Botulinum Toxin A in the Treatment of Oropharyngeal or Esophageal Dysphagia

doi:10.4236/ijohns.2013.26053

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International Journal of Otolaryngology and Head & Neck Surgery, 2013, 2, 253-258

Published Online November 2013 (http://www.scirp.org/journal/ijohns)

http://dx.doi.org/10.4236/ijohns.2013.26053

Open Access IJOHNS

Botulinum Toxin A in the Treatment of Oropharyngeal or

Esophageal Dysphagia

Caroline Beutner1, Katharina Bartsch2, Harald Schwörer3, Rainer Laskawi2, Saskia Rohrbach4

1Department of Otorhinolaryngology, Duesseldorf University Hospital, Duesseldorf, Germany

2Department of Otorhinolaryngology, Georg-August-University Hospital Göttingen, Göttingen, Germany

3Department of Gastroenterology an d Endocrinology, Georg-August-University Hospital Göttingen, Göttingen, Germany

4Department of Audiology and Phoniatrics, Charité, Berlin, Germany

Email: [email protected]

Received July 22, 2013; revised August 25, 2013; accepted September 10, 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Objectives: In this retrospective analysis, we explored the effect of botulinum toxin A (BTA) injection to treat oro-

pharyngeal dysphagia or esophageal dysfunction caused by diseases of the upper (UES) and lower (LES) esophageal

sphincter. Methods: In total, 48 patients (17 patients with UES diso rders, and 31 patients with LES dysfunction; mean

age 64 years) wer e treated between 1996 and 2007 in our hospital. Comorbid diseases as well as maintenance medica-

tion were documented to evaluate the overall health status of our patients. The mean duration of symptoms, the number

of pre-treatments and the specification of dysphagia were considered. Results: One month after injection, the response

rates were 73.3% (UES group) and 76.6% (LES group). Most patients in the UES group received 30 - 40 units BTA

(Botox®) whereas most patients in the LES group were treated with 100 units BTA. In cases of re-injection, 50% of

patients in the UES group experienced an escalation of dosage (up to 75 units), whereas the other 50% received the

same dosage. The dosages in the LES group were mostly kept constant. Conclusion: Comparing the two groups with

esophageal dysfunction of fundamentally different etiologies (UES/LES), a discrepancy in the level of symptom relief,

onset and a longer cessation of clinical benefit were observed in the LES group. In this analysis, we were able to show

that injection of BTA is an effective and safe treatment for disorders of the UES and LES.

Keywords: Botulinum Toxin; Dysphagia; Upper Esophageal Sphincter; Lower Esophageal Sphincter

1. Introduction

Because of the complex course of function during swal-

lowing, the underlying cause of esophageal dysphagia is

highly variable. Neuromuscular diseases are especially

common. While the treatment of mild disorders of the

upper esophageal sphincter (UES) is manageable by

swallowing exercises and modification of nutrition, se-

vere disorders in this area often require surgical myo-

tomy of the cricopharyngeal muscle. Disorders of the

lower esophageal sphincter (LES), especially achalasia,

can be treated with pharmacological agents, such as ni-

trates, calcium channel blockers, anticholinergic agents

and beta-adrenergic agonists, but frequently do not pro-

vide satisfactory relief of symptoms 1,2. Pneumatic

dilatation is considered as the treatment of choice, espe-

cially in the primary management of achalasia. The

standard for surgical management is laparoscopic Heller

myotomy, although improvements in long-term remis-

sion rates compared to the open approach are still lack ing

1,3. Since none of these methods yield universally sat-

isfactory results for either UES or LES diseases, an al-

ternative endoscopic treatment option is proposed. The

intramuscular injection of botulinum toxin A (BTA),

which is produced by the bacterium Clostridium botu-

linum, offers a viable alternative treatment. BTA blocks

the cholinergic neuromuscular innervation of intra- and

extrafusal muscle fibers, innervation of striated and

smooth muscle as well as the cholinergic junctio ns of the

autonomous nervous system 4. Earlier studies reported

on the use of BTA in LES- 5,6 and UES 7 -diseases.

