Treatment for sialorrhea (excessive saliva) in people with

Transcription

motor neuron disease/amyotrophic lateral sclerosis (Review)
Young CA, Ellis C, Johnson J, Sathasivam S, Pih N
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2011, Issue 5
http://www.thecochranelibrary.com
Treatment for sialorrhea (excessive saliva) in people with motor neuron disease/amyotrophic lateral sclerosis (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . .
Figure 1.
. . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . .
AUTHORS’ CONCLUSIONS . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . .
APPENDICES . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
INDEX TERMS
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i
[Intervention Review]
motor neuron disease/amyotrophic lateral sclerosis
Carolyn A Young1 , Cathy Ellis2 , Julia Johnson3 , Sivakumar Sathasivam4 , Nicky Pih5
1 The
Walton Centre for Neurology and Neurosurgery, Liverpool, UK. 2 Motor Nerve Clinic, Academic Neurosciences Centre, King’s
College Hospital, London, UK. 3 Speech and Language Therapy Department, King’s College Hospital, London, UK. 4 Neurology
Department, The Walton Centre for Neurology and Neurosurgery, Liverpool, UK. 5 Research Office, Neuro Rehabilitation Unit,
Liverpool, UK
Contact address: Carolyn A Young, The Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley, Liverpool, L9 7LJ,
UK. [email protected].
Editorial group: Cochrane Neuromuscular Disease Group.
Publication status and date: New, published in Issue 5, 2011.
Review content assessed as up-to-date: 30 September 2010.
Citation: Young CA, Ellis C, Johnson J, Sathasivam S, Pih N. Treatment for sialorrhea (excessive saliva) in people with motor
neuron disease/amyotrophic lateral sclerosis. Cochrane Database of Systematic Reviews 2011, Issue 5. Art. No.: CD006981. DOI:
10.1002/14651858.CD006981.pub2.
ABSTRACT
Background
Motor neuron disease (MND), also known as amyotrophic lateral sclerosis, is a progressive, neurodegenerative condition which may
cause dysphagia, as well as limb weakness, dysarthria, emotional lability and respiratory failure. Since normal salivary production is
0.5 to 1.5 litres daily, loss of salivary clearance due to dysphagia leads to salivary pooling and sialorrhea, often resulting in distress and
inconvenience to patients.
Objectives
To systematically review evidence on treatment of sialorrhea in MND, including medications, radiotherapy and surgery.
Search methods
We searched the Cochrane Neuromuscular Disease Group Specialized Register (1 October 2010), the Cochrane Central Register of
Controlled Trials )(CENTRAL) (The Cochrane Library issue 3, 2010), MEDLINE (January 1966 to September 2010), EMBASE
(January 1980 to September 2010), AMED (1985 to September 2010) and CINAHL Plus (January 1937 September 2010). All
bibliographies of the identified randomized trials were reviewed and authors contacted as needed. Known experts in the field were
contacted to identify further published and unpublished papers.
Selection criteria
We included randomized and quasi-randomised controlled studies on any intervention for sialorrhea and related symptoms, in people
with MND.
Data collection and analysis
Review authors summarised data independently in a customised data collection form and confirmed data presented in Cochrane Review
Manager software.
1
Main results
Only one randomized controlled trial was identified. This was a well designed study of botulinum toxin B injected into parotid and
submandibular glands of 20 patients, which showed positive results for four weeks (Jackson 2009). There was low risk of bias in the
study and no significant adverse events reported.
Authors’ conclusions
There is some evidence for use of botulinum toxin injections to salivary glands for the treatment of sialorrhea in MND. Further research
is required on this important symptom. Data are needed on the problem of sialorrhea in MND and its measurement, both by patient
self report measures and objective tests. These will allow the development of better randomized controlled trials.
PLAIN LANGUAGE SUMMARY
Treatment of unintentional drooling of saliva in motor neuron disease
Unintentional drooling of saliva (sialorrhea) is a distressing symptom suffered by up to 25% of patients with motor neuron disease. The
management of sialorrhea currently involves the use of suction, drug treatments and more invasive approaches, including injection of
botulinum toxin to the salivary glands, radiotherapy to the salivary glands and ligation (surgery to tie off ) of the salivary gland ducts.
An extensive search of the literature identified only one randomized controlled trial, of 20 patients, which could be included in the
review. This study reported a beneficial effect of botulinum toxin type B injected into the parotid and submandibular salivary glands
in patients with MND on a single occasion. The study appeared to have low risk of bias, and no serious adverse events were recorded.
Although other treatments are supported by case control studies, there was no evidence to compare the effectiveness of different
treatments for sialorrhea. Further research is needed to compare the different treatments available and to optimise treatment regimens.
BACKGROUND
Motor neuron disease (MND), also known as amyotrophic lateral
sclerosis (ALS), is a progressive neurodegenerative disorder characterised by relatively selective death of upper motor neurons in
the cerebral cortex and lower motor neurons in the brainstem and
spinal cord (Shaw 1999). This gives rise to a combination of upper and lower motor neuron signs and symptoms such as weakness in the limb and bulbar muscles with atrophy, spasticity and
weight loss. The onset of MND can be insidious and it may take
up to 18 months to diagnose the condition. By the time diagnosis
is made, the person may have significant functional deficits and
symptom control needs. Death occurs in most patients within two
to five years after diagnosis, usually from ventilatory muscle weakness causing respiratory failure (Rowland 2001). The incidence of
ALS/MND is one to two per 100,000 of the population (Worms
2001). At any one time, there are approximately 5000 affected
people in the United Kingdom (Shaw 1999) and 25,000 in North
America (McGuire 1996).
In MND, approximately 70% of people present with limb involvement and 30 (Abhinav 2007) with bulbar symptoms such
dysphagia, dysarthria, hoarseness and hypophonia. Eighty per cent
of people with MND will develop bulbar weakness at some stage
of the disease (Oliver 1996). Many people benefit from alternative
feeding methods such as percutaneous endoscopic gastrostomy
(PEG) or radiologically inserted gastrostomy (RIG/PRG) (Leigh
2003; Mitsomoto 2003).
Sialorrhea, the unintentional loss of saliva from the mouth, occurs
in up to 25% of people with MND. Veis and colleagues showed
that for people with MND, sialorrhea is not caused by increased
production of saliva but by the inability to swallow secretions because of tongue spasticity, weakness of face, mouth and pharyngeal
muscles, and loss of oropharyngeal co-ordination and function
(Veis 2000). There are two main types of saliva produced by the
three major salivary glands; serous saliva, which is thin and watery,
and mucoidal saliva, which is thicker and more viscous. The nose
and lungs also contribute to the flow of secretions, usually in the
form of thick, tenacious ’phlegm’ (Newall 1996).
All these forms of secretions can cause patient discomfort. Serous
saliva can be watery and constantly dribbling from the side of the
mouth, and mucoidal saliva may be tenacious and thick, making
it difficult to clear and contributing to the sensation of choking
2
and associated panic. It is important to distinguish between thin,
runny saliva and thick, mucous secretions because the treatment
options differ (Miller 1999). The skin may become excoriated
from constant exposure to moisture, voice quality may be compromised and sleep may be disturbed by secretion build-up. These
symptoms may lead to increased fatigue, embarrassment, social
withdrawal and isolation. Therefore, sialorrhea can significantly
affect quality of life.
