als symptom management - university of kansas medical … symptoms m… · · 2017-02-10richard j...
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ALS Symptom Management
Omar Jawdat, MD
Assistant Professor of Neurology
2/3/2017
Richard J Barohn, MD
Carlayne E. Jackson, MD
April L. McVey, MD
Stacy Rudnicki, MD
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Overview
Historic timeline
Epidemiology and ALS signs and
symptoms
Vignettes about ALS symptoms and their
management
Future direction
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A Historic overview
Charcot (1825–1893) is generally credited for
first describing ALS
During his Tuesday lectures beginning in the late 1860s
and culminating in a publication in 1874
Later work by Gowers and then by Charcot refined the
description into a complete clinical spectrum with
specific examination features.
There has been little change in the clinical understanding
of the phenotypic disease description for nearly
150 years.
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ALS timeline 1830 Bell reports a case of a progressive paralysis of limbs and
tongue with preservation of sensation
1850 Aran names the condition of progressive muscular atrophy
1865 Charcot describes progressive lateral sclerosis (PLS)
1870 Charcot describes progressive bulbar palsy
1874 Charcot names ALS (de la sclerose laterale amyotrophique)
1939 Lou Gehrig’s diagnosis and first clinical trial with vitamin E
1941 Lou Gehrig dies of ALS
1943 Vitamin E injections are shown not to be effective to treat ALS
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ALS timeline 1952 Hirano describes the guam ALS/Dementia/Parkinson Complex
1969 Lambert – Diagnostic criteria using EMG
1980 report of nerve growth factor published
1984 Use of percutaneous endoscopic gastrostomy (PEG) reported in ALS.
1987 Glutamate metabolism abnormality theory reported in ALS.
1993 SOD-1 gene identified.
1994 El Escorial criteria for ALS clinical trial inclusion published.
1995 first positive clinical trial for ALS. Riluzole has an effect on survival, prolonging life by 3 months.
2011 C9orf72 gene discovered, a repeat expansion GGGGCC
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ALS Demographics
Incidence US: 2-3 per 100,000
Prevalence US: 35,000
Male slightly > Female
Peak age onset- 6th decade, range <20 to >80
90-95% sporadic
5-10% familial. Of these- 30-50% C9orf72 hexanucleotide expansion GGGGCC
- 15-20% SOD-1
- 5% TDP-43, VCP, FUS, Ubiquitin mutations
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Other than Riluzole, how do we treat
these symptoms?
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Case 1
70 y/o F with 2 year history of bulbar-onset
ALS presents with excessive drooling.
Chokes constantly on saliva and uses a
PEG for the majority of her nutrition.
Unable to tolerate prior trial of
amitriptyline, scopolamine, and hyosamine
due to side effects.
FVC = 60%
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Case 1
What would you do next?
A. Refer for botulinum toxin type B injections into salivary glands.
B. Write prescription for glycopyrrolate(Robinul).
C. Refer for botulinum toxin type A injections into the salivary glands.
D. Order suction machine and refer to hospice.
E. Refer for low dose radiation therapy to salivary glands.
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AAN Conclusions/Recommendations:
Treatment of SialorrheaConclusions: In patients with medically refractory sialorrhea,
botulinum toxin B (BTxB) injections into the parotid and submandibular glands are probably effective (one Class I study).
There are inadequate data on the effectiveness of botulinum toxin A (BTxA) (one Class III study).
Low-dose irradiation is possibly effective for sialorrhea(two Class III studies).
Recommendations: In patients with ALS who have medically refractory
sialorrhea, BTxB should be considered (Level B) and low-dose radiation therapy to the salivary glands may be considered (Level C).
Miller, R.G., Jackson, C.E, et al. Neurology, 2009. 73(15): p. 1227-33. 10
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Sialorrhea Treatments
Amitriptyline (Elavil) 25-100 mg qhs Nortriptyline (Pamelor) 20-100 mg qhs Diphenydramine (Benadryl) 25-50 mg TID Glycopyrrolate (Robinul) 1-2 mg q 4h Hyoscyamine sulfate (Levsin) 0.125-0.25 mg
q 4-6h Transdermal scopolamine 0.5mg behind ear
q 3 days Atropine sublingual drops (ophthalmic
drops) 1-2 drops SL q 4-6h
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Case 2
67 y/o WM with a history of ALS presents with frequent episodes of uncontrolled crying.