The purpose of this study is to demonstrate the efficacy

of BTA injection as a non-surgical therapeutic option for

oropharyngeal or esophageal dysphagia caused by dys-

function of the UES or LES. Furthermore, recommenda-

tions for the injection technique and the treatment dosage

are stated and any side effects are noted.

C. BEUTNER ET AL.

254

2. Materials and Methods

Between 1996 and 2007, 48 patients (female n = 15,

male n = 33, mean age 64 years, range: 25 - 85 years)

with UES or LES dysfunctions were treated at the Uni-

versity Hospital of Goettingen, Germany. Based on their

symptoms, medical history and on an interdisciplinary

review of the diagnostic results (baseline: flexible laryn-

goscopy and esophagram in patients presumably having

UES dysfunctions; gastrointestinal endoscopy (see Fig-

ure 1) and manometry in patients presumably having

LES dysfunctions), patients were divided into two groups:

UES or LES. MRI, CT-scan or X-ray of the chest were

performed in patients with a history of malignant tumors

or if malignancy was suspected. For baseline characteris-

tics, see Table 1.

Pre-treatment included pneumatic dilatation, pharma-

cological or surgical procedures and showed unsatisfac-

tory results (for details see Table 2). Exclusion criteria

for the treatment with BTA were pregnancy, nursing,

under 18 years of age, malignancies and contraindica-

tions for the treatment with BTA or for general anesthe-

sia. A clinical assessment, describing the severity and fre-

Figure 1. Classical finding from esophago-gastrointestinal

endoscopy of a patient suffering from ac halasia: prestenotic

dilatation and retention of chime.

Table 1. Baseline characteristics of patients with dysphagia

caused by disorders of the UES or LES.

UES

LES Total

Neurologic

disease DystoniaTumor Unknown

etiology

Patients

(n) 17 7 5 3 2 3148

Age/

minimum

[years] 25 59 25 42 55 2525

Age/

maximum

[years] 80 80 75 74 59 8585

quency of the symptoms, was performed 6 months later.

For precise localization, the injection into the UES was

performed under general anesthesia and direct vision

using microscopic controlled endoscopy with a rigid en-

doscope. After having localized the UES (Figure 2), 30 -

75 units of botulinum toxin A (BTA, Botox®, Allergan

Inc., Irvin, CA, USA, freshly reconstituted with 0.9%

sterile saline to a final concentration of 2.5 U BTA/0.1ml)

were injected into both the lateral, ventral-medial and

dorsal-medial part of the cricopharyngeal muscle. An

adjusted injection set consisting of a Kleinsasser-Hecht

forceps holding a butterfly-needle was used for the inj ec-

tion, as shown in Figure 3.

Table 2. Pre-treatments.

Previous therapy UES

(n = 17) LES

(n = 31)Total

(n = 48)

Pharmacologic treatment 10 12 22

Pneumatic dilatation 1 10 11

Percutaneous endo scopic gastrostomy 10 0 10

Tracheostomy 7 0 7

Logopedics 8 0 8

Botulinum toxin inj e c t i o n s 3 1 4

Surgical myotomy 0 1 1

Surgery of the glottis 1 0 1

Figure 2. Direct endoscopic exposure of the UES for a safe

BTA application into both the lateral, ventral-medial and

dorsal-medial part of the cricopharyngeal muscle.

Figure 3. Instruments for transoral BTA injection: adjusted

injection set consisting of a Kleinsasser-Hecht forceps hold-

ing a butterfly-needle.

Open Access IJOHNS

C. BEUTNER ET AL. 255

For treatment of the LES, patients were first sedated

using midazolam and propofol, placed under cardiovas-

cular monitoring and positioned on their left side; 80 -

100 units of BTA (Botox®) were diluted in 0.9% sterile

saline to a final concentration of 2 U BTA/0.1ml. After

having visualized the sphincteric rosette (Figure 4), 20

units of BTA were injected into each quadrant of the

LES and 10 units at each point between quadrants two/

three and four/one (six points) through a 7 mm sclero-

therapy needle. Responders to BTA were defined as pa-

tients with symptom relief for at least 2 months. Patients

who failed to respond after a single treatment were clas-

sified as non-responders without testing for neutralizing

antibodies against BTA. These patients were free to elect

any alternative treatment options.