Riluzole, a putative glutamate release blocker, is currently the only
drug licensed for human use in MND. Its effect is modest, only
prolonging survival by about two to three months in people with
MND (Miller 2007). Therefore, symptom control and maximisation of quality of life are the principal aims of any treatment
(Oliver 1996).
At present, the treatment of sialorrhea is largely a matter of trial
and error, using a variety of drug treatments, natural remedies, oral
suction, and more invasive approaches, such as injection of botulinum toxin into salivary glands, radiotherapy to salivary glands
or ligation of salivary gland ducts. Behavioural techniques are also
advocated in the early management stages such as purposeful swallowing of the saliva as it builds up in the mouth and before speaking. This has been shown to be effective in people with Parkinson’s
disease where a metronome brooch was used as a reminder to cue
a conscious saliva swallow (Marks 2001). Management appears
largely governed by the personal preference of the clinician, and in
the case of more invasive measures, the local availability of these
techniques. Frequently, the person with MND will need to try a
number of treatment options with varying degrees of success.
Several potential treatments have been described in the literature.
Salivation is mainly mediated through parasympathetic stimulation. Acetylcholine is the active neurotransmitter, binding at muscarinic receptors in the salivary glands (Meningaud 2006). Thus,
cholinergic muscarinic receptor antagonists or drugs with these
properties, such as atropine, scopolamine (hyoscine), glycopyrronium bromide and tricyclic antidepressants can be used to treat
sialorrhea in MND (Borasio 1997). Whereas the stimulation of
cholinergic receptors produces thin, serous secretions, that of beta
adrenergic receptors produce thick protein and mucus-rich secretions. Beta blockers have been shown to produce relief from thick
secretions in 12 of 16 people with bulbar MND (Newall 1996).
The mucolytic drug carbocisteine may also be beneficial in MND
as it reduces elastic modules of mucus and improves mucociliary
transport (Sakakura 1985).
Use of botulinum toxin to reduce salivary flow in MND was
first hypothesised in modern day literature by Bushara in 1997
(Bushara 1997). It is thought that botulinum toxin injections
reduce sialorrhea by blocking the release of acetylcholine at the
cholinergic neurosecretory junction of salivary glands (Burgen
1949). There are now several series reported, utilising different
preparations of botulinum toxin and treatment regimens, admin-
istered by direct injection or a transductal approach, with varying outcome measures (Contarino 2007; Costa 2008; Giess 2000;
Jackson 2009; Lipp 2003; Manrique 2005; Porta 2001; Scott 2005
and Verma 2006).
In addition, various destructive measures have been trialled in
open label studies as a means to reduce salivary production. One
approach is radiotherapy to the salivary glands, either once or in
divided fractions (Andersen 2001; Harriman 2001; Neppelberg
2007; Stalpers 2002 and Winterholler 2001). Another area is surgical interventions, to excise salivary glands, or destroy nerve supply to the gland by neurectomy of the tympanic nerve (Janzen
1988).
This literature review shows that several treatments have been described in case series and open label studies, utilising a variety of
outcome measures and treating a range of case severity. A systematic review may benefit clinicians and inform better practice.
OBJECTIVES
We reviewed trials of interventions designed to minimise sialorrhea
in MND.
METHODS
Criteria for considering studies for this review
Types of studies
All randomized and quasi-randomised controlled studies were included in the review. The nature of treatment interventions made
it impossible to include only double-blinded trials and so nonblinded trials were eligible. Non-randomised trials were included
in the Discussion.
Types of participants
Only trials that explicitly stated that participants had been diagnosed with probable or definite motor neuron disease or amyotrophic lateral sclerosis according to recognised criteria, preferably the El Escorial Criteria (Brooks 2000) were included for review. Participants were over 18 years of age and of either sex.
Types of interventions
The following interventions were compared with each other,
placebo or no intervention:
1. Any drug treatment administered via any route.
3
2. Injection of botulinum toxin in parotid and/or
submandibular glands.
3. Radiotherapy to the salivary glands.
4. Surgical techniques, for example the ligation of parotid and
submandibular salivary ducts.
5. Other treatments identified in the literature, for example
complementary therapies.
Searching other resources
All bibliographies of the identified randomized trials were reviewed
and authors contacted as needed. Known experts in the field and
pharmaceutical companies were contacted to identify further published and unpublished papers. Papers in languages other than English were included and translated as necessary.
Data collection and analysis
Types of outcome measures
Selection of studies
Primary outcomes
1. Subjective improvement in sialorrhea reported by
participants in the short-term (one to 12 weeks) and long-term
(more than 12 weeks). Subjective improvement was measured
using a validated scale, or by asking participants if they improved
or not.
Secondary outcomes
1. Reduction in the amount of saliva production in the shortterm (one to 12 weeks) and long-term (more than 12 weeks),
using an objective measure such as the weight of swabs or
amount of tissue used pre- and post-intervention.
2. Quality of life of participants measured by a validated scale
in the short-term (one to 12 weeks) and long-term (more than
12 weeks).
3. Adverse effects attributable to any intervention.
Titles and abstracts identified from the searches were checked by all
review authors independently, to produce shortlists of potentially
relevant studies. The shortlists were crosschecked (CAY) and a final
shortlist agreed by discussion and consensus. The full text of all potentially relevant studies was obtained for independent assessment
by all review authors, who independently completed data extraction forms. These covered inclusion criteria and graded methodological quality. The data extraction forms were crosschecked for
any discrepancies (CAY). Decisions were based on consensus views
between all review authors.
Data extraction and management
Data extraction onto a specially designed form was performed
independently by two review authors (JJ, SS) and checked by the
other two (CE, CAY). One review author entered the data into
the software (CE) and one checked the data entered (CAY).
Assessment of risk of bias in included studies
Search methods for identification of studies
Electronic searches
We searched the Cochrane Neuromuscular Disease Group Specialized Register (1 October 2010) using the following search terms:
Sialorrhoea OR sialorrhea OR Drooling OR dribbling OR Saliva
OR Salivation OR hypersalivation OR Dysphagia OR Deglutition
Disorder OR Swallowing difficulties AND Motor Neurone Disease OR Amyotrophic Lateral Sclerosis OR ALS OR MND OR
Progressive Bulbar Palsy. This strategy was adapted to search the
Cochrane Central Register of Controlled Trials (CENTRAL) (The
Cochrane Library issue 3, 2010), MEDLINE (January 1966 to
September 2010), EMBASE (January 1980 to September 2010),
AMED (1985 to September 2010) and CINAHL Plus (January
1937 to September 2010). The search strategies can be found in
Appendix 1; Appendix 2; Appendix 3, Appendix 4 and Appendix
5 respectively.
We assessed risk of bias according to the methods in the Cochrane
Handbook for Systematic Reviews of Interventions (Higgins
2008). The methodological quality assessment took into account
sequence generation, allocation concealment, blinding (for patient
reported outcomes, objective outcomes, clinician reported outcomes, carer reported outcomes), whether incomplete outcome
data was addressed, selective outcome reporting and other sources
of bias such as exactness of the description of the clinical status,
explicit outcome criteria, and how studies dealt with baseline differences between the experimental groups. We graded these items
’Yes’ for a low risk of bias, ’No’ for a high risk of bias and ’Unclear’
when the risk of bias was uncertain or the item was not relevant
to the study. We specified that if agreement was poor, we would
reassess the studies and reach agreement by consensus. We have
described the risk of bias of included studies, and discussed the
overall reliability of the evidence in the light of this. Had data
been appropriate for this, we would have undertaken sensitivity
analyses to demonstrate the effect of downweighting or ignoring
those studies that had received low scores in the individual aspects
of quality criteria on the meta-analyses.