These are out of proportion to the triggers and are a source of embarrassment to the patient.
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Case 2
What would you recommend?
A. Ativan 0.5mg TID
B. Amitriptyline 50mg qhs (Elavil)
C. Dextromethorphan/quinidine (Nuedexta)
D. Paroxetine 10mg qam (Paxil)
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AAN Conclusion/Recommendation:
Treatment of PBA
Conclusion:
The combination of dextromethorphan/quinidine (DM/Q) is probably effective for pseudobulbar affect in ALS (one Class I study).
Recommendation:
DM/Q should be considered for symptoms of pseudobulbar affect in patients with ALS (Level B).
Miller, R.G., Jackson, C.E, et al. Neurology, 2009. 73(15): p. 1227-33. 14
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STAR Pivotal Trial Study Design
PBA- ALS (n = 197)
- MS (n = 129)
64 study sites- North America
(47 sites)
- Latin America
(17 sites)
Randomized N = 107N = 326
N = 110
N = 109
12 weeksDouble-Blind Phase
12 weeksOpen-Label Phase
DM/Q
20/10 BID
Placebo
BID
DM/Q 30/10
BID
Pioro EP, et al. Ann Neurol. 2010;68(5):693-702.15
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PBA STAR Trial Results
STAR Trial. Avanir Pharmaceuticals, Aliso Viejo, CA; 2009.
Mean C
hange F
rom
Baselin
e
(%)
Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 Week 10 Week 11 Week 12
*P < .05
****
****
***
*
PlaceboDM/Q
0
-20
-40
-60
-80
-100
Mean Weekly Episode Decrease
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PBA STAR Trial Adverse Reactions
Adverse Drug Reactions With an Incidence of ≥3% of
Subjects and ≥2x Placebo in NUEDEXTA-Treated SubjectsNUEDEXTA
n = 107
Placebo
n = 109
Diarrhea 13% 6%
Dizziness 10% 5%
Cough 5% 2%
Vomiting 5% 1%
Pioro EP, Brooks BR, Cummings J, et al. Dextromethorphan plus ultra-low dose quinidine reduces pseudobulbar affect. Ann Neurol. 2010;68(5):693-702.
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PBA DM/Q (Nuedexta) Dosing
One capsule daily by mouth for initial 7 days of therapy
Then 1 cap twice daily.
Other meds that may help with PBA, although no controlled trial has been conducted include:
- Amitriptyline
- SSRIs
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Case 3
56 y/o F with bulbar ALS
Has severe difficulty swallowing
20 pound weight loss over the past 3 mo
FVC = 20%
Refused PEG in the past and prior neurologist said her FVC was now too low.
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Case 3
What would you recommend?
A. Refer to Speech Pathologist for education on techniques to minimize risk of aspiration since PEG is too dangerous.
B. Refer patient to hospice for supportive care.
C. Proceed with PEG placement using NIV support during procedure.
E. Refer to Radiology for a RIG tube under local anesthesia.
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AAN Conclusion/Recommendation:
Timing of PEGConclusion: There are no studies of ALS-specific
indications for the timing of PEG insertion, although patients with dysphagia will possibly be exposed to less risk if PEG is placed when forced vital capacity (FVC) is above 50% of predicted (one Class III study).
Recommendation: There are insufficient data to support or
refute specific timing of PEG insertion in patients with ALS (Level U).
Miller, R.G., Jackson, C.E, et al. Neurology, 2009. 73(15): p. 1227-33. 21
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Dysphagia
Indications for PEG Placement:
Significant weight loss
Frequent choking/swallowing difficulty
Prolonged meal times
FVC < 50%
Aspiration pneumonia
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PEG Placement in
“High Risk” Patients
Uncontrolled, retrospective experience of 33 patients with erect or supine FVC <50% underwent PEG placement with NIV support.
