Transcript Practice Parameter or Technology Assessment: TITLE (an

Practice Parameter update: The care
of the patient with amyotrophic lateral
sclerosis (an evidence-based review)
Report of the Quality Standards
Subcommittee of the American Academy
of Neurology
R. G. Miller, MD, FAAN; C. E. Jackson, MD, FAAN; E. J. Kasarskis,
MD, PhD, FAAN; J. D. England, MD, FAAN; D. Forshew, RN; W.
Johnston, MD; S. Kalra, MD; J. S. Katz, MD; H. Mitsumoto, MD,
FAAN; J. Rosenfeld, MD, PhD, FAAN; C. Shoesmith, MD, BSc;
M. J. Strong, MD; S. C. Woolley, PhD
© 2009 American Academy of Neurology
The AAN develops these presentation slides as
educational tools for neurologists and other
health care practitioners. You may download
and retain a single copy for your personal use.
Please contact [email protected] to learn
about options for sharing this content beyond
your personal use.
© 2009 American Academy of Neurology
Presentation Objectives
• To review the evidence on care of the
patient with amyotrophic lateral sclerosis
(ALS)
- Drug, nutritional, and respiratory therapies
- Multidisciplinary care, symptom management, and
cognitive/behavioral impairment
• To present evidence-based
recommendations
© 2009 American Academy of Neurology
Overview
•
•
•
•
Background
Gaps in care
AAN guideline process
Analysis of evidence, conclusions,
recommendations
• Recommendations for future research
© 2009 American Academy of Neurology
Background
• In 1999, the American Academy of Neurology (AAN) published an
evidence-based practice parameter for managing patients with
amyotrophic lateral sclerosis (ALS).1
• Since that publication, there have been some important new studies,
including a randomized controlled trial of noninvasive ventilation
(NIV) in ALS.2
• Although only one drug, riluzole, has shown modest benefit and
received US Food and Drug Administration (FDA) approval, there
have been advances in symptomatic treatment for patients with this
disease.
• This revision updates the riluzole practice advisory and addresses
other management issues for care of patients with ALS.
© 2009 American Academy of Neurology
Gaps in Care
• As of the publication of this guideline update, only one
drug, riluzole, has received FDA approval.
• The evidence for recent advances in symptomatic
treatment for patients with ALS was not systematically
examined before this parameter update.
• Consensus-based general principles of ALS
management have been developed to guide clinicians in
managing patients with ALS.
© 2009 American Academy of Neurology
AAN Guideline Process
Clinical Question
Evidence
Conclusions
Recommendations
© 2009 American Academy of Neurology
Clinical Questions
• The first step in developing guidelines is to
clearly formulate questions to be answered.
• Questions address areas of controversy,
confusion, or variation in practice.
• Questions must be answerable with data
from the literature.
• Answering the question must have the
potential to improve care/patient outcomes.
© 2009 American Academy of Neurology
Literature Search/Review
Rigorous, Comprehensive, Transparent
Complete
Search
Review abstracts
Review full text
Select articles
Relevant
© 2009 American Academy of Neurology
AAN Classification of
Evidence
• All studies rated Class I, II, III, or IV
• Five different classification systems:
– Therapeutic
• Randomization, control, blinding
– Diagnostic
• Comparison to gold standard
– Prognostic
– Screening
– Causation
© 2009 American Academy of Neurology
AAN Level of
Recommendations
• A = Established as effective, ineffective or harmful (or
established as useful/predictive or not useful/predictive)
for the given condition in the specified population.
• B = Probably effective, ineffective or harmful (or
probably useful/predictive or not useful/predictive) for the
given condition in the specified population.
• C = Possibly effective, ineffective or harmful (or possibly
useful/predictive or not useful/predictive) for the given
condition in the specified population.
• U = Data inadequate or conflicting; given current
knowledge, treatment (test, predictor) is unproven.
Note that recommendations can be positive or negative.
© 2009 American Academy of Neurology
Translating Class to
Recommendations
• A = Requires at least two consistent Class
I studies.*
• B = Requires at least one Class I study or
two consistent Class II studies.
• C = Requires at least one Class II study or
two consistent Class III studies.