4
Measures of treatment effect
We analysed all the primary and secondary outcomes under consideration. If data proved adequate for meta-analysis, we planned
to calculate a weighted treatment effect across trials using the
Cochrane statistical package, Review Manager (RevMan). The results were to be expressed as relative risks (RRs) with 95% confidence intervals (CIs) and risk differences (RDs) with 95% CIs for
dichotomous outcomes, and weighted mean differences (WMDs)
and 95% CIs for continuous outcomes.
Adverse events
We summarised any adverse events, and would have categorised
any deemed severe, or leading to cessation of treatment.
Economic issues
We planned to discuss the cost-effectiveness of interventions where
there was information available to do this.
Assessment of heterogeneity
We planned to test for heterogeneity across trials, and if found we
undertook to do sensitivity analyses by repeating the calculation
omitting the trials which had low scores on individual quality
items. If heterogeneity was not explained by variations in trial
quality we undertook to use a random-effects approach to obtain
the pooled estimates from the group of trials.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
Electronic searches produced 158 references. The number of references retrieved from each database was MEDLINE = 86, EMBASE = 46, AMED = 2, CINAHL Plus = 22, CENTRAL = 10,
Register = 14 but most of these were excluded because of duplication between databases, or because they did not report a clinical
trial (reviews, case reports, and so on). We screened 19 studies in
full text and excluded a further study on the basis of the translation
of the abstract.
Of the remaining studies, the majority did not meet eligibility criteria as randomized controlled trials in patients with MND. There
was an uncontrolled trial of beta antagonists (Newall 1996). A
number of studies of botulinum toxin injections to the parotid
and/or submandibular glands (Contarino 2007; Costa 2008; Giess
2000; Manrique 2005; Porta 2001; Scott 2005; and Verma 2006)
were not controlled. One placebo-controlled study randomized
patients to three different doses of botulinum toxin or placebo,
using an unspecified method, but it was not possible to separate
the data on the 12 MND patients from the 20 other participants
suffering from Parkinson’s disease, multiple system atrophy or corticobasal degeneration (Lipp 2003). Levitski compared botulinum
toxin to amitriptyline but randomization was not described and
patients purchased their treatment which may have biased results
(Levitskii 2005). There were several uncontrolled studies on the
effect of radiotherapy to the submandibular and parotid glands
(Andersen 2001; Harriman 2001; Neppelberg 2007; Stalpers 2002
and Winterholler 2001). See Characteristics of excluded studies.
We identified one randomized controlled trial in MND (Jackson
2009) (see Characteristics of included studies). This study randomized 20 patients with MND and sialorrhea refractory to medical therapy to either botulinum toxin type B to parotid and submandibular glands, or placebo. Participants were assessed at baseline which was the day of randomization and injection under electromyographic guidance, and then at 2,4,8 and 12 weeks, with a
telephone follow-up at 1 week which could trigger an attendance
if the Revised ALS Functional Rating Scale (ALSFRS-R) swallowing or respiratory scale had changed by more than one point.
Two injections were given to each of the parotid and submandibular glands bilaterally, i.e.eight injections per patient. The injection, via a monopolar electromyography needle attached to a 1 ml
syringe, contained either 1 ml normal saline, or botulinum toxin
type B 2,500 units diluted with normal saline to a total volume of
1 ml. Absence of motor unit activity was used to confirm needle
placement in glandular/soft tissue. Each parotid gland received
0.1 ml at two sites, directing the needle between the sternocleidomastoid muscle and angle of mandible. Each submandibular
gland received two injections of 0.15 ml, placing the needle in
the submandibular triangle. Pretreatment with topical lidocaine/
prilocaine (EMLA cream) was available if requested prior to the
injection.
The primary outcome was the participant’s global impression of
change recorded on a 5 point Likert scale 8 weeks after injection.
Secondary outcome measures were listed as change in saliva volumes, number of times suctioned, patient and caregiver assessment of benefit, ALSFRS-R, and quality of life measured using
the schedule for evaluation of individual quality of life directing
weighting (SEIQoL-DW), a quality of life self rating scale using
five cues chosen and rated by the patient. Concomitant treatment
with anticholinergic drugs was kept stable or allowed to reduce
during the trial and outcome measures were collected at the same
time of day and after the patients had refrained from eating or
drinking for one hour. Questionnaires were done independently
by patient and caregiver and completed before any interaction with
the study physicians.
Following the 12 week double-blind phase, participants could enrol into an open label extension for three months. This used the
same method of injection except that the dose of botulinum toxin
5
could be adjusted so that the total dose did not exceed 5,000 units.
Risk of bias in included studies
Only one study met criteria to be included in the review (Jackson
2009). In this study, all participants had probable or definite ALS
according to World Federation of Neurology criteria and had to
have sialorrhea which was refractory to treatment with at least two
anticholinergic medications (or be intolerant of anticholinergic
treatments.) Participants were aged 21 to 85 years, had forced vital
capacity >20% predicted, could not have received any previous
treatment with botulinum toxin, and were recruited from three
“ALS centers”.
Randomisation assignment was by a random numbers table (even
botulinum toxin, odd normal saline) stratified in blocks of four
for each of the three sites. Opaque envelopes retained securely by
an unblinded investigator were opened sequentially whenever a
patient was randomized, this investigator would then prepare an
injection containing botulinum toxin or saline in a closed room
away from the blinded investigator and participant. The unblinded
investigator had no direct contact with the patients.
The 20 participants showed no statistically significant differences
between treatment and placebo groups for age, disease duration,
bulbar involvement, medical treatment, ALSFRS-R, SEIQOLDW, baseline patient assessment of saliva thickness or problem
severity, or volume of saliva. There was a higher proportion of
male patients in the placebo group (67% versus 36%).
Of 20 subjects randomized, 18 completed the double-blind phase
with one lost to follow-up and one suffering fatal cardiac arrest,
both from the treatment arm. The investigator and the safety monitor felt the death was unrelated to study medication. Fifteen of 18
eligible patients entered the open label extension, 7/9 treatment
group and 8/9 placebo group. No information was given about
why patients declined the open label study. One further patient
was lost to follow-up during the open label study, from the arm
which was originally placebo. No data are provided about outcomes from the open label phase.
An unblinding questionnaire was done for both patients and investigators at 12 weeks. Seventy per cent of investigators and 90%
subjects guessed the treatment allocation correctly, suggesting that
despite excellent attempts to maintain blinding the double-blind
was not preserved. This may have produced bias in the primary
outcome and other self report measures.
The study appeared to be at low risk of bias. A summary of the
review authors’s judgements on each risk of bias item can be found
at Figure 1
Figure 1. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.
6
Effects of interventions
Primary outcome
The primary outcome measure of the subjective improvement in
sialorrhea reported by participants in the short-term was ascertained by asking patients eight weeks after the injection. This
outcome measure of patient-rated impression of change was dichotomised to improvement or not, and analysed using Fisher’s
exact test. It showed a consistent difference in favour of botulinum
toxin, which was statistically significant at week 2 (treatment 82%
improved, placebo 38%, P < 0.05) and week 4 (treatment 90%,
placebo 44%, P < 0.05). However the difference was not statistically significant at week 8, which was the a priori primary outcome.