To evaluate the overall health status of our patients,

we asked them about attendant disorders and any main-

tenance medications. In addition to the dysphagia, 41.2%

of the UES group had a cerebral infarction or brain hem-

orrhage; 25.8% of both groups had a tumor disease and

22.6% were suffering from reflux esophagitis or gastritis.

Maintenance medication in all patients included frequent

use of proton pump inhibitors (PPI, 58.5% in the UES

group, 41.9% in the LES group) and anti-neuromuscular

or antispasmodic agents (41.2% in the UES group);

25.8% of patients in the LES group used calcium channel

blockers, 12.9% of patients needed prokinetics and 12.0 %

used HMG-CoA-reductase enzyme inhibitors.

In patients with severe dysphagia, nutrition was en-

sured by a permanent endoscopic gastrostomy (PEG).

Patients unable to swa llo w so lids were dependent on high -

caloric fluid alimentation. In cases of severe achalasia,

swallowing liquids was only possible in combination wit h

special maneuvers or positions. In the UES group, be-

sides dysphagia, the primary symptoms were aspiration

Figure 4. Endoscopic view of the sphincteric rosette of the

LES for BTA injections into each quadrant and each point

between quadr ant two/three and four/one (six points).

(n = 10) as shown in Figure 5, dysarthria (n = 8) and

weight loss (n = 7). In the LES group, patients repo rted a

loss of weight (n = 14), postprandial vomiting (n = 11),

regurgitation and retrosternal pain (n = 9) in addition to

the dysphagia. For duration of symptoms before the

treatment see Table 3.

3. Results and Analysis

The 48 patients received a total of 101 injections of BTA

into the LES or UES.

In the UES group, (n = 17), the majority (52.9%) re-

ceived a single BTA injection, 23.5% were treated twice,

17.6% received three injections and one patient received

four injections. In those receiving more than one injec-

tion the dosage was accelerated in 4 cases and remained

unchanged in 4 cases. The initial dosage ranged from 30

to 75 U. 29.4% received 30 U, 53% received 40 - 50 U,

11.8% got 51 - 65 U and 5.9% (one patient) received 75

U. The majority of patients in this group who required a

second injection (17.6%) were treated after an interval of

at least 150 days.

In the LES group, (n = 31), 38.7% received one injec-

Figure 5. Videofluoroscopy in one representative patient in

the UES group, suffering from hypertrophy of the crico-

pharyngeal muscle before and after treatment with botu-

linum toxin A. The prestenotic pooling of contrast medium

and laryngeal penetration with aspiration is shown in the

left image (arrowhead). After injection of BTA, a normal-

ized UES function without retention or aspiration is ob-

served in this patient (right image).

Table 3. Duration of symptoms.

Duration of symptoms [months]UES

(n = 17) LES

(n = 31)*Total

(n = 48)*

0 - 3 5 2 7

4 - 6 4 1 5

7 - 12 0 4 4

13 - 24 2 2 4

>24 6 21 27

Median 6.5 >24 >24

*One patient without inform a tion about the dura tion of sym ptoms.

Open Access IJOHNS

C. BEUTNER ET AL.

256

tion, 19.4% were treated twice, 22.6% had three injec-

tions, and 35% received four or more injections. In those

receiving more than one injection 16 patients had no

change in dosage and in 3 patients the dosage increased.

The initial dosage ranged from 40 to 100 U. 81% re-

ceived 100 U. This dosage remained constant in the fol-

lowing four treatments. 3% were injected with 40 - 50 U

and in 16%, due to disconnection of the needle, there was

no clear information on the actual dosage. Most patients

were retreated after an interval of over 150 days.

