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Botulinum	toxin	improves	dysphagia
associated	with	multiple	sclerosis
Article		in		European	Journal	of	Neurology	·	March	2011
DOI:	10.1111/j.1468-1331.2010.03189.x	·	Source:	PubMed
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Botulinum toxin improves dysphagia associated with multiple
sclerosis
D. A. Restivoa, R. Marchese-Ragonab, F. Pattic, C. Solarod, D. Maimonea, G. Zappala´a and
A. Pavonea
aDepartment of Neurology, ‘‘Nuovo Garibaldi’’ Hospital, Catania; bENT Department, University of Padua, Padua; cDepartment of
Neurological Sciences, Centro Sclerosi Multipla, University of Catania, Catania; and dDepartment of Neurology, ASL 3 genovese, Genova,
Italy
Keywords:
botulinum toxin, crico-
pharyngeal musce, dys-
phagia, multiple sclerosis,
swallowing
Received 4 April 2010
Accepted 12 July 2010
Objective: To evaluate the efficacy of botulinum neurotoxin type A (BoNT/A) for
severe oro-pharyngeal dysphagia associated with multiple sclerosis (MS).
Patients and methods: BoNT/A was injected percutaneously into the hyperactive cri-
copharyngeal muscle of 14 dysphagic MS patients under electromyographic control.
Patients were evaluated by videofluoroscopic and electromyographic examinations
and by the Penetration/Aspiration Scale (PAS), at week 1, 4, 12, 16, 18, and 24 after
BoNT/A injection.
Results: All patients showed a significant improvement in all the swallowing outcome
measures.
Conclusion: No specific treatment for oro-pharyngeal dysphagia related to MS has
been described to date. Our preliminary findings suggest a potential benefit from
BoNT/A treatment in MS patients with dysphagia associated with upper esophageal
sphincter hyperactivity.
Introduction
Swallowing permits the ingestion of fluids and food-
stuffs without aspiration. It is a complex process regu-
lated by a trigger center in the brainsteam, the central
program generator that receives inputs from the cere-
bral cortex and the peripheral muscles, other than from
oral, laryngeal, and pharyngeal mucosal areas and
directs the final sequence of swallowing [1].
Disruption of normal swallowing, dysphagia, is a
frequent and life-threatening complication of multiple
sclerosis (MS) [2,3].
Recent studies show that swallowing symptoms are
much more frequent than previously assumed [2,4]. The
real prevalence of dysphagia in MS seems to be quite
high and may be estimated as 30–40% [2–7].
The pathophysiology of dysphagia in MS patients is
variable reflecting the multifocal areas of central ner-
vous system that may be involved by the inflammation
process.
Although all phases of swallowing can be involved,
oro-pharyngeal dysphagia because of hyperactivity of
the cricopharyngeal (CP) muscle of the upper esopha-
geal sphincter (UES) is considered the prevalent
abnormality [4,8]. In a recent study on a large group of
MS patients, pharyngeal phase disorders were the more
common observed swallowing impairment, occurring in
28.7% of the dysphagic patients [4].
No specific pharmacologic treatment for oro-phar-
yngeal dysphagia associated to MS has been described
up to now. Surgical myotomy of the CP muscle is the
treatment of choice for UES hyperactivity because of
different neurologic disorders [9–11].
However, this treatment requires general anesthesia,
is not always effective [9–11], and has never been
described in MS patients.
In the last years, chemical myotomy of the CP muscle
by botulinum neurotoxin type A (BoNT/A) has shown
to be effective to treat oro-pharyngeal dysphagia asso-
ciated with UES hyperactivity [12–16]. This treatment is
safe and can be successfully performed either as alter-
native to more invasive procedures or to identify sub-
jects who might benefit from surgical myotomy [15].
In this open-label pilot study, we evaluated the
efficacy of BoNT/A in fourteen MS patients with oro-
pharyngeal dysphagia because of UES hyperactivity, by
Correspondence: Dr D. A. Restivo, Department of Neurology,
‘‘Nuovo Garibaldi’’ Hospital, Catania, via Palermo, 95100, Catania,
Italy (tel.: +39 095-7598124; fax: +390957598105; e-mail: darestivo@
libero.it; darestivo@tiscali.it).
486
� 2010 The Author(s)
European Journal of Neurology � 2010 EFNS
European Journal of Neurology 2011, 18: 486–490 doi:10.1111/j.1468-1331.2010.03189.x
detecting objective changes in a number of clinical,
neurophysiologic, and radiologic outcome measures.