At two weeks 38% placebo patients and 82% of botulinum toxin
treated patients reported improvement on a patient global impression of change measure, and at four weeks the figures were 44%
and 90% respectively. These proportions were statistically significantly different at P < 0.05. At 8 weeks and 12 weeks there was
no significant difference (8 weeks placebo 22%, botulinum 67%;
12 weeks placebo 14%, botulinum 50%).
Long-term outcomes (more than 12 weeks) were not collected for
any variable.
Secondary outcomes
The objective outcome measure of change in volume of saliva produced, as measured with funnel and tube over 5 minutes, consistently favoured botulinum toxin. This difference reached statistical significance at week 2 (treatment 0.07, SD 0.2; placebo 0.84,
SD 0.8, P < 0.05) and week 4 (treatment 0.02, SD 0.04; placebo
0.97, SD 0.5, P < 0.05) but not thereafter. No data were provided
on number of times suctioned.
Other secondary outcome measures of patient assessment of saliva
problem and thickness, and caregiver assessment of saliva problem, showed trends in favour of botulinum toxin. These reached
statistical significance (VAS analysed with repeated measures of
variance, P < 0.05) at different times in the 12 week follow-up,
with patient assessment of both saliva thickness and problem statistically significant at 12 weeks. It should be noted that the unblinding questionnaire done at this time point revealed 90% patients could correctly guess their treatment allocation.
Quality of life of participants measured by using the SEIQOL-DW
favoring botulinum toxin. The clinicians’ assessment of marked
improvement showed a statistically significant difference with botulinum toxin but not placebo at week 2 only.
Treatment appeared safe with no increase in aspiration pneumonia, dysphagia or deteriorating vital capacity related to the trial
medication. There were no severe adverse events related by investigators or safety monitors to study medication. As this was a single
dose study, cessation of treatment from adverse events does not
apply. However, the paper does not describe any restrictions from
the investigators on participants entering the open label phase, although reasons for three patients not to proceed to the open label
study (two from treatment and one from placebo arms) were not
specified.
DISCUSSION
Extensive literature review identified just one randomized controlled study of treatment of sialorrhea in MND. This was a positive study of a single session of botulinum toxin type B injections
to parotid and submandibular glands, which produced both subjective and objective benefits in patients for some weeks after the
injection. The eligibility criteria specified that the study population had to have inadequate response to, or intolerance of, anticholinergic medications, and concomitant drug treatment had to
be stable or reducing during follow-up. Randomisation and analysis appeared good and data completeness was satisfactory. The
intervention was described with sufficient detail to allow replication by other clinicians.
Despite excellent methodology to maintain blinding, the majority
of participants and investigators correctly guessed their treatment
allocation at the end of the double-blind phase. This loss of blinding may be a corollary of identifying an effective treatment. The
clinical context is that patients with MND almost always show an
inexorably progressive course, and thus sialorrhea does not spontaneously remit but instead would be anticipated to worsen as bulbar function deteriorates. Therefore, drug effect is a major source
of unblinding in a controlled trial. When choosing outcome measures it may therefore be preferable to utilise objective quantitative
measures less influenced by unblinding, such as volume of saliva
produced in unit time, as the primary outcome.
Careful consideration of trial design for future studies will be important. Ethical considerations suggest that the placebo controlled
phase should be as short as the postulated mechanism of action
of the treatment allows. Volunteers who commence on placebo
phase might also be automatically offered the active intervention
unless safety considerations have arisen in the first phase (delayed
commencement design). Trials will have greater scientific utility
7
if all patients remain blinded but this is more difficult with such
a design where participants will know they are all on active agent
in the second half of the study. With blinding maintained the
patients on active treatment throughout contribute data on longterm safety and sustained response, and the patients who switch
to active provide more information on efficacy. Trials are likely to
need multi-centre involvement, and the randomization may include comparing more than one dose against placebo, given the
lack of preliminary data.
There are other non randomized trials, typically open label, on use
of botulinum toxin to reduce saliva production in MND. These
support a beneficial effect of botulinum toxin, some utilising objective, quantitative outcome measures. Giess and colleagues injected botulinum toxin in the parotid glands only of three MND
patients and in the parotid and submandibular glands of two
MND patients (Giess 2000). A significant reduction in the number of paper handkerchiefs used daily was found four weeks after
the last injection. Four of the five participants reported improvement in quality of life associated with marked reduction of sialorrhea, evidenced by reduced radiotracer uptake on parotid salivary
gland scintigraphy after the botulinum injections. One participant with rapidly progressive disease did not show clinical benefit after repeated parotid and submandibular gland injections, despite a markedly reduced radiotracer uptake in the parotid glands.
In another open-labelled study, botulinum toxin was injected in
the parotid glands of 10 participants with MND (Verma 2006).
Of the eight people who completed the study, five showed improvement of 2.5 or more on the visual analogue scale (VAS). In
addition, the paper tissue count was significantly lower at four
weeks after treatment. Injection of both parotid and submandibular glands was reported by Costa and colleagues, who showed 70%
mean reduction in VAS of sialorrhea severity in 12/16 patients,
and 60% reduction in cotton roll weight to judge saliva production (Costa 2008). Porta and colleagues reported improvement in
sialorrhea in three of the four participants with MND who had
ultrasound guided botulinum toxin injections in both parotid and
submandibular glands (Porta 2001). In this study, a visual analogue scale completed by participants was used to assess the rate
of salivation. In a study by Manrique and colleagues, four of the
five participants with MND injected with botulinum toxin in the
parotid and submandibular glands reported significant improvement of symptoms and quality of life based on a clinical questionnaire (Manrique 2005). Another study reported an overall significant reduction of sialorrhea, as measured by cotton rolls weight,
and significant improvement in four clinical evaluation scales in a
group of 18 participants (nine with MND and nine with Parkinson’s disease) who had undergone ultrasound guided injections of
botulinum toxin in the parotid and mandibular glands (Contarino
2007).
Botulinum toxin injections to the salivary glands have a number
of potential side effects, the more common ones include viscous
saliva, local pain, chewing weakness and, because the individual
dose response is unpredictable, dry mouth (Costa 2008; Porta
2001). Treatment generally appears well tolerated, though serious
adverse effects such as infection of salivary gland and dysphagia
are reported (Winterholler 2001).
The published data on radiotherapy of salivary glands to reduce
saliva production in MND is all open label. Andersen and colleagues reported on a prospective pilot study of low-dose radiation
therapy to the parotid and submandibular glands of participants
with MND (Andersen 2001). On each side, the radiation dose
was 7 gray (Gy) (Gy as a single dose in the first 13 participants and
7.5 Gy in the last five participants. Sixteen of the 18 participants
treated reported satisfactory to good reduction in drooling lasting
up to four to six months, one participant developed xerostomia
and needed saliva substitutes and another participant reported no
effect. Another study reported treating the submandibular and
parotid glands of five MND participants with a single fraction of
8 Gy and four participants with two fractions of 6.25 Gy (total
12.5 Gy) (Harriman 2001). It was found that 8 Gy of radiation
was effective in controlling drooling and increasing the dose did
not improve initial control. In the 8 Gy group, four of the five
participants had significant subjective benefit at two weeks posttreatment. In this group, three of five participants completed the
two-month visit and of these, two had significant benefit both subjectively (measured by a questionnaire) and objectively (measured
by the weight of tissue rolls). In the 12.5 Gy group, one of three
participants alive at two weeks post-treatment reported subjective
benefit, while both the participants that completed the two-month
visit showed subjective and objective improvement. Long-term
control of sialorrhea was difficult to evaluate as the participants
entered in the study were very ill and their life expectancy was very
short. Stalpers and Moser reported treating 19 participants with
MND with radiotherapy to the parotid glands (Stalpers 2002).
