Transcript Tips, tricks and know how for treating sleep disorders in neurology

Tips, tricks and know how for
treating sleep disorders in
neurology
Suzanne Stevens, MD, MS, D-ABSM
Clinical Assistant Professor, Department
of Neurology
Director, Sleep Medicine Clinic
Restless Leg Syndrome (RLS) =
Willis Ekbom Disease (WED)
Reasons for the name change
The name Willis-Ekbom disease:
1.
2.
3.
4.
Eliminates incorrect descriptors—the condition often involves parts of
the body other than legs
Promotes cross-cultural ease of use
Responds to trivialization of the disease
Acknowledges the first known description by Sir Thomas Willis in 1672
and the first detailed clinical description by Dr. Karl Axel Ekbom in 1945.
17th Century Description of RLS by Sir Thomas Willis
considered restless legs. Although Willis syndrome was thought to be the
release of animal humors into the nerves of the legs, he offered
an excellent observation:
“…Wherefore to some, when being abed they
betake themselves to sleep, presently in the arms
and legs, leapings and contractions of the
tendons, and so great a restlessness and
tossings of the members ensue, that the diseased
are no more able to sleep, than if they were in a
place of the greatest torture.”
— Willis T. The Practice of Physick, 1685.
Willis’ Treatment: Laudanum
Dr. Karl-Axel Ekbom published his doctoral thesis in 1945 as a monograph entitled
“Restless legs – a clinical study of a hitherto overlooked disease in the legs
characterized by peculiar paresthesia (anxietas tibiarum), pain, and weakness and
occurring in two main forms, asthenia crurum paraesthetica and asthenia crurum
dolorosa.” He carried out the investigation at the neurologic outpatient service of
the Serafimer Hospital during the years 1943 to 1945. He was able to collect 34
severe and 120 mild cases of the paresthetic form of the disease and 15 cases of
the painful form.
In the following years, he gave several descriptions of restless legs as a symptom
of iron deficiency (sideropenia) and, in some patients, bleeding peptic ulcers.
Restless legs was found in blood donors, and a further series of reports dealt with
the syndrome in subjects with, among other things, amputated limbs; this is
interesting from the pathogenic point of view. Restless legs was also compared
with growing pains and akathisia – a symptom
associated with phenothiazine treatment.
Patient 1
• 50 yo male with 2 years
of uncomfortable
sensation in legs at
nighttime. He notices it
while watching TV
around 7 PM and has to
get up and walk around
to get relief. It occurs
almost nightly. He has
trouble getting to sleep
and has daytime
sleepiness.
Patient 1
• PMH: unremarkable
• SH: denies etoh, denies
tob
• FH: he has a brother with
RLS
• Exam: Completely
normal, no signs of
neuropathy
How do you diagnose RLS?
Diagnostic Criteria
Criteria A-C must be met
A. An urge to move the legs, usually accompanied by or thought to be caused by
uncomfortable and unpleasant sensations in the legs. These symptoms must:
1. Occur or worsen during periods of rest or inactivity such as lying down or
sitting;
2. Be partially or totally relieved by movement, such as walking or stretching, at
least as long as the activity continues;
3. Occur exclusively or predominantly in the evening or night rather than during
the day.
B. The above features are not solely accounted for as symptoms of another
medical or a behavioral condition (e.g., leg cramps, positional discomfort, myalgia,
venous stasis, leg edema, arthritis, habitual foot tapping).
C. The symptoms of RLS cause concern, distress, sleep disturbance, or
impairment in mental, physical, social, occupational, educational, behavioral, or
other important areas of functioning.