Research design and methods
Twenty-five MS patients (9 men, 15 women; mean age:
37.8 ± 5.5 years) with severe dysphagia (mean duration
of dysphagia: 4.7 ± 0.9 years) for both solid and liquid
foods were enrolled into the study. None of the patients
was underwent swallowing therapy in the 3 months
before and during the study. This was performed to rule
out any bias that may alter the results of the study.
Inclusion criteria: (i) both sex; (ii) age older than
18 years; (iii) EDSS not major than 7.5; (iv) subjects in a
stable phase of the disease, without relapses or a wor-
sening major than 1 point at the EDSS in the previous
3 months; (v) swallowing difficulty for liquids, solids or
both, present for at least two consecutive months.
Exclusion criteria: (i) neurologic disease other than
MS; (ii) Age > 60 years: patients older than 60 years
were excluded from the study because non-specific
swallowing abnormalities may occur around and espe-
cially above the age of 60 years [17]; (iii) intercurrent
illness or upper gastrointestinal disease; (iv) inability to
give informed consent because of cognitive impairment.
All patients underwent brain MRI studies. Amongst
these 25 patients, fourteen subjects (6 men, 8 women;
mean age: 37.1 ± 5.3 years; mean duration of disease:
9.7 ± 2.6 years; mean duration of dysphagia: 4.7 ±
1.0 years; 5 with Relapsing-Remitting, 6 with primary
progressive, and 3 with secondary progressive form;
mean EDSS: 5.5 ± 0.04;), because of clear signs of
UES hyperactivity (evaluated by videofluoroscopy,
and/or by CP electromyography) were eligible to
undergo treatment with BoNT/A. Clinical data of these
14 patients are reported in Table 1.
In all the 14 patients, episodic dysphagia for liquid
food had progressed to severe dysphagia for both li-
quids and solids with frequent inhalation. All patients
gave their written informed consent to the treatment.
The patients were advised of the potential risks of the
treatment. Within the informed consent paper, a list
with the potential adverse effects of the treatment (lar-
yngeal muscle paralysis, dysphonia, cervical muscle
weakness, dysphagia worsening, local hematoma, pain
in the injection site) was included. The study, conducted
in accordance to the Declaration of Helsinki, was
approved by theHospital Ethical committee.
Dysphagia assessment
Swallowing function was evaluated by both radiologic
(videofluoroscopy) and simultaneous needle electro-
myography (EMG) of the CP and pharyngeal inferior
constrictor (IC) muscles, and by the Penetration/
Aspiration Scale (PAS) [18]. The examinations were
performed before and 1, 4, 12, 16, 18, and 24 weeks
after BoNT/A injection.
Radiologic evaluation
Videofluoroscopy with modified barium swallowing
was performed. Three different food consistencies of
standardized bolus size were used: thin liquid (equiva-
lent to milk), semi-solid (equivalent to jelly), and solid
(dry toast coated in barium).
Neurophysiologic evaluation
Simultaneous EMG of CP and IC muscles was per-
formed using concentric needle electrodes, according to
the protocol proposed by Elidan et al. [19]. Briefly, for
Table 1 Clinical data of 14 patients with dysphagia associated with multiple sclerosis
Age Sex Form of MS EDSS MS duration Dysphagia duration (years) PAS (baseline) PAS (week 4)
33 M RR 5.5 9 6.2 7 1
36 M SP 6.5 9 5.4 7 1
32 F RR 4 8 4 8 3
34 M PP 4.5 9 3.8 6 2
30 M RR 4.5 6 5.8 7 1
29 F RR 5.5 7 6 7 1
44 F PP 6.5 15 6.1 7 2
47 F PP 6.5 14 3.6 7 1
40 M PP 6.5 11 4.5 7 1
39 F RR 5.5 13 4.4 6 1
43 M PP 4 9 3.9 7 2
40 F PP 5.5 9 4 6 1
37 F SP 5.5 10 3.3 7 1
35 F SP 6.5 8 5.1 7 1
M, male; F, female; EDSS, expanded disability severity score; RR, relapsing-remitting; PP, primary progressive; SP, secondary progressive; PAS,
penetration/aspiration scale.