The prescribed radiation dose in all participants was 12 Gy in two
fractions once a week (Stalpers 2002). Three participants received
one fraction only, of which two already had a satisfactory response
after the first fraction, and one did not want a second fraction.
Fourteen participants reported a satisfactory response within two
to three weeks of the initial radiation, complete in 11 and partial in three. Four participants without improvement after initial
treatment were re-irradiated, with only one showing partial improvement. Adverse effects of radiotherapy in these studies were
mild, such as parotid pain and dry mouth (Andersen 2001).
From a surgical point of view, there are very few published case series. In one small series, five MND patients having submandibular
gland excisions had only limited control of drooling whereas one
having unilateral tympanic neurectomy showed better treatment
response (Janzen 1988).
8
AUTHORS’ CONCLUSIONS
Implications for practice
There is extremely limited evidence from randomized controlled
trials about treatments to reduce sialorrhea in MND. The well
designed trial on botulinum toxin type B injected into parotid and
submandibular glands showed beneficial effects for four or more
weeks (Jackson 2009).
research designs must also reflect the need for objective outcome
measures such as rate of production of saliva or salivary gland
scintigraphy. These are necessary because an effective intervention
may have an unblinding effect. Placebo controlled trials with intent-to-treat analysis are still important, as there may be many
unpredictable factors which influence sialorrhea, such as mouth
breathing, general hydration, diet, disease stage, and concomitant
medication.
Implications for research
There is a need for considerable further work on treating this distressing symptom. Fundamental understanding of the nature of
sialorrhea is required to differentiate between thick, mucous secretions and watery, salivary drooling. It would also be useful to
validate a patient self report measure, as the previous studies have
used different VAS and many unvalidated questionnaires. Future
ACKNOWLEDGEMENTS
The Cochrane Neuromuscular Group staff have provided invaluable assistance with literature searches and advice on the Cochrane
software. We thank Prof Vasya Vlassov for assistance with Russian
translation, and the Walton Centre Neurological Disability Fund
for grant support.
REFERENCES
References to studies included in this review
Jackson 2009 {published data only}
Jackson CE, Gronseth G, Rosenfeld J, Barohn RJ, Dubinsky
R, Simpson CB, et al.Randomized double-blind study of
botulinum toxin type B for sialorrhea in ALS patients.
Muscle and Nerve 2009;39(2):137–43. [PUBMED:
19145653]
References to studies excluded from this review
Andersen 2001 {published data only}
Andersen PM, Grönberg H, Franzen L, Funegard U.
External radiation of the parotid glands significantly reduces
drooling in patients with motor neurone disease with bulbar
paresis. Journal of the Neurological Sciences 2001;191(1-2):
111–4. [PUBMED: 11677000]
Bhatia 1999 {published data only}
Bhatia KP, Münchau A, Brown P. Botulinum toxin is a
useful treatment in excessive drooling in saliva. Journal of
Neurology, Neurosurgery and Psychiatry 1999; Vol. 67,
issue 5:697. [PUBMED: 10577041]
Carod 2003 {published data only}
Carod Artal FJ. Treatment of sialorrhoea in neurological
diseases with trans-dermic injections of botulinum toxin
type A in the parotid glands [Tratamiento de la sialorrea
en enfermedades neurologicas mediante inyecciones
transcutaneas de toxina botulinica A en las glandulas
parotidas.]. Neurologia 2003;18(5):280–4. [PUBMED:
12768517]
Contarino 2007 {published data only}
Contarino MF, Pompili M, Tittoto P, Vanacore N, Sabatelli
M, Cedrone A, et al.Botulinum toxin B ultrasound-guided
injections for sialorrhea in amyotrophic lateral sclerosis
and Parkinson’s disease. Parkinsonism and Related Disorders
2007;13(5):299–303. [PUBMED: 16807056]
Costa 2008 {published data only}
Costa J, Rocha ML, Ferreira J, Evangelista T, Coelho
M, de Carvalho M. Botulinum toxin type-B improves
sialorrhea and quality of life in bulbar onset amyotrophic
lateral sclerosis. Journal of Neurology 2008;255(4):545–50.
[PUBMED: 18283399]
Giess 2000 {published data only}
Giess R, Naumann M, Werner E, Riemann R, Beck M, Puls
I, et al.Injections of botulinum toxin A into the salivary
glands improve sialorrhoea in amyotrophic lateral sclerosis.
Journal of Neurology, Neurosurgery, and Psychiatry 2000;69
(1):121–3. [PUBMED: 10864618]
Gilio 2010 {published data only}
Gilio F, Iacovelli E, Frasca V, Gabriele M, Giacomelli E,
Picchiori F, et al.Botulinum toxin type A for the treatment
of sialorrhoea in amyotrophic lateral sclerosis: A clinical
and neurophysiological study. Amyotrophic Lateral Sclerosis
2010;11(4):359-63.
Harriman 2001 {published data only}
Harriman M, Morrison M, Hay J, Revonta M, Eisen A,
Lentle B. Use of radiotherapy for control of sialorrhea in
patients with amyotrophic lateral sclerosis. The Journal of
Otolaryngology 2001;30(4):242–5. [PUBMED: 11771037]
Heiman-Patterson 2001 {published data only}
Heiman-Patterson TD, Rampal N, Brannagan TH, Acosta
T, Forshew DA, Bromberg MB. The Spectrum of Patient
Symptoms in ALS and Symptom Management. Neurology
56;8 Suppl 3:A99.
9
Levitskii 2005 {published data only}
Levitskii GN, Alekhin AV, Serdiuk AV, Morgunova MS,
Koneva ON, Skvortsova VI. Pharmacological therapy of
sialorrhea in patients with motor neuron disease. Zhurnal
Nevropatologii i Psikhiatrii Imeni S. S. Korsakova 2005;105
(3):19–22. [PUBMED: 15822738]
Lipp 2003 {published data only}
Lipp A, Trottenberg T, Schink T, Kupsch A, Arnold G. A
randomized trial of botulinum toxin A for treatment of
drooling. Neurology 2003;61(9):1279–81. [PUBMED:
14610139]
Manrique 2005 {published data only}
Manrique D. Application of botulinum toxin to reduce
the saliva in patients with amyotrophic lateral sclerosis.
Brazilian Journal of Otorhinolaryngology 2005;71(5):566–9.
[PUBMED: 16612515]
Neppelberg 2007 {published data only}
Neppelberg E, Haugen DF, Thorsen L, Tysnes OB.
Radiotherapy reduces sialorrhea in amyotrophic lateral
sclerosis. European Journal of Neurology 2007;14(12):
1373–7. [PUBMED: 17941851]
Newall 1996 {published data only}
Newall AR, Orser R, Hunt M. The control of oral secretions
in bulbar ALS/MND. Journal of the Neurological Sciences
1996;139 Suppl:43–4. [PUBMED: 8899657]
Porta 2001 {published data only}
Porta M, Gamba M, Bertacchi G, Vaj P. Treatment of
sialorrhoea with ultrasound guided botulinum toxin type A
injection in patients with neurological disorders. Journal of
Neurology, Neurosurgery and Psychiatry 2001;70(4):538–40.