All PEGs were successfully placed.
Mean survival was 211 days with most patients (67%) surviving more than 180 days.
FVC at time of PEG did not predict survival.
Gregory et al., Neurol 2002;58:485-487. 23
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What is the efficacy of PEG on
survival?
Studies using appropriate controls or
multivariate analysis demonstrated that
PEG is probably effective in prolonging
survival in ALS, although insufficient data
exist to quantitate the survival advantage
(2 Class II studies).
Del Piano et al 1999, Desport JC et al 200524
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Case 4
62 y/o male with ALS complains of restless sleep.
Arises 4-5 times a night to urinate.
Severely fatigued during the day and having trouble concentrating.
FVC = 80%
No improvement with Triazolam.
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Case 4
What would you recommend?
A. Refer for sleep study since FVC is normal.
B. Initiate NIV with no further workup.
C. Refer for evaluation of possible BPH.
D. Check supine FVC and/or MIP.
E. Prescribe Zolpidem (Ambien).
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AAN Recommendations:
PFTs
Recommendations:
Nocturnal oximetry may be considered to detect hypoventilation (regardless of the FVC) (Level C).
Supine FVC and MIP may be considered useful in routine respiratory monitoring, in addition to the erect FVC (Level C).
Sniff nasal pressure (SNP) may be considered to detect hypercapnia and nocturnal hypoxemia (Level C).
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AAN Conclusions/Recommendation:
Impact of NIV on Survival
Conclusions: NIV is probably effective in prolonging
survival (one Class I, three Class III studies).
NIV is probably effective in slowing the rate of FVC decline (one Class I, one Class III study).
Recommendation: NIV should be considered to treat respiratory
insufficiency in ALS, both to lengthen survival and to slow the rate of FVC decline (Level B).
Bourke SC et al. Lancet Neurol 2006;5:140–147.28
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Respiratory Insufficiency
Early Symptoms
Dyspnea on exertion
Supine dyspnea
Marked fatigue
Excessive daytime somnolence
Frequent nocturnal arousals
Vivid dreams
Morning headaches
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Respiratory Insufficiency
Late symptoms
Dyspnea at rest
Tachypnea
Fatigue while talking or eating
Weak cough
Inability to clear secretions
Drowsiness
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Respiratory Insufficiency
Medicare Criteria for Implementing NIV
FVC < 50% of predicted or
MIP < -60 cm H2O or PCO2 > 45mm Hg or Nocturnal SpO2 < 88%
for 5 minutes
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Respiratory Insufficiency
Treatment of Hypoventilation
Order Bi-PAP ST
Start with IPAP of 8 cm H20 and EPAP of 3-4 cm H20.
Initially use at night only.
Titrate IPAP by 2-3 cm H20 increments based on symptoms and tolerability.
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Respiratory Insufficiency
Treatment of Hypoventilation
Prescribe at least 2 different interfaces. (nasal mask, nasal pillows, full-face/oronasal mask)
Perform nocturnal oximetry studies every 3 months to avoid desats < 90%.
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Respiratory Insufficiency
Bi-level with AVAPS
Average Volume Assured Pressure Support (AVAPS)
Provides a fixed tidal volume.
Automatically adjusts the inspiratory pressure.
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How to Set Up AVAPS
Choose a mode: ST or PC
Set EPAP 4-5 cm
Set IPAP min at target and IPAP max
Choose a target tidal volume
For the average patient, set at 8cc/kg
IBW
For those with bulbar disease, set at
6cc/kg IBW
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Respiratory Insufficiency
Respiratory symptom management
Loosen phlegm Nebulized acetylcysteine or saline Guaifenesin Hydration Alkalol mucus wash
Treat nasal congestion Nasal steroid inhaler Heated humidifier Antihistamine Pseudoephedrine
Provide sedation Zolpidem 5-10mg qhs Amitriptyline 25-50mg qhs
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Respiratory Insufficiency
Exacerbation Prevention
Pneumococcal, and influenza vaccines
Swallowing evaluation
PEG placement before FVC < 50%
Maintain adequate hydration
Control secretions
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Case 5
80 y/o female with bulbar onset ALS presents with frequent cough for the past 2 months. Cough worsens when lying supine.