“URGE”
IRLSSG Diagnostic Criteria
Four Core Symptoms are required
“U R G E”
U = Urge to move the limb(s)
R = Rest worsens the sensation
G = Get up & Go is Good
(temporary relief with movement)
E = Evening / night worsening
Differential Diagnosis
• Neuroleptic-induced akathisia
• Fidgets
• Semiconscious leg jiggling
• Involuntary leg movements (PLM, propriospinal myoclonus at sleep onset,
rhythmic movement disorder)
• Peripheral neuropathy
• Nocturnal leg cramps
• Vascular or neurogenic claudication
• Pruritus
• Arthritic leg discomfort
• Fibromyalgia
• Painful myopathies
• Varicose veins or venous insufficiency
• Deep vein thrombosis
• Fasciculations
• Positional discomfort
• Painful legs and moving toes
Patient 1
• 50 yo male with 2 years
of uncomfortable
sensation in legs at
nighttime. He notices it
while watching TV
around 7 PM and has to
get up and walk around
to get relief. It occurs
almost nightly. He has
trouble getting to sleep
and has daytime
sleepiness.
• He meets criteria for RLS
What work up would you
consider?
PSG?
• Not for RLS only, with no suspicion for
underlying sleep disorder, even if they are
kicking in their sleep.
• If BMI is elevated and snoring present,
PSG would be warranted for OSA but not
for RLS
Work up for RLS with normal
exam
• If not already done:
• Chem panel
– Looking for kidney
disease or any other
abnormality
• CBC
• Ferritin
• If at all suspicious for
neuropathy:
– EMG
– B12, TSH, etc.
Ferritin
• Ferritin is an acute phase reactant. If a
patient has had recent fever or suffers a
chronic inflammatory disorder, it is also
important to measure transferrin saturation
and total iron-binding capacity.
Ferritin alone can be deceiving
• Iron status should be evaluated in all
patients with RLS.
• In addition to ferritin, it is helpful to obtain
transferrin saturation, which is the ratio of
serum iron to TIBC.
• Supplemental iron is recommended if
ferritin is < 50 ng/mL or transferrin
saturation is < 20%.
Treatment options for Primary
RLS
• If ferritin below 50, iron supplementation
• 65 mg elemental iron with a glass of OJ or
Vitamin C tablets to increase absorption
• GI side effects are most common and may
require slow release, or iron formulated for
gastric bypass patients (more easily
absorbed)
Treatment options continued
•
•
•
•
Dopaminergic medications
Alpha 2 delta ligand: Gabapentin, Horizant
Clonazepam
Opioids, tramadol
Medical Devices for RLS
Ther Clin Risk Manag. 2015; 11: 1789–1794.
Published online 2015 Dec 3. doi: 10.2147/TCRM.S87208
Patient 1
• Ferritin = 225, transferrin saturation normal
• Other labs normal
• How to proceed with treatment?
Patient 1
• 50 yo male with 2 years
of uncomfortable
sensation in legs at
nighttime. He notices it
while watching TV
around 7 PM and has to
get up and walk around
to get relief. It occurs
almost nightly. He has
trouble getting to sleep
and has daytime
sleepiness.
• He meets criteria for RLS
What treatment is appropriate?
• (Audience answers)
Treatment patient 1
• Ropinerole .25 mg at dinner and may
repeat at bedtime
• **TIP is to give first dose BEFORE
symptoms typically begin**
Patient 1
• F/U 3 months and feels great!
• F/U 6 months later and is worried as his
symptoms have worsened
• He takes ropinerole at dinner time and
bedtime, but now while at work his legs
bother him during meetings between 1-3
PM. He has also noticed it has spread to
his arms. He asks you if it will keep
getting worse
Patient 1
• What has happened?
• How do you help this patient?
Augmentation
• Augmentation is worsening on RLS
symptoms and earlier symptom onset during
the day due to dopaminergic medications.
• This is thought to be due to short acting
dopaminergic medications downregulating
dopamine receptors
• 30% or so of people on dopaminergic
medications can have augmentation at any
time during their course
Fig. 7. Proposed circadian changes in the dopaminergic output signal which could account for the circadian nature of the RLS
symptoms and which could provide a biological rational for the clinical spectrum of dopamine-drug-induced augmentation. DA,
dopamine; R...