[PUBMED: 11254784 ]
Scott 2005 {published data only}
Scott KR, Kothari MJ, Venkatesh YS, Murphy T, Simmons
Z. Parotid gland injections of botulinum toxin a are effective
in treating sialorrhea in amyotrophic lateral sclerosis.
journal of Clinical Neuromuscular Disease 2005;7(2):62–5.
[PUBMED: 19078785]
Stalpers 2002 {published data only}
Stalpers LJ, Moser EC. Results of radiotherapy for drooling
in amyotrophic lateral sclerosis. Neurology 2002;58(8):
1308. [PUBMED: 11971112]
Verma 2006 {published data only}
Verma A, Steele J. Botulinum toxin improves sialorrhea
and quality of living in bulbar amyotrophic lateral
sclerosis. Muscle and Nerve 2006;34(2):235–7. [PUBMED:
16583370]
Winterholler 2001 {published data only}
Winterholler MG, Erbguth FJ, Wolf S, Kat S. Botulinum
toxin for the treatment of sialorrhoea in ALS: serious side
effects of a transductal approach. Journal of Neurology,
Neurosurgery, and Psychiatry 2001; Vol. 70, issue 3:417–8.
[PUBMED: 11248905]
Additional references
Abhinav 2007
Abhinav K, Stanton B, Johnston C, Hardstaff J, Orrell
RW, Howard R, et al.Amyotrophic Lateral Sclerosis in
South-East England: A Population based study. The SouthEast England register for amyotrophic lateral sclerosis
(SEALS Registry). Neuroepidemiology 2007 ;29(1-2):44–8.
[PUBMED: 17898523]
Borasio 1997
Borasio GB, Voltz R. Palliative care in amyotrophic lateral
sclerosis. Journal of Neurology 1997;244(Suppl 4):S11–7.
[PUBMED: 9402548]
Brooks 2000
Brooks BR, Miller RG, Swash M, Munsat TL, World
Federation of Neurology Research Group on Motor Neuron
Diseases. El Escorial revisited: revised criteria for the
diagnosis of amyotrophic lateral sclerosis. Amyotrophic
Lateral Sclerosis and Other Motor Neuron Disorders 2000;1
(5):293–9. [PUBMED: 11464847]
Burgen 1949
Burgen AS, Dickens F, Zatman LJ. The action of botulinum
toxin on the neuro-muscular junction. Journal of Physiology
1949;109(1-2):10–24. [PUBMED: 15394302]
Bushara 1997
Bushara KO. Sialorrhoea in amyotrophic lateral sclerosis:
a hypothesis of a new treatment - botulinum toxin A
injections of the parotid glands. Medical Hypotheses 1997;
48(4):337–9. [PUBMED: 9160288 ]
Higgins 2008
Higgins JPT, Green S (editors). Cochrane Handbook
for Systematic Reviews of Interventions Version 5.0.2
[updated September 2009]. The Cochrane Collaboration,
2009.. Available from www.cochrane-handbook.org. The
Cochrane Collaboration.
Janzen 1988
Janzen VD, Rae RE, Hudson AJ. Otolaryngologic
manifestations of amyotrophic lateral sclerosis. The Journal
of Otolaryngology 1988;17(1):41–2. [PUBMED: 3343721 ]
Leigh 2003
Leigh PN, Abrahams S, Al-Chalabi A, Ampong MA,
Goldstein LH, Johnson J, et al. King’s MND Care and
Research Team. The management of motor neurone
disease. Journal of Neurology, Neurosurgery and Psychiatry
2003;74(Suppl 4):iv32–iv47. [PUBMED: 14645465]
Marks 2001
Marks L, Turner K, O’Sullivan J, Deighton B, Lees A.
Drooling in Parkinson’s disease: a novel speech and language
therapy intervention. International Journal of Language
and Communication Disorders 2001;36 Suppl:282–7.
[PUBMED: 11340797]
McGuire 1996
McGuire D, Garrison L, Armon C, Barohn R, Bryan W,
Miller RG, et al.Relationship of the Tufts Quantitative
Neuromuscular Exam (TQNE) and the Sickness Impact
Profile (SIP) in measuring progression of ALS. SSNJV/
CNTF ALS Study Group. Neurology 1996;46(5):1442–4.
[PUBMED: 8628496]
10
Meningaud 2006
Meningaud JP, Pitak-Arnnop P, Chikhani L, Bertrand
JC. Drooling of saliva: a review of the etiology and
management options. Oral Surgery, Oral Medicine, Oral
Pathology, Oral Radiology and Endodontics 2006;101(1):
48–57. [PUBMED: 16360607]
Miller 1999
Miller RG, Rosenberg JA, Gelinas DF, Mitsumoto H,
Newman D, Sufit R, 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(7):1311–23.
[PUBMED: 10227612]
Miller 2007
Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for
amyotrophic lateral sclerosis (ALS)/motor neuron disease
(MND). Cochrane Database of Systematic Reviews 2007,
Issue 1. [DOI: 10.1002/14651858; PUBMED: 17253460]
Mitsomoto 2003
Mitsomoto H, Davidson M, Moore D, Gad N, Brandis M,
Ringel S, et al. ALS CARE Study Group. Percutaneous
endoscopic gastrostomy (PEG) in patients with ALS and
bulbar dysfunction. Amyotrophic Lateral Sclerosis and Other
Motor Neuron Disorders 2003;4(3):177–85. [PUBMED:
13129795]
Oliver 1996
Oliver D. The quality of care and symptom control - the
effects on the terminal phase of ALS/MND. Journal of the
Neurological Sciences 1996;139 Suppl:134–6. [PUBMED:
8899674]
Rowland 2001
Rowland LP, Shneider NA. Amyotrophic lateral sclerosis.
New England Journal of Medicine 2001;344(22):1688–700.
[PUBMED: 11386269]
Sakakura 1985
Sakakura Y, Majima Y, Saida S, Ukai K, Miyoshi Y.
Reversibility of reduced mucociliary clearance in chronic
sinusitis. Clinical Otolaryngology and Allied Sciences 1985;
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Shaw 1999
Shaw PJ. Motor neurone disease. BMJ 1999;318(7191):
1118–21. [PUBMED: 10213726]
Veis 2000
Veis S. Salivary flow in persons with ALS. 11th International
Symposium on ALS/MND, Aarhus, Denmark (Poster).
2000.
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Worms PM. The epidemiology of motor neuron diseases: a
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2001;191(1-2):3–9. [PUBMED: 11676986]
∗
Indicates the major publication for the study
11
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Jackson 2009
Methods
Randomised placebo controlled trial
Participants
20 patients (11 treatment, 9 control) with MND and intractable sialorrhea refractory to
at least two anticholinergic medications, aged between 21 to 85 years
Interventions
Treatment - botulinum toxin B injected under electromyographic guidance into parotid
and submandibular glands bilaterally
Control - identical injections using normal saline only
Outcomes
Primary - global impression of change by subject at week 8 post injection
Secondary - patient and caregiver assessment of saliva thickness on VAS 0-100, thin to
thick
Patient and caregiver assessment of saliva problem severity on VAS 0-100, none to serious
Changes in volume of saliva produced in 5 minutes, and number of times suctioned
SEIQOL-DW 0-100 where higher score means better quality of life
ALSFRS-R
Clinician assessment of marked improvement
Notes
Funding from patient organisation and from pharmaceutical company. Trial described
as independent in design, execution, analysis and publication from commercial funding
source
Risk of bias
Bias
Authors’ judgement
Support for judgement
Adequate sequence generation?
