to relieve this urge Symptoms began years ago and have worsened over time, hard to tolerate for the past two months Symptoms keep him up at night on 5/7 nights per week

Diagnosis for trouble falling asleep

A. Insomnia B. Restless leg syndrome C. Peripheral neuropathy D. Osteoarthritis of the hip

I n s

• m

n i a R e s t l e s s l e g s y n d r

• m

e P e r i p h e r a l n e u r

• p

a t h y O s t e

• a

r t h r i t i s

• f

t h e h i p

2% 0% 2% 96%

2/10/2017 2

Diagnosis of restless leg syndrome

Also called Willis-Ekbom disease (WEB) Criteria:

• An urge to move the legs, often triggered by unpleasant sensation
• Begins/worsens during inactivity
• Urge relieved, at least in part, by movement
• Worse during the evening
• Symptoms cause distress or impairment

** rule out other etiologies including myalgias, venous stasis, edema, cramping, position, habitual foot tapping

Additional history

PMH: Obstructive sleep apnea (OSA), hypertension, hyperlipidemia, degenerative joint disease Medications: pramipexole 0.25 mg nightly, tramadol 50 mg prn, hydrocodone/acetaminophen 5/325 prn, diphenhydramine prn Physical Exam: No hip pain, intact strength and sensation in legs

What would you choose as initial nightly treatment?

A. Pregabalin (Lyrica) 75 mg B. Pramipexole (Mirapex) 0.5 mg C. Carbidopa/levodopa (Sinemet) 25/100

• D. Ropinirole (Requip) 0.25 mg

E. Clonazepam (Klonopin) 0.5 mg

P r e g a b a l i n ( L y r i c a ) 7 5 m g P r a m i p e x

• l

e ( M i r a p e x ) . 5 m g C a r b i d

• p

a / l e v

• d
• p

a ( S i n e m e . . R

• p

i n i r

• l

e ( R e q u i p ) . 2 5 m g C l

• n

a z e p a m ( K l

• n
• p

i n ) . 5 m g

12% 36% 6% 43% 4%

What would you choose as initial nightly treatment?

• A. Pregabalin (Lyrica) 75 mg
• B. Pramipexole (Mirapex) 0.5 mg
• C. Carbidopa/levodopa (Sinemet) 25/100
• D. Ropinirole (Requip) 0.25 mg
• E. Clonazepam (Klonopin) 0.5 mg

2/10/2017 3

Recommended dosing

Dopamine Agonists Starting Dose Maximum recommended dose Pramipexole (Mirapex) 0.125mg 0.75mg Ropinirole (Requip) 0.25mg 4mg Rotigotine (Neupro) 1mg/day 3mg/day Alpha-2 Delta Ligands Starting Dose Maximum recommended dose Pregabalin (Lyrica) 50-75mg 150-450mg Gabapentin (Neurontin) 100-300mg 900-2400mg Gabapentin enacarbil (Horizant) 300-600mg 600-1200mg

• D. Garcia-Borreguero et al. / Sleep Medicine 21 (2016) 1–11

Dopamine agonists vs Alpha-2-delta ligands: NEJM 2014

“Comparison of Pregabalin with Pramipexole for Restless Legs Syndrome” (sponsored by Pfizer)

719 participants IRLS severity at 12 weeks vs placebo

• pramipexole 0.5 mg (<0.001)
• pregabalin 300 mg (<0.001)
• not pramipexole 0.25 mg (0.36)

At 52 weeks: More augmentation with pramipexole

• Pregabalin 300 mg 5/235 (2.1%)
• Pramipexole 0.25 mg 12/225 (5.3%, P=0.08)
• Pramipexole 0.5 mg 18/235 (7.7%, P=0.001)

Allen RP et al. NEJM, 2014

Additional history

• He has noted leg discomfort on airplane rides for many years but did not

seek care

• In 2011 periodic leg movements were noted in a sleep study, he was

questioned about restless leg symptoms and was started on pramipexole 0.25mg (note recommended starting dose is 0.125 mg), this helped for several years

• In 2014 symptoms returned and pramipexole dose increased from 0.25

mg to 0.5 mg to 1 mg (maximum recommended dose is 0.75 mg)

• The time of onset and intensity of his symptoms worsened: starting 5-6

pm, now include arm symptoms, more severe

Characteristics of augmentation

RLS symptoms

• start earlier in the day (two hours used as cut off)
• more severe
• faster onset of symptoms following rest
• affect other parts of the body (arms)
• shorted duration of medication efficacy and/or
• paradoxical response to treatment

2/10/2017 4

Management of augmentation: step 1

Check serum iron: Serum ferritin goal >50-75 ng/mL Screen for other triggers such as

• exacerbating medications including dopamine antagonists,

antihistamines, antidepressants (except bupropion)

• sleep deprivation or sleep disruptor (OSA)
• Medical conditions such as renal insufficiency or pregnancy
• alcohol use
• decreased mobility