Christopher J. Earley, James Connor, Diego Garcia-Borreguero, Peter Jenner, John Winkelman, Phyllis C. Zee, Richard Allen
Altered Brain iron homeostasis and dopaminergic function in Restless Legs Syndrome (Willis–Ekbom Disease)
Sleep Medicine, Volume 15, Issue 11, 2014, 1288–1301
http://dx.doi.org/10.1016/j.sleep.2014.05.009
Treatment of augmentation
• Ideas?
Augmentation treatment options
• Change to long acting dopaminergic
• Change class of medication to alpha 2
delta ligand
• Check ferritin to make sure it hasn’t
dropped
Augmentation treatment options
• Neupro patch
Augmentation options
•
•
•
•
•
Gabapentin
Lyrica
Clonazepam
Opioids/tramadol
If ferritin is abnormal, iron therapy
• The key is to get them off of short acting
dopamine agonists
Patient 1
• For augmentation, you decide to change
him from his ropinerole to Horizant.
• Horizant 600 mg at dinnertime was started
and he was told to stop the ropinerole.
You gave him samples and told him to
start it the day of the clinic visit, as well as
to stop the ropinerole
Patient 1
• He calls the office the next day, irritated
and mad, stating that he didn’t get a wink
of sleep last night and the Horizant isn’t
worth a darn and ended up taking
ropinerole at 3 am just to get some “damn
sleep.”
Medications Commonly Used for Insomnia.
Winkelman JW. N Engl J Med 2015;373:1437-1444.
THIS is where the tips, tricks and
know how come into play!
• When changing medications due to
augmentation, either
– Overlap them
– OR provide short term supply of tramadol/pain
pill and a sleeping pill if needed
– Prepare them that the next 2 weeks may be
rough
Behavioral Treatments
• Hot baths in evening
• Getting involved in an activity suppresses
RLS activity (ie distraction)
• Avoiding nicotine and caffeine
• Some people note diphenhydramine
worsens RLS
• Avoiding alcohol if this worsens
• Stretches at night
Patient 2
• 65 yo female with myasthia gravis
• 3 years of urges to move legs in the
evening beginning 6 PM, relieved with
movement, worsened with rest, worse in
the evening time.
• No bed partner, but currently uses CPAP
for OSA
Patient 2
• Meds: Imuran, Mestinon, Lipitor, HCTZ
•
•
•
•
•
•
•
•
Exam:Body mass index is 36.86 kg/(m^2).
She is awake, alert, oriented to time, place and person. Speech is fluent.
NEUROLOGICAL EXAMINATION:
Cranial Nerves II – XII: Palpebral fissures are 9/10 mm with mild right eyelid
ptosis with fatigability on the right and she does not have any diplopia.
Orbicularis oculi and oris strength is 5. No fatigability, Tongue strength is
normal.
Motor Examination: Neck flexors and extensors are 5. Upper extremity strength
is diffusely 5, lower extremity strength is diffusely 5 except , hip flexors 4+,
Shoulder abductors 4+
Sensory Examination: Intact pinprick, light touch, timed vibration and
proprioception. hyperesthia in the right ulnar nerve distribution.
Reflexes: 2 at the biceps, brachioradialis, triceps, knee and ankle. Plantar
responses are flexor.
Gait and Station: Gait is normal.
Patient 2
• Treatment options:
Patient 2
• Clonazepam –
• Gabapentin• Dopamine agonist-
Patient 2
• Mirapex .125 mg at dinner and .125 mg at
bedtime
• This was effective for several months
• She called stating she was having break
through symptoms and ultimately her
Mirapex dose was raised to Mirapex .5 mg
at dinner and .5 mg at bedtime
Patient 2
• Then she returns to clinic stating she has
started compulsive internet shopping and
compulsively eating resulting in weight
gain
• What is causing the new compulsions?