Low risk
Random numbers table
Allocation concealment?
Low risk
Sequentially numbered opaque envelopes kept
securely in locked cabinet. Preparation of botulinum toxin and saline injections in closed
room. Treatment allocation and injection preparation by unblinded investigator who had no
other contact with blinded investigators or subjects
Blinding?
Patient reported outcomes
Unclear risk
Good methodology to maintain blinding but
unblinding questionnaire suggests blinding not
maintained in patients, and clinicians
Blinding?
Objective outcomes
Low risk
Measurement of saliva volume produced with
standard avoidance of food or drink one hour
prior to assessment
12
Jackson 2009
(Continued)
Blinding?
Clinician reported outcomes
Unclear risk
maintained in clinicians, and patients
Blinding?
Caregiver reported outcomes
Unclear risk
maintained for patients; caregivers blinding not
assessed but uncertain
Incomplete outcome data addressed?
All outcomes
Low risk
Free of selective reporting?
Low risk
Free of other bias?
Low risk
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Andersen 2001
Non randomized study. Compared saliva secretion rate before and after treatment with single dose radiotherapy (7 to 7.5 Gray) delivered bilaterally to the larger part of the parotids and the posterior part of the
submandibular glands. Found reduction in drooling in 16/18 MND patients. 1/18 developed xerostomia
and 1 reported no effect
Bhatia 1999
Non randomized study. 1/4 patients had MND, this patient had botulinum toxin 10 U injected into each
parotid gland. No improvement reported
Carod 2003
Non randomized study. Treated 3 patients (1 with MND, 1 Parkinson’s disease and 1 pontine stroke)
with botulinum toxin A to parotid glands. Showed efficacy of injections by improvement on severity and
frequency scores for sialorrhea
Contarino 2007
Non randomized study. Treated patients with MND and with Parkinson’s disease. Demonstrated efficacy
in reducing sialorrhea but suggested risks of procedure may be greater in MND patients
Costa 2008
Non randomized study. Open label study of botulinum toxin B injected into the parotid and submandibular
glands in 16 MND patients. 75% achieved the primary end point of > 50% improvement in visual
analogue scale of severity and disability of sialorrhea. 15/16 patients reported some benefit in reducing
saliva. Objective measures also demonstrated a 60% reduction in saliva
Giess 2000
Non randomized study. Open label study treating 5 MND patients with botulinum toxin A. Demonstrated
reduction in saliva production by quantifying paper handkerchief use and by salivary gland scintigraphy
13
(Continued)
Gilio 2010
Non randomized study. Open label study of 26 MND patients with botulinum toxin type A. Demonstrated
reduction in saliva production by cotton roll weight and improvement in VAS of impact of drooling on
daily life
Harriman 2001
Non randomized study. No information given on diagnostic criteria for MND or of patient characteristics
to allow comparison of groups. No control group included. No allocation concealment, risk of bias
therefore felt to be high. Study compared two radiotherapy regimens to improve sialorrhea: 8 Gray in single
fraction to submandibular gland as well as sublingual and tail of parotid compared with 12.5 Gray total
radiation dose in two fractions. Found 8 Gray effective in reducing sialorrhea with no benefit increasing
dose to 12.5 Gray total radiation in late stage MND patients
Heiman-Patterson 2001
Questionnaire survey, not randomized
Levitskii 2005
Compared botulinum toxin to amitripylline. Randomisation process was not described and risk of bias
was high as patients needed to purchase treatment in the study. Authors concluded that amitripylline
was treatment of choice due to efficacy and low cost, but if efficacy limited by side effects, a lower dose
combined with botulinum toxin can be effective
Lipp 2003
Double-blind, placebo controlled study randomising patients to one of three dose regimens of botulinum
toxin A. Study demonstrated objective efficacy at the higher dose of 75 MU per parotid injection, but the
study was not included in the review as it was not possible to analyse the efficacy in the MND patients
alone. The treatment group comprised patients with MND, Parkinson’s disease, multiple system atrophy
and corticobasal degeneration
Manrique 2005
Non randomized study. Open label with no control group. Botulinum toxin A 30 U for each submandibular, 20 U for each parotid gland. Found improvement in sialorrhea measured by clinical questionnaire in
4/5 MND patients followed up for one year
Neppelberg 2007
Non randomized study. Open label with no control group. 14 patients received single fraction radiotherapy
(7.5 Gray) and 5 patients received botulinum toxin A injections 20 U into the parotid glands, 2 of these
also had radiotherapy. After radiotherapy reduction in mean salivary secretion 60% at 1 week, 51% at 2
weeks, 21% at 3 months, compared to pre-treatment. Mean salivary flow not reduced after botulinum
treatment
Newall 1996
Non randomized study. Treated 16 MND patients with thick secretions with oral beta antagonists. 75%
showed relief with the medications
Porta 2001
Non randomized study investigating botulinum toxin A injections in patients with various neurological
disorders, including MND (4/10)
Scott 2005
Non randomized study. Open label prospective study of 6 MND patients treated with bilateral parotid
injections of botulinum toxin A, with improvement in 5/7 patients treated at a lower dose (10 U) and 3/
4 at higher dose (20 U). Improvement was measured by measurement of tissue use
Stalpers 2002
Non randomized study. Open label and retrospective. 19 patients treated with radiotherapy (prescribed
12 Gray in 2 fractions once a week). Response judged by report of patient about drooling 2 to 3 weeks
after radiotherapy completed. 14/17 reported complete or partial improvement. 4 non-responders had a
second course of radiotherapy, only 1 had partial benefit; 2 non- responders had a third course, no benefit.
14
(Continued)
Side effects mild (parotid pain, mouth dryness) and temporary
Verma 2006
Non randomised study. Open label with no control group. Treated 10 patients with botulinum toxin and
showed improved degree of sialorrhea and drooling score
Winterholler 2001
Non randomised study. Open label pilot of botulinum toxin A 12.5 U injected into each parotid and
sublingual gland by transductal approach. Response measured by measuring saliva production, and technetium 99 m scintigraphy. 2/2 bulbar MND patients showed benefit. Pilot stopped due to severe adverse
events (severe swelling of sublingual gland in first and worsening of dysphagia in second patient)
15
DATA AND ANALYSES
This review has no analyses.
APPENDICES
Appendix 1. MEDLINE OvidSP Search Strategy
1 randomized controlled trial.pt.
2 controlled clinical trial.pt.
3 randomized.ab.
4 placebo.ab.
5 drug therapy.fs.
6 randomly.ab.
7 trial.ab.
8 groups.ab.
9 or/1-8
10 (animals not (animals and humans)).sh.
11 9 not 10
12 Sialorrhoea.mp.
13 sialorrhea.tw. or sialorrhea/
14 (drool$ or dribbl$ or hypersalivat$).mp.
15 saliva$.tw. or saliva/
16 salivation/
17 dysphagia.mp.
18 Deglutition Disorder$.tw.
19 Deglutition Disorders/
20 (swallow$ adj1 difficult$).mp.
21 or/12-20
22 exp Motor Neuron Disease/
23 (moto$1 neuron$1 disease$1 or moto?neuron$1 disease).mp.
24 Amyotrophic Lateral Sclerosis.tw.
25 ((Charcot marie$1 adj5 syndrome$1) or (Lou Gehrig$1 adj5 syndrome$1)).mp.