Management of augmentation: Step 2

• 1. If mild, consider keeping the same medication

a) move the timing earlier b) split the dose to two times c) increase the dose if still below maximum recommended dose (do

• nly once)
• 2. Change medications to long acting DA agonist (rotigotine) or alpha-2-

delta ligand a) Switch medications b) Cross titration c) Wash out period

Our patient – further clinical course

Reduced pramipexole to 0.5 then 0.25, but was increasingly using tramadol and hydrocodone/acetaminophen from hip surgery Ferritin 71.2, iron tabs did not help Cross taper: gabapentin 300mg ->600mg with wean of pramipexole Timing did improve, but symptoms still very bothersome in legs and arms Rotigotine patch prescribed, patient did not want to pursue DA agonist Changed to gabapentin enacarbil (Horizant) without improvement Told stop taking diphenhydramine prn Still taking 2 hydrocodone/acetaminophen nightly to control symptoms After 2.5 months of inadequately treated symptoms despite trial of gabapentin, gabapentin enacarbil, iron supplementation, stopping pramipexole, tramadol, and diphenhydramine and prescription of rotigotine patch

What would you do next?

• A. Push for trial of rotigotine patch (Neupro)
• B. Pregabalin 75 mg with plan to increase to 150
• C. Intravenous iron infusion
• D. Methadone 5 mg

Push for trial of rotigotine p... Pregabalin 75 mg with plan t... Intravenous iron infusion Methadone 5 mg

13% 13% 4% 71%

2/10/2017 5

Our patient

He has no personal history of substance abuse Methadone 5mg started Provided great relief and patient reported urge to move the legs resolved

Management of refractory RLS

Around the clock symptoms DA agonist and alpha-2 delta ligand do not work Consider opioids

• Low dose oxycodone
• Methadone

**Screen for history of substance abuse, use of other sedating medications

Opioids for RLS

10 year longitudinal study (Silver et al. Sleep Medicine, 2011)

• Subjects: 164 patients on pramipexole, 77 patients on pergolide, and 76

patients on methadone.

• First year discontinuation (side effects): pramipexole 17%, pergolide 23%,

methadone 15%

• Annual discontinuation rate over 5 years: pramipexole 9% , pergolide 8%,

methadone 0%

• Methadone dose: Median dose at six months: 10mg, median daily dose

after 8–10 years no more than 10 mg greater than at 6 months

Opioids for RLS

RCT of long acting oxycodone/naloxone 5mg/2.5mg (Trenkwalder et al. Lancet Neurol 2013, study funded by Mundipharma Research)

• Subjects: 132 to prolonged release oxycodone/naloxone vs 144 to

placebo

• At 12 weeks of treatment mean IRLS rating scale drop on
• xycodone/naloxone: 16.5 vs placebo: 9.4 (p<0·0001)

Before using ensure risk of abuse is low by screening for a history of substance abuse

2/10/2017 6

A note about supplemental iron

Data mixed slow but can be very effective for some patients PO iron:

• 325 mg of ferrous sulfate BID, combine with vitamin C

IV iron: (Cho Y et al. Sleep Med 2013)

• Low-molecular weight iron dextran 250mg weekly x 4 (total dose of 1 g)

Side effects: allergic reaction headache, nausea, muscle pain, edema

• One and six weeks after treatment and the treatment benefits lasted from
• ne month to 22 months.
• NOTE parenteral infusion risk with low molecular weight iron dextran is lower (1 per 200,000) than

that with high molecular weight iron dextran. Other formulations also available.

Take home points

RLS Pitfalls

• Starting medication when not needed or prn dosing would be enough
• Starting higher dose than needed to control symptoms
• Escalating DA agonist dose despite worsening symptoms
• Missing iron deficiency
• Missing exacerbating medications that can be safely discontinued

For severe RLS symptoms

• Consider supplemental intravenous iron
• Consider long acting, low dose opioid

Case 2

Patient history

20-year-old woman with a history of chronic refractory migraine and hip pain who presents for trouble falling asleep and staying asleep for 1.5 years Sleep/wake pattern: Bedtime: 10 pm, sleep latency: 6 hours, wake time: 5 pm When awake in bed at night watches television, colors, talks on the phone Awakenings from sleep: 6-7 times with frequent trouble falling asleep Ideal (dessert island) bedtime: 2 am; Goal sleep schedule: 11:30 pm-7:30 am Never feels well rested, endorses daytime sleepiness Snores sometimes, no gasping, choking, witnessed pauses

2/10/2017 7

Diagnosis

A. Delayed sleep-wake phase disorder B. Chronic insomnia

• C. Obstructive sleep apnea
• D. Idiopathic hypersomnia

Delayed sleep-wake phase d... Chronic insomnia Obstructive sleep apnea Idiopathic hypersomnia

75% 7% 2% 17% 6pm 12am 6am 12pm Advanced sleep-wake phase disorder Typical habitual sleep period Delayed sleep-wake phase disorder Hour of the day