• U = Studies not meeting criteria for
Class I through Class III.
© 2009 American Academy of Neurology
Translating Class to
Recommendations, cont.
* In exceptional cases, one convincing
Class I study may suffice for an “A”
recommendation if 1) all criteria are met,
2) the magnitude of effect is large (relative
rate improved outcome >5 and the lower
limit of the confidence interval is >2).
© 2009 American Academy of Neurology
Applying This Process
to the Issue
We will now turn our attention to the
guidelines.
© 2009 American Academy of Neurology
Clinical Questions
1.
2.
3.
4.
5.
6.
Does riluzole prolong survival or slow disease
progression in ALS?
Does lithium carbonate prolong survival or slow
disease progression in ALS?
What is the effect of enteral nutrition administered via
percutaneous endoscopic gastrostomy (PEG) on
weight stability?
When is PEG indicated in ALS?
What is the efficacy of nutritional support via PEG in
prolonging survival?
What is the effect of enteral nutrition delivered via PEG
on quality of life (QOL)?
© 2009 American Academy of Neurology
Clinical Questions, cont.
7.
What is the efficacy of vitamin and nutritional
supplements on prolonging survival or QOL?
8. What are the optimal pulmonary tests to detect
respiratory insufficiency?
9. Does NIV improve respiratory function or increase
survival?
10. How do invasive ventilation and NIV affect QOL?
11. What factors influence acceptance of invasive
ventilation and NIV?
12. What is the efficacy of targeted respiratory
interventions for clearing secretions?
© 2009 American Academy of Neurology
Clinical Questions, cont.
13. How should a physician tell patients that they have
ALS?
14. Does multidisciplinary management improve
outcomes?
15. What are the most effective treatments for sialorrhea?
16. What pharmacologic measures reduce pseudobulbar
affect?
17. What pharmacologic interventions reduce fatigue?
18. What interventions reduce cramps?
19. What interventions reduce spasticity?
20. What pharmacologic interventions reduce depression?
© 2009 American Academy of Neurology
Clinical Questions, cont.
21. What pharmacologic interventions reduce anxiety?
22. What pharmacologic interventions reduce insomnia?
23. What is the prevalence and natural history of cognitive
and behavioral impairment in ALS?
24. How is cognitive or behavioral impairment in ALS
diagnosed?
25. What is the effect of cognitive or behavioral impairment
on management of patients with ALS?
26. What treatments are effective for cognitive or
behavioral impairment in ALS?
27. What treatments for dysarthria optimize
communication in ALS?
© 2009 American Academy of Neurology
Clinical Questions, cont.
28. What treatments reduce pain and dyspnea in the
terminal phase of ALS?
29. Do hospice care, spiritual interventions, or advance
directives improve quality of life in the terminal phase
of ALS?
30. What is the optimal method of withdrawing both NIV
and invasive ventilation in ALS?
© 2009 American Academy of Neurology
Methods
• OVID, MEDLINE EMBASE, CINAHL,
Science Citation Index, BIOETHICSLINE,
International Pharmaceutical Abstracts
(IPAB), OVID Current contents, MedlineProQuest, EIFL, and INVEST
– 1998 through September 2007
– Relevant, fully published, peer-reviewed
articles
© 2009 American Academy of Neurology
Methods, cont.
• Search terms
– Combined the words ALS, Lou Gehrig's
disease, and motor neuron disease with the
following words using AND:
•
•
•
•
respiratory, respiratory failure, respiratory insufficiency
nutrition, enteral nutrition, malnutrition, weight loss, gastrostomy
clinical trials
mechanical insufflation-exsufflation, high frequency chest wall
oscillation, Vest, Bipap, tracheostomy ventilation, dysphagia,
mechanical ventilation, noninvasive ventilation, hypoventilation,
• bronchial secretions, sleep-disordered breathing, breath stacking
• sialorrhea, pseudobulbar palsy, pseudobulbar affect, emotional
lability
© 2009 American Academy of Neurology
Methods, cont.
• Search terms, cont.