Dependent on PEG for majority of nutrition.
FVC = 20%.
Unable to clear airway secretions despite frequent use of suction machine.
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Case 5
What would you recommend?
A. Antibiotic therapy for empiric treatment of aspiration pneumonia
B. Prescription for cough medication
C. Prescribe Mechanical Insufflation/Exsufflation device (MIE)
D. Prescribe High Frequency Chest Wall Oscillation device (HFCWO)
E. Hospice referral
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AAN Recommendations:
Airway Secretion Clearance
Recommendations:
MIE (cough assist) may be considered to clear secretions in patients with ALS who have reduced peak cough flow, particularly during an acute chest infection (Level C).
There are insufficient data to support or refute HFCWO for clearing airway secretions in patients with ALS (Level U).
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Secretion Management
Use expiratory aids when FVC<50% or PECF < 160 l/min:
- Mechanical insufflator/exsufflator (MIE)
• Cough Assist
- High Frequency Chest Wall Oscillation (HFCWO)
• (The Vest, MedPulse Smart Vest)
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Secretion Management
Mechanical Insufflation-Exsufflation
Assists patients to clear retained secretions non-invasively.
Applies a positive pressure to the airway (insufflation) followed by a rapid shift to a negative pressure (exsufflation) simulating a cough.
May be applied by mask or mouthpiece or invasively via endotracheal or tracheostomy tube.
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Secretion Management
Typical MI-E Settings
Pressures (positive and negative)
• Start low, 10 to 15 cm H20
• Get patient acclimated to device
• Increase pressures as tolerated, ideally 35 to 45 cm H20
Times (Inhale, Exhale and Pause)
• Adults: 2 to 3 sec
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Secretion Management
HFCWO
Air generator rapidly inflates and deflates the vest, gently compressing the chest wall up to 25 times per second.
Thins secretions
Mucus is dislodged from the bronchial walls and moves it to more central airways.
Once mucus has moved to more central airways it is removed by coughing or suctioning.
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Secretion Management
HFCWO
10-20 minutes twice a day or more frequently if respiratory infection
Use with NIV when FVC<30%
May require concomitant use of a suction machine or Cough Assist
Frequency settings: 10-14 Hz (5-20 Hz)
Pressure settings:
30-40 cm (10-100 cm)
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Mexiletine trial
60 patients
12 week study
300mg/d or 900mg/d or placebo
Safe but 30% at 900mg discontinued
No diff ALSFRS-R
Significant decrease in cramp frequency
and intensity
Weiss M. et al, A Randomized Trial of Mexiletine in ALS: Safety and Effects on Muscle Cramps and Progression.
Neurology. 2016;86(26):1474-81.
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Symptomatic Rx for ALS
Symptoms Rx
Sialorrhea Anti-cholinergics
Botulinum toxin
Pseudobulbar affect Dextromethorphan/quinidine
(Nuedexta)
Dysphagia PEG
Respiratory insufficiency NIV
Cramps Mexilitene
Spasticity Botox or baclofen
Fatigue Modafinil
AAN ALS Practice Parameters. Miller et al, Neurology 2009;1218 and 1227.
Miller et al Neurology 2013;2136
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Conclusion
We have improved the clinical
management of ALS to help patients and
families:
- Multidisciplinary clinics
- Symptomatic management
Our goal is to provide hope to patients
and families and search for better
treatments
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Future Directions We continue to have many questions
unanswered (timing of NIV, which NIV
device is better, PEG and survival,
siahlorrhea meds, cramp meds)
We need more clinical trials in ALS for
both disease modifying agents and
symptom management.
New opportunities for comparative
effectiveness and real time clinical trials
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Thank You!
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