BoNT/A for dysphagia in MS 487
� 2010 The Author(s)
European Journal of Neurology � 2010 EFNS European Journal of Neurology 18, 486–490
CP recording, the needle was inserted 1.5 cm lateral to
the palpable border of the cricoid cartilage in a postero-
medial direction. In normal subjects, a high-frequency
tonic electromyographic activity is observed as the
needle penetrates the muscle and a 300–600-ms pause is
seen during voluntary swallowing. For IC muscle
recording, the needle is inserted approximately 3 cm
above the point of insertion for the CP muscle, lateral
to the lateral border of the thyroid cartilage. In normal
subjects, no EMG activity is present at rest, whereas a
tonic EMG activity is observed during voluntary
swallowing. Therefore, voluntary swallowing is elec-
tromyographically characterized by a burst of activa-
tion in the IC muscle and a synchronous EMG pause in
the CP muscle, corresponding to UES relaxation. The
CP pause was calculated from the end of the electro-
myographic activity to the reoccurrence of the inter-
ference pattern. The CP electromyographic pause was
considered abnormal when its duration was <300 ms.
Penetration/Aspiration Scale
Dysphagia severity was scored by the PAS [18]. This is
an eight-point widely used scale for semi-quantitative
assessment of the degree of endoscopically and/or
radiologically measured penetration and aspiration:
1 = material does not enter the airway; 2 = material
enters the airway, remains above the vocal folds, and
is ejected from the airway; 3 = material enters the
airway, remains above the vocal folds, and is not
ejected from the airway; 4 = material enters the air-
way, contacts the vocal folds, and is ejected from the
airway; 5 = material enters the airway, contacts the
vocal folds, and is not ejected from the airway;
6 = material enters the airway, passes below the vocal
folds, and is ejected into the larynx or out of the
airway; 7 = material enters the airway, passes below
the vocal folds, and is not ejected from the trachea
despite effort; 8 = material enters the airway, passes
below the vocal folds, and no effort is made to eject
[18].
Treatment
BoNT/A (Botox; Allergan, Irwine, CA, USA) was
percutaneously injected into the CP muscle under EMG
control using a teflon-coated needle electrode. For each
patient, 10 units of botulinum toxin (dilution 2 ml,
0.9% saline) were injected in each side of the muscle.
Statistical evaluation
Data were evaluated by analysis of variance (ANOVA).
The level of significance was set at P < 0.05.
Results
MRI studies showed the presence of at least one lesion
within the brainsteam. In nine of 14 patients, the lesion
was localized in the medulla oblongata. Before BoNT/
A treatment, in all patients, videofluoroscopy showed
reduction in pharyngeal clearance and incomplete CP
opening. Electromyography showed a remarkable
decrease of the maximal IC muscle activation with
decreased discharge frequency and an excessive CP
tonic hyperactivity leading to reduced or impossible
relaxation. The mean CP muscle electromyographic
pause was 132 ± 96.7 ms. The mean PAS score was:
6.85 ± 0.53.
After a single BoNT/A injection in each side of the
CP muscle, dysphagia completely disappeared in 10 of
12 patients (PAS = 1) and significantly improved in
the remaining four patients (PAS = 2 in three pa-
tients; PAS = 3 in one patient). Mean PAS score sig-
nificantly ameliorated comparing with pre-treatment
value (score before BoNT/A = 6.8 ± 0.5; score at
week 1 = 1.4 ± 0.6; P < 0.0002) and all patients
were able to voluntarily swallow. Figure 1 shows the
mean and standard deviation changes in PAS score
before and 1, 4, 12, 16, 18, and 24 weeks after botuli-
num toxin injection. Radiologic and electromyographic
studies confirmed normal swallowing and correct IC/
CP muscles coordination.
Videofluoroscopy showed normal pharyngeal clear-
ance and physiologic CP opening in all patients after
BoNT/A treatment, compared with baseline.
Electromyography showed significant increase or
reappearance of the CP electromyographic pause, when
compared with pre-treatment values. After a single
BoNT/A injection in each side of the UES, the tonic CP
muscle hyperactivity ameliorated and the physiologic
inhibition reoccurred (mean CP muscle pause before
Figure 1 Mean Penetration/Aspiration Scale (PAS) before and 1,
4, 12, 16, 18, and 24 weeks after BoNT/A treatment. Error bars
indicate standard deviation. *P < 0.001; **P < 0.0002.