• palliative care, diagnosis, telling the diagnosis, breaking the news,
advance directives, hospice
• botulinum toxin A, botulinum toxin B, parotid irradiation,
anticholinergic drugs, amitriptyline, glycopyrrolate, benztropine,
transdermal hyoscyamine, atropine, trihexyphenidyl hydrochloride,
propranolol, metoprolol, dextromethorphan, quinidine, opioids,
opiates, lorazepam
• oxygen, dyspnea, pain, anxiety, sleep, depression, cramps,
spasticity, insomnia, deep venous thrombosis, communication
devices, fatigue, constipation
• multidisciplinary clinic, specialty clinic
• cognitive impairment, dementia, frontotemporal dementia, executive
dysfunction
© 2009 American Academy of Neurology
Methods, cont.
• All panelists reviewed each article for inclusion.
• Risk of bias was determined using the
classification of evidence for each study
(Classes I–IV).
• Strength of practice recommendations were
linked directly to levels of evidence (Levels A, B,
C, and U).
• Conflicts of interest were disclosed.
© 2009 American Academy of Neurology
Literature Review
• Inclusion criteria:
– Relevant to the clinical questions
– Limited to human subjects
– Randomized controlled trials, cohort studies, case
control studies, case series, meta-analyses, and
review papers
• Exclusion criteria:
– Articles related to postpolio conditions, cancer, or
non-ALS disease
– Articles not peer-reviewed
© 2009 American Academy of Neurology
AAN Classification of Evidence
for Therapeutic Intervention
•
Class I: A randomized, controlled clinical trial of the intervention of interest
with masked or objective outcome assessment, in a representative
population. Relevant baseline characteristics are presented and
substantially equivalent among treatment groups or there is appropriate
statistical adjustment for differences. The following are also required: a.
concealed allocation, b. primary outcome(s) clearly defined, c.
exclusion/inclusion criteria clearly defined, d. adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias. e. For
non inferiority or equivalence trials claiming to prove efficacy for one or both
drugs, the following are also required**: 1. The authors explicitly state the
clinically meaningful difference to be excluded by defining the threshold for
equivalence or non-inferiority. 2. The standard treatment used in the study
is substantially similar to that used in previous studies establishing efficacy
of the standard treatment. (e.g. for a drug, the mode of administration, dose
and dosage adjustments are similar to those previously shown to be
effective).
© 2009 American Academy of Neurology
AAN Classification of Evidence
for Therapeutic Intervention, cont
3. The inclusion and exclusion criteria for patient selection and the
outcomes of patients on the standard treatment are comparable to those of
previous studies establishing efficacy of the standard treatment. 4. The
interpretation of the results of the study is based upon a per protocol
analysis that takes into account dropouts or crossovers.
•
Class II: A randomized controlled clinical trial of the intervention of interest
in a representative population with masked or objective outcome
assessment that lacks one criteria a–e above or a prospective matched
cohort study with masked or objective outcome assessment in a
representative population that meets b–e above. Relevant baseline
characteristics are presented and substantially equivalent among treatment
groups or there is appropriate statistical adjustment for differences.
•
Class III: All other controlled trials (including well-defined natural history
controls or patients serving as own controls) in a representative population,
where outcome is independently assessed, or independently derived by
objective outcome measurement.***
© 2009 American Academy of Neurology
AAN Classification of Evidence
for Therapeutic Intervention, cont
•
Class IV: Studies not meeting Class I, II or III criteria including consensus or
expert opinion.
**Note that numbers 1–3 in Class Ie are required for Class II in equivalence
trials. If any one of the three is missing, the class is automatically
downgraded to Class III.
***Objective outcome measurement: an outcome measure that is unlikely to
be affected by an observer’s (patient, treating physician, investigator)
expectation or bias (e.g., blood tests, administrative outcome data).
© 2009 American Academy of Neurology
AAN Classification of Evidence
for Diagnostic Accuracy
•
Class I: A cohort study with prospective data collection of a broad spectrum
of persons with the suspected condition, using an acceptable reference
standard for case definition. The diagnostic test is objective or performed
and interpreted without knowledge of the patient’s clinical status. Study
results allow calculation of measures of diagnostic accuracy.