In 75.5% of all patients (combined LES and UES), a

good improvement was obtained (responders), while

24.4% of all patients showed no relief of symptoms after

1 month. In 3 patients, we received no information about

the therapeutic effect. After 1 month, the respon se rate in

the LES group was higher (76.6%) than in the UES

group (73.3%, see Table 4). The effect was noticed after

0 - 2 days in 43.8% of all patients, while 14.6% of all

patients showed an effect between day 3 and 8.

Interestingly, in some patients without subjectively

reported symptom relief after the treatment, the objective

assessment including esophageal manometry, video-

fluoroscopy and esophagogastroscopy showed an im-

provement and did not correlate with the persisting com-

plaints of the patients. No severe side effects occurred. In

all patients, mild side effects such as reflux (n = 3), pyro-

sis (n = 3), esophagitis/gastritis (n = 1) and retrosternal

pain (n = 1) were manageable by modification of the

dosage after the first interval.

4. Discussion

The aim of this analysis was to describe the outcome

parameters for BTA-based therapy for patients suffering

from oropharyngeal or esophageal dysphagia, with re-

gard to the different etiologies of the two entities. Our

objective was to evaluate the clinical efficacy, to deter-

mine a recommended technique and treatment dosage,

and to report on the resultant side effects. The response

rates in the UES group (73.3%) were high compared to

an overview of reported studies between 1994 and 2004,

8 describing a success rate varying from 20% to 100%

9. This may be caused by the high initial doses we in-

jected, discussed below, compared to those in the litera-

ture.

The number of responders in our LES group (76.6%)

was comparable to those described in the literature. An-

nese and Bassotti compared 12 of the largest studies (in-

volving at least 30 patients suffering from achalasia) be-

tween 1996 and 2004 having response rates of 75% -

93% after 1 month, 10 of whom 95% had not been

treated before 11. Even though Storr et al. claim that

the same benefit from BTA injections could be expected

in untreated or pre-treated patients, 12 a possible ex-

planation for the slightly lower outcome in our group

Table 4. Onset of the effect.

Onset of the effect UES

(n = 17) LES

(n = 31) Total

(n = 48)

(days)

0 - 2 4 17 21

3 - 5 1 4 5

6 - 8 2 0 2

>8 2 0 2

Onset unknown 2 2 4

No informat i o n a bout the e f f ect2 1 3

No effect 4 7 11

could be the high number of pre-treated patients. A lower

muscle connective tissue ratio, found in non-responders,

13 could be caused by previous treatments.

The response rates for all patients, irrespective of

group, showed no dependence on duration of symptoms

before the first treatment. There was a trend towards bet-

ter outcome in younger patients 14-16 and additional

earlier onset of effect in patients with disorders of the

LES, especially in patients suffering from severe acha-

lasia, in contrast to patients with UES disorders. This

supports the results of a previou s study 17.

The number of patients in the LES group, wh o showed

an effect that lasted longer than a minimum of 5 months

after the fir st injection , was hig her th an in the U ES group

(29% versus 12%). The reason for these variable dura-

tions of effect after BTA injections, also observed in dis-

orders of the autonomic nervous system, remains unclear

18. The discrepancy of symptom relief between the

LES group (smooth muscle) compared to the UES group

(skeletal muscle) may be caused by the different neuro-

transmitters at the neuromuscular junctions. A study by

Torbey et al. 19 showed a relaxation of smooth muscles

in rats in both cholinergic and peptinergic neurons

through botulinum toxin injections. In several studies, an

earlier onset and a longer cessation of improvement

5,6,14 suggest a higher sensitivity of the smooth mus-

cle to BTA compared to injections in striated muscles.

Different predictors of outcome are controversially dis-

cussed. Pasricha et al. assessed the decrease in LES

pressure as a good predictive factor, 6 whereas others

described a correlation of esophageal clearance with

symptom improvement 14. The best predictors of suc-

cessful outcome after BTA injections into the UES seem

to be a good remaining swallowing function, a proven

cricopharyngeal muscle hypertonicity 13 or isolated

cricopharyngeal muscle pathology 20,21. Evaluation of

outcome is still a challenge because of the discrepancy

between symptomatic and objective measures of im-

provement 3.