26 ((Charcot marie$1 adj5 disease) or (Lou Gehrig$1 adj5 disease)).mp.
27 progressive bulbar palsy.tw.
28 or/22-27
29 11 and 21 and 28
Appendix 2. EMBASE OvidSP Search Strategy
1 crossover-procedure/
2 double-blind procedure/
3 randomized controlled trial/
4 single-blind procedure/
5 (random$ or factorial$ or crossover$ or cross over$ or cross-over$ or placebo$ or (doubl$ adj blind$) or (singl$ adj blind$) or assign$
or allocat$ or volunteer$).tw.
6 or/1-5
7 human/
8 6 and 7
16
9 nonhuman/ or human/
10 6 not 9
11 8 or 10
12 sialorrhoea/
13 (sialorrhea or sialorrhoea).tw.
15 saliva$.tw. or saliva/
16 salivation/ or salivation.tw.
17 dysphagia.mp.
18 Deglutition Disorder$.tw. or Deglutition Disorders/
20 or/12-19
21 exp motor neuron disease/
22 amyotrophic lateral sclerosis.tw.
23 moto$1 neuron$1 disease$1.mp.
24 moto?neuron$1 disease$1.mp.
25 ((charcot marie$1 adj5 diseas$1) or (lou gherig$1 adj5 disease$1)).mp.
26 ((charcot marie$1 adj5 syndrome$1) or (lou gherig$1 adj5 syndrome$1)).mp.
27 progressive bulbar palsy.tw.
28 or/21-27
29 11 and 20 and 28
Appendix 3. EBSCOhost CINAHL Search Strategy
S35 S34 and S29 and S18
S34 S30 or S31 or S32 or S33
S33 progressive bulbar palsy
S32 amyotrophic lateral sclerosis
S31 motorneuron* disease* or moto* neuron* disease*
S30 (MH “Motor Neuron Diseases”) or (MH “Amyotrophic Lateral Sclerosis”)
S29 S19 or S20 or S21 or S22 or S23 or S24 or S25 or S26 or S27 or S28
S28 drool* or dribbl* or hypersalivat*
S27 swallow* difficult*
S26 (MH “Deglutition Disorders”)
S25 deglutition disorder*
S24 dysphagia
S23 (MH “Saliva”) or (MH “Salivation”)
S22 saliva
S21 sialorrhea
S20 (MH “Sialorrhea”)
S19 sialorrhoea
S18 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13 or S14 or S15 or S16 or S17
S17 ABAB design*
S16 TI random* or AB random*
S15 ( TI (cross?over or placebo* or control* or factorial or sham? or dummy) ) or ( AB (cross?over or placebo* or control* or factorial
or sham? or dummy) )
S14 ( TI (clin* or intervention* or compar* or experiment* or preventive or therapeutic) or AB (clin* or intervention* or compar* or
experiment* or preventive or therapeutic) ) and ( TI (trial*) or AB (trial*) )
S13 ( TI (meta?analys* or systematic review*) ) or ( AB (meta?analys* or systematic review*) )
S12 ( TI (single* or doubl* or tripl* or trebl*) or AB (single* or doubl* or tripl* or trebl*) ) and ( TI (blind* or mask*) or AB (blind*
or mask*) )
S11 PT (“clinical trial” or “systematic review”)
17
S10 (MH “Factorial Design”)
S9 (MH “Concurrent Prospective Studies”) or (MH “Prospective Studies”)
S8 (MH “Meta Analysis”)
S7 (MH “Solomon Four-Group Design”) or (MH “Static Group Comparison”)
S6 (MH “Quasi-Experimental Studies”)
S5 (MH “Placebos”)
S4 (MH “Double-Blind Studies”) or (MH “Triple-Blind Studies”)
S3 (MH “Clinical Trials+”)
S2 (MH “Crossover Design”)
S1 (MH “Random Assignment”) or (MH “Random Sample”) or (MH “Simple Random Sample”) or (MH “Stratified Random
Sample”) or (MH “Systematic Random Sample”)
Appendix 4. AMED OvidSP Search Strategy
1 Randomized controlled trials/
2 Random allocation/
3 Double blind method/
4 Single-Blind Method/
5 exp Clinical Trials/
6 (clin$ adj25 trial$).tw.
7 ((singl$ or doubl$ or treb$ or trip$) adj25 (blind$ or mask$ or dummy)).tw.
8 placebos/
9 placebo$.tw.
10 random$.tw.
11 research design/
12 Prospective Studies/
13 meta analysis/
14 (meta?analys$ or systematic review$).tw.
15 control$.tw.
16 (multicenter or multicentre).tw.
17 ((study or studies or design$) adj25 (factorial or prospective or intervention or crossover or cross-over or quasi-experiment$)).tw.
18 or/1-17
19 Sialorrhea/
20 (sialorrhea or sialorrhoea).mp.
22 saliva$.mp. or saliva/
23 dysphagia.mp.
24 Deglutition Disorder$.tw.
25 Deglutition Disorders/
27 or/19-26
28 Motor Neuron Disease/
29 moto$1 neuron$1 disease$1.mp.
30 Moto?neuron$1 Disease$1.mp.
31 Amyotrophic Lateral Sclerosis/
32 amyotrophic lateral sclerosis.tw.
33 (progressive adj5 bulbar palsy).mp.
34 or/28-33
35 18 and 27 and 34
18
Appendix 5. Cochrane Central Register of Controlled trials search strategy
#1MeSH descriptor Motor Neuron Disease explode all trees
#2“motor neuron disease” OR “motor neuron disease” OR “motoneuron disease” OR “amyotrophic lateral sclerosis”
#3(Charcot NEAR syndrome*)
#4(Gehrig* NEAR syndrome*)
#5(Charcot NEAR diseas*) OR (Gehrig* NEAR disease*)
#6(#1 OR #2 OR #3 OR #4 OR #5)
#7sialorrhoea OR sialorrhea OR drool* OR dribbl* OR hypersalivat* OR saliva* OR dysphagia OR deglutition NEXT disorder* OR
swallow* NEXT difficult*
#8(#6 AND #7)
HISTORY
Protocol first published: Issue 1, 2008
Review first published: Issue 5, 2011
CONTRIBUTIONS OF AUTHORS
Ms N Grundy and Dr S Sathasivam drafted the protocol and revised it following peer review. Prof CA Young, Dr C Ellis, Ms J Johnson
and Dr S Sathasivam checked all abstracts, agreed a shortlist, and performed data extraction independently on shortlisted papers. Dr
C Ellis and Prof CA Young wrote the tables. Prof Young wrote the paper and all authors have read and agreed the final version.
DECLARATIONS OF INTEREST
None
SOURCES OF SUPPORT
Internal sources
• The Walton Centre for Neurology & Neurosurgery Neurological Disability Fund, UK.
External sources
• No sources of support supplied
19
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
We used updated risk of bias methodology, described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins
2008).
INDEX TERMS
Medical Subject Headings (MeSH)
Amyotrophic Lateral Sclerosis [∗ complications]; Botulinum Toxins [∗ administration & dosage]; Motor Neuron Disease [complications];
Neuromuscular Agents [∗ administration & dosage]; Parotid Gland; Randomized Controlled Trials as Topic; Salivation [drug effects];
Sialorrhea [∗ drug therapy; etiology]; Submandibular Gland
MeSH check words
Humans
20

Treatment for sialorrhea (excessive saliva) in people with

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