Patient 2
• Dopamine agents can cause compulsions
• Not an infrequent phenomena and can be
very distressful and embarrassing
Patient 2
• Gabapentin was then used at 100 mg tid
but this resulted in sedation during the
daytime
• Horizant was then used with improvement
in her symptoms
Cephalalgia. 2015 Dec 6. pii: 0333102415620907. [Epub ahead of print]
Susceptible genes of restless legs syndrome in migraine.
Fuh JL1, Chung MY2, Yao SC1, Chen PK3, Liao YC1, Hsu CL4, Wang
PJ5, Wang YF1, Chen SP1, Fann CS4, Kao LS6, Wang SJ7.
Author information
Abstract
OBJECTIVE:
Several genetic variants have been found to increase the risk of restless
legs syndrome (RLS). The aim of the present study was to determine if
these genetic variants were also associated with the comorbidity
of RLS and migraine in patients.
CONCLUSIONS:
MEIS1 variants were associated with an increased risk of RLS in migraine
patients. It is possible that an imbalance in iron homeostasis and the
dopaminergic system may represent a link between RLS incidence and
migraines.
© International Headache Society 2015.
Z Gerontol Geriatr. 2015 Nov 23. [Epub ahead of print]
Intravenous iron administration in restless legs syndrome : An observational
study in geriatric patients.
Lieske B1, Becker I2, Schulz RJ1, Polidori MC3, Kassubek J3, Roehrig G4,5.
Author information
Of the patients 7 (41 %) received 500 mg ferric carboxymaltose (FCM) and 10
patients (59 %) received iron gluconate (62.5 mg) based on the degree of iron
deficiency. As assessed by the international RLS severity scale (IRLS) symptoms
were recorded 3 times: at the beginning of iron therapy (t0), after 2 weeks (t1) and
after 12 weeks (t2).
RESULTS:
A total of 17 patients (13 female, 4 male, mean age 73.2 ± 5.9 years) were
included. The IRLS score significantly improved in all patients as shown by an
average decrease from 30.2 (± 4.3) to 20.2 (± 4.7) (p < 0.001) after 2 weeks of i.v.
iron treatment and to 23.2 ± 6.6 (p < 0.001) after 12 weeks. There was a high
correlation between ferritin values and the IRLS score (C 0.729, p < 0.001). The
part of the IRLS referring to activities of daily living (ADL) improved from a median
of 3 (scores 3-4) to 2 (scores 2-3, p = 0.001) after 2 weeks (effect size - 0.6).
CONCLUSION:
In this study group of geriatric outpatients i.v. administration of iron was associated
with a significant improvement of symptoms inRLS as assessed by the IRLS score
2 weeks after treatment. In geriatric patients with RLS associated with iron
deficiency, i.v. iron administration should be considered regarding improvement
of RLS symptoms and ADL.
Curr Med Res Opin. 2015 Nov 16:1-9. [Epub ahead of print]
Effects of rotigotine on daytime symptoms in patients with primary restless legs
syndrome: a randomized, placebo-controlled study.
Garcia-Borreguero D1, Allen R2, Hudson J3, Dohin E4, Grieger F5, Moran
K6, Schollmayer E5, Smit R7, Winkelman J8.
Abstract
OBJECTIVE:
This 12 week double-blind, placebo-controlled study (ClinicalTrials.gov: NCT01569464)
was conducted to evaluate the effects of rotigotine transdermal patch on daytime
symptoms in patients with idiopathic restless legs syndrome (RLS).
METHODS:
Adult patients with moderate-to-severe RLS were randomized to rotigotine (optimal
dose: 1-3 mg/24 h) or placebo. A modified four-assessment version (4:00 pm, 6:00 pm,
8:00 pm, and 10:00 pm) of the Multiple Suggested Immobilization Test (m-SIT) was
performed at baseline and end of 4 week maintenance (EoM). Primary study outcomes
were change from baseline to EoM in International Restless Legs Syndrome Rating
Scale (IRLS) and in average of means for the m-SIT Discomfort Scale (m-SIT-DS)
(combined average of mean values from each of the individual assessments).