•
Class II: A case control study of a broad spectrum of persons with the
condition established by an acceptable reference standard compared to a
broad spectrum of controls or a cohort study where a broad spectrum of
persons with the suspected condition where the data was collected
retrospectively. The diagnostic test is objective or performed and interpreted
without knowledge of disease status. Study results allow calculation of
measures of diagnostic accuracy.
© 2009 American Academy of Neurology
AAN Classification of Evidence
for Diagnostic Accuracy, cont.
•
Class III: A case control study or cohort study where either persons with the
condition or controls are of a narrow spectrum. The condition is established
by an acceptable reference standard. The reference standard and
diagnostic test are objective or performed and interpreted by different
observers. Study results allow calculation of measures of diagnostic
accuracy.
•
Class IV: Studies not meeting Class I, II or III criteria including consensus,
expert opinion or a case report.
© 2009 American Academy of Neurology
Analysis of Evidence
Question 1: Does riluzole prolong
survival or slow disease progression in
ALS?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– Riluzole is safe and effective for slowing disease
progression to a modest degree in ALS (four Class I
studies).
Recommendation:
– Riluzole should be offered to slow disease
progression in patients with ALS (Level A).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 2: Does lithium carbonate
prolong survival or slow disease
progression in ALS?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– There are inadequate data on the effectiveness of
lithium carbonate (one Class III study).
Recommendation:
– There are insufficient data at this time to support or
refute treatment with lithium carbonate in patients with
ALS (Level U).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 3: What is the effect of
enteral nutrition administered via PEG
on weight stability?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– Enteral nutrition administered via PEG is probably
effective in stabilizing body weight/body mass index
(two Class II, seven Class III studies).
Recommendation:
– In patients with ALS with impaired oral food intake,
enteral nutrition via PEG should be considered to
stabilize body weight (Level B).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 4: When is PEG indicated in
ALS?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– 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).3
Recommendation:
– There are insufficient data to support or refute specific
timing of PEG insertion in patients with ALS (Level
U).3
© 2009 American Academy of Neurology
Analysis of Evidence
Question 5: What is the efficacy of
nutritional support via PEG in
prolonging survival?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– 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 (two
Class II studies).
Recommendation:
– PEG should be considered for prolonging survival in
patients with ALS (Level B).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 6: What is the effect of
enteral nutrition delivered via PEG on
QOL?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– No evidence exists regarding the effect of enteral
nutrition on quality of life.
Recommendation:
– There are insufficient data to support or refute PEG
for improving quality of life in patients with ALS (Level
U).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 7: What is the efficacy of
vitamin and nutritional supplements on
prolonging survival or QOL?
© 2009 American Academy of Neurology
Conclusions
Conclusions:
– Creatine, in doses of 5-10g daily, is established as
ineffective in slowing the rate of progression or in
improving survival in ALS (two Class I studies).
– Vitamin E 5,000 mg/d plus riluzole is probably
ineffective in improving survival or functional
outcomes (one Class I study). Vitamin E (1,000 mg/d
plus riluzole) was marginally effective in slowing the
progression of ALS from milder to more severe ALS
health states using a single measure but is ineffective
using multiple other measures (one Class I study).
© 2009 American Academy of Neurology
Recommendations
Recommendations:
– Creatine, in doses of 5-10g daily, should not be given
as treatment for ALS because it is not effective in
slowing disease progression (Level A).
– High-dose vitamin E should not be considered as
treatment for ALS (Level B), while the equivocal
evidence regarding low-dose vitamin E permits no
recommendation (Level U).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 8: What are the optimal
pulmonary tests to detect respiratory
insufficiency?
© 2009 American Academy of Neurology
Conclusions
Conclusions:
– Nocturnal oximetry and maximal inspiratory pressure
(MIP) are possibly more effective in detecting early
respiratory insufficiency than erect FVC (two Class III
studies).
– Supine FVC is possibly more effective than erect FVC
in detecting diaphragm weakness and correlates
better with symptoms of nocturnal hypoventilation
(two Class III studies).
© 2009 American Academy of Neurology
Conclusions, cont.
Conclusions, cont.:
– Sniff transdiaphragmatic pressure (Pdi) and sniff
nasal pressure (SNP) are possibly effective in
detecting hypercapnia and nocturnal hypoxemia (two
Class III studies).