488 D. A. Restivo et al.
� 2010 The Author(s)
European Journal of Neurology � 2010 EFNS European Journal of Neurology 18, 486–490
BoNT/A = 132 ± 96.7 ms; at week 1 = 375 ± 89.2
ms; P < 0.002). Figure 2 shows the mean and standard
deviation of the CP pause changes, before and 1, 4, 12,
16, 18, and 24 weeks after botulinum toxin injection
(Fig. 2).
The beneficial clinical effect of BoNT/A was evident
after 4.3 ± 1.4 days (range 3–7 days). At week 1, the
improvement was evident in all patients, remained
unchanged up to week 12, and decreased but remained
significant (P < 0.001) at week 16 and 18. The mean
effect duration was 14.6 ± 1.5 weeks (range 12–18
weeks), which severity did not differ from pre-treatment
value (P > 0.05).
All patients underwent a further BoNT/A treatment
at week 24 and experienced the same improvement
observed after the first injection. Therefore, treatment
was repeated every 3–4 months according to the
response of each patient. Overall, all patients remained
able to voluntary swallow for the whole period of
treatment. Treatment with BoNT/A was well tolerated,
and no relevant local or systemic side effects were
reported. At week 12, all patients had gained 4–9 (mean
weight at baseline: 61.3 ± 9.6; mean weight at week 12:
67.2 ± 9.8) kilograms in body weight (Fig. 3). No
adverse effects were reported. No adverse side effects
were observed during and after the further follow-up
treatments.
Discussion
In MS patients, oro-pharyngeal dysphagia is probably
more frequent than previously presumed [1–6].
Although all phases of swallowing can be involved, the
oro-pharyngeal phase isthe most frequently impaired in
MS [1–4,7]. Oro-pharyngeal swallowing has a double
control, voluntary, and involuntary (reflexive), pri-
marily because of the coordination of two muscles: the
IC muscle, which represents the voluntary component,
and the CP muscle of the UES, which represents the
involuntary component. During voluntary swallowing,
the IC muscle is activated and this activation is syn-
chronous with the CP muscle relaxation, so that the
bolus can transit into the upper esophageal tract. In
patients with oro-pharyngeal dysphagia associated to
MS, this equilibrium between the two muscle compo-
nents might be deranged. In our MS patients, in fact,
EMG analysis disclosed reduced EMG activity with
low discharge frequency in the IC muscle. This condi-
tion may be because of a reduced central drive to the IC
muscle and may cause loss of the physiologic equili-
brium between the two muscles with consequent
reflexive hyperactivation of the CP muscle. Therefore,
in these patients, a long-lasting block of the para-
sympathetic fibers innervating the UES induced by
botulinum toxin might be useful in treating CP hyper-
activity.
Percutaneous injection of BoNT/A has been already
used to successfully treat CP muscle hyperactivity
associated with various neurologic diseases [12–15].
Moreover, in a recent study, Alfonsi et al., demon-
strated that dysphagic patients with CP muscle EMG
hyperactivity have the best response to botulinum toxin
injections, when compared to patients with neurogenic
dysphagia associated with other electrophysiologic
patterns, but without CP muscle EMG hyperactivity
[19]. Our preliminary results demonstrated that BoNT/
A is a safe and very effective treatment also for oro-
pharyngeal dysphagia associated with MS.
The advantage of BoNT/A is that it can be per-
formed in outpatient clinics, needing neither hospitali-
zation nor general anesthesia. It can be repeated when
the symptoms reappear, retains the same efficacy, and
requires no specific follow-up. However, this treatment
Figure 2 Time course of cricopharyngeal (CP) muscle pause.
Mean CP muscle pause (expressed in ms) before and 1, 4, 12, 16,
18, and 24 weeks after BoNT/A injection. Error bars indicate
standard deviation.
Figure 3 Patient�s body weight (kg) before and 12 weeks after
botulinum toxin injection.
BoNT/A for dysphagia in MS 489
� 2010 The Author(s)
European Journal of Neurology � 2010 EFNS European Journal of Neurology 18, 486–490
may have potential risks. The diffusion of BoNT/A into
the nearby laryngeal muscles might lead to laryngeal
muscle weakness/paralysis or to worsening of the pre-
existing dysphagia. For this reason, the treatment must
be performed under electromyographic guidance by an
expert operator, to identify the target muscle and to
rule out the possible diffusion of the botulinum toxin
into the nearby districts. Randomized controlled trials
are needed to confirm this observation.
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European Journal of Neurology � 2010 EFNS European Journal of Neurology 18, 486–490
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