The dosages of BTA injected into th e UES or LES re-

Open Access IJOHNS

C. BEUTNER ET AL. 257

ported in the literature are similar to our initial dosages.

Dosages from 10 - 100 units (all dosages transformed to

Botox®) with different injections techniques (transoral,

percuateneous with or without electromyography, per-

cuataneous CT-guided, with rigid or flexible endoscopes

or in open techniqu e during vocal cord lateralization) are

repor ted concerning the UES 7,9,20-24.

We decided to inject dosages of BTA ranging from 30

to 75 U into the UES, with exact localization under gen-

eral anesthesia, based upon evaluation of the results from

dose-range studies. These studies showed a dosage-re-

lated effect and relief of symptoms 25,26 without ob-

servation of severe complications 8. Injections of com-

parable high dosages are usually administered under

general anesthesia and direct endoscopic view to ensure

safe injection and correct localization of the needle to

minimize the risk of complications. The dosages of BTA

injection in patients with disorders of the LES, especially

of achalasia, vary from 80 U 6,14 to 200 U 1,11.

Since the mean dosage used by most centers was about

100 U BTA, in the majority of our patients, we chose to

inject this amount. There was no clear dose/effect rela-

tionship described in the first injection (investigation of

118 patients suffering from achalasia) 11. To inhibit the

complete nerve regeneration in the smooth muscle,

which is responsible for the recurrence of symptoms, a

timely re-injection might be useful. Re-injection with

100 U BTA into the LES is recommended after 30 days

11. Nevertheless, we have to consider that short re-in-

jection intervals and the amount of toxin might risk a

receptor blockage by antibodies. The role of antibodies

as a result of autoimmune response possibly leading to

variable duration of the effect has to be clarified.

The number of complications reported after BTA in-

jection into the UES or LES is low. Uncontrolled diffu-

sion into the hypopharyngeal musculature 22, transient

chest pain (also occurring in the placebo group) 14,

unilateral vocal fold paresis 9, abnormal acid reflux

27 and aspiration with death after delayed medical in-

tervention 13 have been described. Mediastinitis and

ulceration of the esophagus without perforation after

BTA injection are rare complications 28. In our patients,

no severe side effects or systemic effects were noted.

The necessity for BTA re-injection, because of its re-

versible effect, seems disadvantageous, but no additional

adverse effects have been described after long-term ap-

plication 4. Likewise, the indication for revision in

surgery must also be considered. The predictive value of

outcome of BTA injection into the UES compared to a

myotomy is still controversially discussed 7,20.

While evaluating the different treatment methods

available for a patient’s relief of dysfunctions of the UES

or LES causing dysphagia, numerous factors must be

taken into account. These include the endoscopist’s or

surgeon’s experience 13, the risk of complications in

surgery, the patient’s age, coexisting diseases 29, the

overall morbidity of the patient, long-term results and

economic factors.

In conclusion, comparing the two groups of esophag-

eal dysfunction with fundamentally different etiologies

(UES/LES), intramuscular BTA injections represent a

safe and feasible technique with a lack of significant side

effects in both groups, especially for older patients with

co-morbid illness. Symptom relief, onset and duration of

clinical benefit were better in dysfunctions of the LES,

explainable by the history of malignant tumor resection

in the UES group with scarred tissue and the presumably

better effect of BTA in smooth muscles. Further studies

are needed providing objective data that correlate with

symptom improvement.

5. Summary

The pharmacological and surgical treatment of severe

oropharyngeal or esophageal dysphagia often gives un-

satisfactory results. This paper reports an alternative

treatment option, using endoscopic applied intramuscular

injection of Botulinum toxin A in the upper or lower

esophageal sphincter. 48 treated patients suffering from

oropharyngeal or esophageal dysphagia confirmed the

clinical efficacy of this method. The recommended dos-

age and technique of injection showed no significant side

effects.

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