© 2009 American Academy of Neurology
Recommendations
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).
– SNP may be considered to detect hypercapnia and
nocturnal hypoxemia (Level C).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 9: Does NIV improve
respiratory function or increase
survival?
© 2009 American Academy of Neurology
Conclusions/Recommendation
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).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 10: How do invasive
ventilation and NIV affect QOL?
© 2009 American Academy of Neurology
Conclusions
Conclusions:
– NIV is possibly effective in raising QOL for patients
with ALS who have respiratory insufficiency (five
Class III studies).
– Tracheostomy invasive ventilation (TIV) is possibly
effective in preserving QOL for patients with ALS, but
possibly with a greater burden for their caregivers
(two Class III studies).
© 2009 American Academy of Neurology
Recommendations
Recommendations:
– NIV may be considered to enhance QOL in patients
with ALS who have respiratory insufficiency (Level
C).
– TIV may be considered to preserve QOL in patients
with ALS who want long-term ventilatory support.
(Level C).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 11: What factors influence
acceptance of invasive ventilation and
NIV?
© 2009 American Academy of Neurology
Conclusions/Recommendation
Conclusions:
– Nocturnal oximetry is possibly effective in detecting early
respiratory insufficiency and the early use of NIV possibly
increases compliance (two Class III studies).
– Bulbar involvement and executive dysfunction possibly lower
compliance with NIV (two Class III studies).
Recommendation:
– NIV may be considered at the earliest sign of nocturnal
hypoventilation or respiratory insufficiency in order to improve
compliance with NIV in patients with ALS (Level C).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 12: What is the efficacy of
targeted respiratory interventions for
clearing secretions?
© 2009 American Academy of Neurology
Conclusions
Conclusions:
– Mechanical insufflation/exsufflation (MIE) is possibly
effective for clearing upper airway secretions in
patients with ALS who have reduced peak cough
flow, although the clinically meaningful difference is
unknown (four Class III studies).
– High frequency chest wall oscillation (HFCWO) is
unproven for adjunctive airway secretion
management (two Class III studies with conflicting
results).
© 2009 American Academy of Neurology
Recommendations
Recommendations:
– MIE 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).
© 2009 American Academy of Neurology
Clinical Context
– Medications with mucolytics like guaifenesin
or N-aceylcysteine, a B-receptor antagonist
(such as metoprolol or propanolol), nebulized
saline, or an anticholinergic bronchodilator
such as ipratropium are widely used;
however, no controlled studies exist in ALS.
© 2009 American Academy of Neurology
Analysis of Evidence
Question 13: How should a physician
tell patients that they have ALS?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– There have been no controlled trials of breaking the
news in ALS.
Recommendation:
– There is insufficient evidence to support or refute any
specific method of disclosing the diagnosis in ALS
(Level U).
© 2009 American Academy of Neurology
Clinical Context
– Useful strategies have been developed for
disclosing a diagnosis of cancer (see
appendix e-1 of the published guideline).4
© 2009 American Academy of Neurology
Analysis of Evidence
Question 14: Does multidisciplinary
management improve outcomes?
© 2009 American Academy of Neurology
Conclusions/Recommendations
Conclusions:
– Two Class II studies and one Class III study show that
multidisciplinary clinics specializing in ALS care are probably
effective in several ways: increased use of adaptive equipment;
increased utilization of riluzole, PEG, and NIV; improved quality
of life; and lengthened survival. However, one Class II study with
low use of treatments found no survival benefit.
Recommendations:
– Specialized multidisciplinary clinic referral should be considered
for patients with ALS to optimize health care delivery (Level B)
and prolong survival (Level B), and may be considered to
enhance quality of life (Level C).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 15: What are the most
effective treatments for sialorrhea?
© 2009 American Academy of Neurology
Conclusions/Recommendations
Conclusions:
– 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).
© 2009 American Academy of Neurology
Clinical Context
– In ALS and other diseases, anticholinergic
medications are generally tried first to reduce
sialorrhea, although effectiveness is
unproven.1 Botulinum toxin has been effective
in controlled trials in Parkinsonism as well as
ALS.5
© 2009 American Academy of Neurology
Analysis of Evidence
Question 16: What pharmacologic
measures reduce pseudobulbar affect?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– The combination of dextromethorphan/quinidine (DM/Q) is
probably effective for pseudobulbar affect in ALS (one Class I
study), although side effects may limit its usefulness.