Secondary outcomes included average of means of Periodic Limb Movement during
Wakefulness Index (PLMWI; PLM/hour) for the combination of m-SIT.
Curr Med Res Opin. 2015 Nov 16:1-9. [Epub ahead of print]
Effects of rotigotine on daytime symptoms in patients with primary restless
legs syndrome: a randomized, placebo-controlled study.
Garcia-Borreguero D1, Allen R2, Hudson J3, Dohin E4, Grieger F5, Moran
K6, Schollmayer E5, Smit R7, Winkelman J8.
RESULTS:
A total of 150 patients were randomized and 137 (rotigotine: 92/101 [91.1%]; placebo:
45/49 [91.8%]) completed maintenance. All 150 randomized patients were assessed
for efficacy. At EoM, mean change in IRLS was -14.9 ± 9.3 with rotigotine vs. 12.7 ± 7.6 with placebo (ANCOVA, LS mean treatment difference [95% CI]: -0.27 [2.96, 2.42]; p = 0.8451). Changes in average of means of m-SIT-DS values of each
individual SIT were comparable with rotigotine (-2.68 ± 2.31) vs. placebo (2.62 ± 2.61) (ANCOVA, LS mean treatment difference [95% CI]: 0.07 [-0.61, 0.75];
p = 0.8336) and comparable reductions in PLMWI were observed in both treatment
groups (8.34 [-8.50, 25.17]; p = 0.3290). Rotigotine was generally well tolerated.
Application site reactions (rotigotine: 20 patients [19.8%]; placebo: 4 [8.2%]) and
nausea (16 [15.8%]; 3 [6.1%]) were the most common AEs.
CONCLUSIONS:
Rotigotine was beneficial in improving overall RLS symptom severity (assessed by
IRLS) and RLS symptom severity at various times of the day (m-SIT-DS); however,
superiority to placebo was not established.
Association of low ferritin with PLM in the Wisconsin Sleep Cohort.
Li J1, Moore H 4th1, Lin L1, Young T2, Finn L2, Peppard PE2, Mignot E3.
Author information
Abstract
OBJECTIVE:
The origins of periodic leg movements (PLMs), a strong correlate of restless legs
syndrome (RLS), are uncertain. This study was performed to assess the
relationship between PLMs and peripheral iron deficiency, as measured with
ferritin levels corrected for inflammation.
METHODS:
We included a cross-sectional sample of a cohort study of 801 randomly
selected people (n = 1008 assays, mean age 58.6 ± 0.3 years) from Wisconsin
state employee agencies. A previously validated automatic detector was used to
measure PLMs during sleep. The patients were categorized into RLS symptomspositive and RLS symptoms-negative based on a mailed survey response and
prior analysis. Analyses were performed using a linear model with PLM category
above and below 15 PLM/h (periodic leg movement index, PLMI) as the
dependent variable, and adjusting for known covariates, including previously
associated single-nucleotide polymorphisms (SNPs) within BTBD9,
TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD. Ferritin and C-reactive
protein (CRP) levels were measured in serum, and ferritin levels corrected for
inflammation using CRP levels.
RESULTS:
After controlling for cofactors, PLMI ≥ 15 was associated with low (≤50 ng/mL)
ferritin levels (OR = 1.55, p = 0.020). The best model was found using quasi-least
squares regression of ferritin as a function of PLMI, with an increase of
0.0034 PLM/h predicted by a decrease of 1 ng/mL ferritin (p = 0.00447).
CONCLUSIONS:
An association was found between low ferritin and greater PLMs in a general
population of older adults, independent of genetic polymorphisms, suggesting a
role of low iron stores in the expression of these phenotypes. Patients with high
PLMI may require to be checked for iron deficiency.
If you do not change direction, you may
end up where you are heading.
Lao Tzu
Before you marry someone, ask yourself,
'Will they be a good killing partner during
the zombie apocalypse?'
Maybe all one can do is hope to end up with the
right regrets.
Arthur Miller