Circadian misalignment

• DSPS accounts for 10% of insomnia patients
• Negative health impacts of circadian misalignment
• Negative effect on memory, concentration, attention (Wright et al. Journal of

Cognitive Neuroscience. 2006)

• Causes insulin resistance (Scheer et al. Proceedings of the National Academy of
• Sciences. 2009)
• Possible cancer progression (Hahm et al. Chronobiology international. 2014)
• May negatively impact seizure control (Kendis et al. Behavioural neurology. 2015)

Treatment to shift her schedule

A. Begin rising at desired wake time of 7:30 am and get sunlight exposure on waking B. Get into bed at habitual sleep time (i.e. 4 am not 10 pm) and take melatonin 5mg, then move bedtime progressively 30 minutes earlier everyday until at desired sleep time C. Get into bed at habitual sleep time (i.e. 4 am not 10 pm) and progressively delay bedtime by 2 hours until at desired bedtime

B e g i n r i s i n g a t d e s i r e d w a k e . . . G e t i n t

• b

e d a t h a b i t u a l s l e . . G e t i n t

• b

e d a t h a b i t u a l s l e . .

32% 17% 51%

2/10/2017 8

Chronotherapy

Delay bedtime by 2-3 hours each night until at desired bedtime. Based on idea that it is easier for those with delayed sleep phase disorder to delay bedtime than to awaken earlier No randomized control trials, only case series Evidence from case series that there is a high rate of relapse, one report of resultant free-running schedule

Our patient

She was able to shift schedule using chronotherapy to desired time for several months She then traveled over the summer and after return had worsening of headaches, no longer able to keep her schedule Bedtime: 11 pm Sleep latency: 5 hours Wake time: 2 pm (variable)

Anchors of circadian treatment: melatonin and light

Entrainment of the biologic clock is achieved primarily by light Other zeitgeibers (environmental cues that help entrain): physical activity, social interaction, eating Light regulates the production of melatonin by the pineal gland Melatonin release begins in the evening 19:30 - 21:30 in dim light conditions, peaks overnight, and is suppressed by bright light

Recommended melatonin dosing to shift the clock

(assume bedtime is when patient is falling asleep)

• A. 3 mg 30 minutes prior to bedtime

B. 10 mg 30 minutes prior to bedtime

• C. 0.5 mg 5 hours prior to bedtime
• D. 3 mg 5 hours prior to bedtime

3 mg 30 minutes prior to be... 10 mg 30 minutes prior to b... 0.5 mg 5 hours prior to bed... 3 mg 5 hours prior to bedtime

32% 26% 5% 37%

2/10/2017 9

Recommended melatonin dosing to shift the clock

• A. 3 mg 30 minutes prior to bedtime
• B. 10 mg 30 minutes prior to bedtime
• C. 0.5 mg 5 hours prior to bedtime
• D. 3 mg 5 hours prior to bedtime

How to use melatonin

Melatonin can be used to help with sleep initiation or clocking shifting It can be a soporific (sleep aid) at 3-5 mg at bedtime For clock-shifting, dose of melatonin is less important than the timing of the dose

• 0.5 mg similar to 3 mg
• Give 5 hours before bedtime

Typical habitual sleep period Melatonin -> delay

Melatonin -> advance 6pm 12am 6am 12pm Typical habitual sleep period Melatonin-> delay Dim light melatonin onset Core body temperature minimum Light -> advance Light -> delay 6pm 12am 6am 12pm Dim light melatonin onset Core body temperature minimum

Typical habitual sleep period

Typical habitual sleep period

2/10/2017 10

Our patient

For circadian misalignment:

• 30 minutes of bright light (sunlight or light box of 10,000 Lux) on

waking and

• melatonin 0.5 mg 5 hours before bedtime
• Progressive move light exposure, melatonin, and wake 30 minutes earlier

each day Do not go to bed until sleepy, limit time in bed Consider: sleep study (frequent awakenings, snoring, daytime sleepiness)

Blue light

Melanopsin photoreceptors respond most strongly to blue light (around 450–480 nm) This suppresses melatonin release Concern that blue light (from indoor lighting, computers, cell phones) in the evening may phase delay some users Consider blue blocking glasses, phone applications (Night Shift on iPhone, Twilight or other apps on Android)

Summary

Think about the interplay of sleep with commonly treated neurologic conditions (headache, epilepsy, multiple sclerosis, concussion, Parkinson’s) Consider diagnosis of delayed sleep-wake phase disorder for those with complaint of trouble falling asleep as night Bright light (sunlight or light box) with melatonin can be powerful tools to help shift the circadian clock and improve sleep

Do you have patients with a neurologic or psychiatric diagnosis and sleep concerns?

Consider referral to UCSF’s new Neuro/Psyc Sleep Clinic (housed within neurology)

• Phone: 415-353-2273
• Fax: 415-353-2898