Recommendation:
– If approved by the FDA, and if side effects are acceptable, DM/Q
should be considered for symptoms of pseudobulbar affect in
patients with ALS (Level B).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 17: What pharmacologic
interventions reduce fatigue?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– There are no controlled studies of pharmacologic agents
relieving fatigue in ALS. Riluzole may cause fatigue in some
patients (two Class III studies).
Recommendation:
– In patients developing fatigue while taking riluzole, once risks of
fatigue vs modest survival benefits have been discussed,
withholding the drug may be considered (Level C).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 18: What interventions
reduce cramps?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– Studies of gabapentin, vitamin E, and riluzole for
treating cramps were all negative (Class III). There
are safety concerns about quinine.
Recommendation:
– There are insufficient data to support or refute any
specific intervention for the treatment of cramps in
ALS (Level U).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 19: What interventions
reduce spasticity?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– Evidence is insufficient to recommend exercise or
medication for treating spasticity in ALS (Class III).
Recommendation:
– There are insufficient data to support or refute
exercise or medication for treating spasticity in ALS
(Level U).
© 2009 American Academy of Neurology
Clinical Context
– In multiple sclerosis and cerebral palsy,
benzodiazepam, baclofen, dantrolene, and
tizanidine are effective in reducing spasticityrelated symptoms.6
© 2009 American Academy of Neurology
Analysis of Evidence
Question 20: What pharmacologic
interventions reduce depression?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– There have been no controlled trials of treatment for
depression in ALS.
Recommendation:
– There are insufficient data to support or refute specific
treatments for depression in ALS (Level U).
© 2009 American Academy of Neurology
Clinical Context
– There is consensus amongst experts that
depression should be treated in patients with
ALS7; however, there are no controlled
studies of benefit or harm.
© 2009 American Academy of Neurology
Analysis of Evidence
Question 21: What pharmacologic
interventions reduce anxiety?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– There have been no trials of treatment for anxiety in
ALS.
Recommendation:
– There are insufficient data to support or refute specific
treatment for anxiety in ALS (Level U).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 22: What pharmacologic
interventions reduce insomnia?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– There have been no studies of treatment for insomnia
in ALS.
Recommendation:
– There are insufficient data to support or refute specific
treatment for insomnia in ALS (Level U).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 23: What is the prevalence
and natural history of cognitive and
behavioral impairment in ALS?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– A significant proportion of patients with ALS
demonstrate cognitive impairment and some have
dementia (two Class II, multiple Class III studies).
Neither behavioral impairment in ALS nor the natural
progression of cognitive or behavioral impairments
have been adequately studied.
Recommendation:
– Screening for cognitive and behavioral impairment
should be considered in patients with ALS (Level B).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 24: How is cognitive or
behavioral impairment in ALS
diagnosed?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– Neuropsychological assessment is possibly effective
for identifying cognitive impairment in ALS (one Class
II, one Class III).
Recommendation:
– Screening tests of executive function may be
considered to detect cognitive impairment in patients
with ALS prior to confirmation with formal
neuropsychological evaluation (Level C).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 25: What is the effect of
cognitive or behavioral impairment on
management of patients with ALS?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– Insufficient data exist on the effect of cognitive or
behavioral impairment on the management of patients
with ALS.
Recommendation:
– There are insufficient data to support or refute the
impact of cognitive and behavioral impairment on
management in ALS (Level U).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 26: What treatments are
effective for cognitive or behavioral
impairment in ALS?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– Data are inadequate regarding the effect of NIV on
cognition.
Recommendation:
– There are insufficient data to support or refute
treatment of cognitive or behavioral impairment in
ALS (Level U).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 27: What treatments for
dysarthria optimize communication in
ALS?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– No controlled studies examined communication in
ALS.
Recommendation:
– There are insufficient data to support or refute
treatment to optimize communication in ALS (Level
U).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 28: What treatments reduce
pain and dyspnea in the terminal phase
of ALS?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– No controlled studies examined treating pain or
dyspnea in late-stage ALS.
Recommendation:
– There are insufficient data to support or refute specific
treatments for pain and dyspnea in terminal ALS
(Level U).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 29: Do hospice care, spiritual
interventions, or advance directives
improve quality of life in the terminal
phase of ALS?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– No controlled studies examined hospice, spiritual
care, or advance directives in ALS.
Recommendation:
– There are insufficient data to support or refute
hospice, spiritual care, or advance directives in ALS
(Level U).
© 2009 American Academy of Neurology
Analysis of Evidence
Question 30: What is the optimal
method of withdrawing both NIV and
invasive ventilation in ALS?
© 2009 American Academy of Neurology
Conclusion/Recommendation
Conclusion:
– There are no controlled studies examining withdrawal
of ventilation in ALS.
Recommendation:
– There are insufficient data to support or refute specific
strategies for withdrawal of ventilation in ALS (Level
U).
© 2009 American Academy of Neurology
Clinical Context
– Protocols based on consensus for withdrawal
of mechanical ventilation in intensive care
units (Class IV)8 include counseling and
symptom control with opioids,
benzodiazepines, and anticholinergic
medications.9 We could find no controlled
studies in any disease.
© 2009 American Academy of Neurology
Clinical Context
– This evidence-based review indicates some
progress in evaluating new therapies for
patients with ALS. More high-quality studies
have been reported leading to more confident
recommendations regarding the value of NIV
and PEG.
© 2009 American Academy of Neurology
Clinical Context
– It is one thing to publish an evidence-based
practice parameter for the management of
patients with ALS, and it is quite another to be
able to track adherence in practice and to
determine whether the publication of
evidence-based guidelines has changed
outcomes.
© 2009 American Academy of Neurology
Clinical Context, cont.
– The ALS patient CARE database was
developed with the hope of standardizing new
and effective therapies for patients with ALS
and tracking outcomes to raise the standard
of care.10
– Data obtained from the ALS CARE program
have shown that the underutilization of many
therapies (especially PEG and NIV) has
persisted in the years since the original
practice parameter on this topic, though there
have been gains.
© 2009 American Academy of Neurology
Clinical Context, cont.
– These findings suggest that an evidencebased practice parameter may over time
become more widely accepted and change
practice. However, the persistent
underutilization of therapies that improve
survival and QOL poses a challenge for ALS
clinicians to continue to raise the standard of
care for patients with ALS.
© 2009 American Academy of Neurology
Future Research
This evidence-based review indicates some
progress in evaluating new therapies for
patients with ALS. More high-quality studies
have been reported leading to more confident
recommendations regarding multidisciplinary
clinics and symptomatic therapy for
pseudobulbar effect and sialorrhea. However,
future research in the following areas is still
greatly needed.
© 2009 American Academy of Neurology
Future Research, cont.
Lithium carbonate
– Study whether lithium slows disease progression or prolongs
survival in ALS in larger clinical trials.
Nutrition
– Develop ALS-specific indications for nutritional adequacy in ALS
and for PEG and radiologically inserted gastrostomy (RIG).
– Study the optimal timing of nutritional therapy administered via
PEG or RIG.
– Conduct clinical studies of novel antioxidants and supplements .
© 2009 American Academy of Neurology
Future Research, cont.
Respiratory Management
– Evaluate SNP as a criterion for NIV initiation.
– Evaluate the impact of early NIV initiation on survival and quality
of life.
– Assess the impact of executive dysfunction on NIV compliance.
– Evaluate the effect of hypoventilation on executive dysfunction.
– Compare techniques for clearing upper airway secretions at
various stages of respiratory and bulbar dysfunction.
– Evaluate pulmonary tests, compliance with NIV, and outcomes in
patients with bulbar dysfunction.
© 2009 American Academy of Neurology
Future Research, cont.
Breaking the News
– Validate measures that can be applied to studies of diagnostic
disclosure.
– Evaluate attitudes of neurologists and patients to strategies for
breaking the news.
– Conduct controlled studies of the effects of different disclosure
strategies on patient satisfaction, preserving hope, and
outcomes.
Multidisciplinary Clinic
– Examine referral bias to clinics.
– Examine factors essential to benefits in clinics, optimal visit
frequency, cost effectiveness of staff, and economic factors in
care.
© 2009 American Academy of Neurology
Future Research, cont.
Symptomatic Management
– Conduct controlled trials of pharmacologic therapy for spasticity,
cramps, constipation, sialorrhea, pseudobulbar affect, pain,
depression, anxiety, fatigue, and therapeutic exercise.
– Examine irradiation and botulinum toxin for sialorrhea in
controlled trials.
Cognitive and Behavioral Impairment
– Develop consensus criteria for cognitive and behavioral
impairment to ensure consistency in diagnosis and research.
– Identify screening tests for cognitive and behavioral impairment.
– Evaluate the natural history of, and treatments for, cognitive and
behavioral impairment, and their impact on compliance and
survival.
© 2009 American Academy of Neurology
Future Research, cont.
Communication
– Validate criteria to examine communication strategies.
– Design clinical trials to compare different strategies for
communication in ALS.
Palliative Care
– Design controlled trials of terminal symptom management,
advanced directives, hospice, and spiritual care.
© 2009 American Academy of Neurology
Acknowledgments
The authors thank Gary Gronseth, MD; Thomas
Getchius; Valerie Cwik, MD; Larry Brower; and
Sid Valo for contributions to the practice
parameters; Christina Metzler and Barbara
Phillips, MS, OTR/L, for their contributions to the
patient summary versions of the guidelines; and
Sharon J. Matland, RN, MBA, for her
contributions to both the practice parameters
and the patient summary versions.
© 2009 American Academy of Neurology
References
1.
2.
3.
4.
5.
6.
Miller RG, Rosenberg JA, Gelinas DF, et al. Practice parameter: the care of the
patient with amyotrophic lateral sclerosis (an evidence-based review): report of the
Quality Standards Subcommittee of the American Academy of Neurology: ALS
Practice Parameters Task Force. Neurology 1999;52:1311-1323.
Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, Gibson GJ. Effects of
non-invasive ventilation on survival and quality of life in patients with amyotrophic
lateral sclerosis: a randomised controlled trial. Lancet Neurol 2006;5:140-147.
Kasarskis EJ, Scarlata D, Hill R, Fuller C, Stambler N, Cedarbaum JM. A
retrospective study of percutaneous endoscopic gastrostomy in ALS patients during
the BDNF and CNTF trials. J Neurol Sci 1999;169:118-125.
Numico G, Anfossi M, Bertelli G, et al. The process of truth disclosure: an
assessment of the results of information during the diagnostic phase in patients with
cancer. Ann Oncol 2009.
Molloy L. Treatment of sialorrhea in patients with Parkinson's disease: best current
evidence. Curr Opin Neurol 2007;20:493-498.
Abbruzzese G. The medical management of spasticity. Eur J Neurol 2002;9 Suppl
1:30-34; discussion 53-61.
© 2009 American Academy of Neurology
References
7.
Andersen PM, Borasio GD, Dengler R, et al. EFNS task force on management of
amyotrophic lateral sclerosis: guidelines for diagnosing and clinical care of patients
and relatives. Eur J Neurol 2005;12:921-938.
8. O'Mahony S, McHugh M, Zallman L, Selwyn P. Ventilator withdrawal: procedures
and outcomes. Report of a collaboration between a critical care division and a
palliative care service. J Pain Symptom Manage 2003;26:954-961.
9. Lanken PN, Terry PB, Delisser HM, et al. An official American Thoracic Society
clinical policy statement: palliative care for patients with respiratory diseases and
critical illnesses. Am J Respir Crit Care Med 2008;177:912-927.
10. Miller RG, Anderson F, Neelam G, Wei Hea. The ALS Patient CARE ProgramNorthern American Patient CARE Database. In: Mitsumoto H, Przedborski, S.,
Gordon, P.H., ed. Amyotrophic Lateral Sclerosis: Taylor & Francis Group, 2006:
633-648.
For a complete list of references, please access the full guidelines at
www.aan.com/guidelines
© 2009 American Academy of Neurology
Questions/Comments
© 2009 American Academy of Neurology
Thank you for your
participation!
© 2009 American Academy of Neurology