Movement Disorders
Vol. 20, No. 5, 2005, pp. 592–597
© 2005 Movement Disorder Society
Long-Term Botulinum Toxin Efficacy,
Safety, and Immunogenicity
Nicte I. Mejia, MD, Kevin Dat Vuong, MA, and Joseph Jankovic, MD*
Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology,
Baylor College of Medicine, Houston, Texas, USA
Abstract: To determine the long-term efficacy of botulinum
toxin (BTX) treatments, we analyzed longitudinal follow-up
data on 45 patients (32 women; mean age, 68.8 years) currently
followed in the Baylor College of Medicine Movement Disor-
ders Clinic, who have received BTX treatments continuously
for at least 12 years (mean 15.8 ⫾ 1.5 years). Their mean
response rating after the last injection, based one a previously
described scale 0-to-4 scale (0 ⫽ no effect; 4 ⫽ marked
improvement) was 3.7 ⫾ 0.6 and the mean total duration of
response was 15.4 ⫾ 3.4 weeks. Although the latency and total
duration of the response to treatment have not changed over
time, the peak duration of response (P ⬍ 0.005) and dose per
visit (P ⬍ 0.0001) have increased since the initial visit. Fur-
thermore, global rating (P ⬍ 0.02) and peak effect (P ⬍ 0.05)
It has been nearly two centuries since the 1817 pub-
lication by Christian Andreas Justinus Kerner, who first
recognized that botulinum toxin (BTX) paralyzed skele-
tal muscles and parasympathetic function and proposed
its use as a therapeutic agent.1 However, it was not until
Alan Scott’s original reports of BTX injections into eye
muscles to correct strabismus in monkeys2 and humans3
that the therapeutic potential of BTX became recognized.
In 1984, BTX was first reported to be effective in bleph-
arospasm.4 We first began to use BTX in the treatment of
focal dystonia in 1981 and in 1987, we published the first
double-blind placebo-controlled trial of BTX.5 With the
chronic use of BTX and expanding list of therapeutic
*Correspondence to: Dr. Joseph Jankovic, Professor of Neurology,
Director of Parkinson’s Disease Center and Movement Disorders
Clinic, Department of Neurology, Baylor College of Medicine, 6550
Fannin, Suite 1801, Houston, TX 77030.
E-mail: josephj@bcm.tmc.edu
Received 2 June 2004; Revised 25 August 2004; Accepted 22
September 2004
Published online 11 January 2005 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/mds.20376
592
have improved. In total, 20 adverse events occurred in 16 of 45
(35.6%) patients after their initial visit and 11 adverse events in
10 of 45 (22.2%) patients at their most recent injection visit.
Antibody (Ab) testing was carried out in 22 patients due to
nonresponsiveness; blocking Abs were confirmed by the mouse
protection assay in 4 of 22 (18%) patients. Of the Ab-negative
patients, 16 resumed responsiveness after dose adjustments
and2 persisted as nonrespondents. Except for 1 patient, the 4
Ab-positive and the 2 clinical nonresponders are being treated
with BTX-B. This longest reported follow-up of BTX injec-
tions confirms the long-term efficacy and safety of this
treatment. © 2005 Movement Disorder Society
Key words: botulinum toxin; long-term; dystonia; efficacy;
complications; immunogenicity
indications beyond disorders associated with hyperactiv-
ity of skeletal muscles, there is a need to examine the
long-term efficacy and safety of BTX.6,7 We report here
the longest follow-up of patients continuously treated
with BTX and review its long-term efficacy and immu-
nogenicity.
PATIENTS AND METHODS
We selected patients from the Baylor College of Med-
icine Movement Disorders Clinic who met the following
inclusion criteria: (1) BTX treatment administered for at
least 12 years; (2) receive treatment at least once a year;
and (3) are currently being followed in our clinic. Pa-
tients were assessed at each injection visit and their
response was rated according to a 0-to-4 scale, described
previously8 (0 ⫽ no effect and 4 ⫽ marked improvement
in severity and function). All clinical information from
the initial and the most recent injection visits was re-
corded in the BTX database, including associated diag-
noses, type of BTX employed, sites of injection, dose in
mouse units (U) of BTX at each site, latency of response
(days), peak effect (0 – 4 scale), total duration of maxi-
 EFFECTS OF LONG-TERM BTX TREATMENT
TABLE 1. Long-term follow up of 45 patients treated with
BTX for more than 12 years: Demographic data
Variable Data
Total patients (n) 45
Age at first injection (yr) 51.8 ⫾ 11.6
Current age (yr) 68.0 ⫾ 12.0
Gender, n (%), male/female 13 (29.9)/32 (71.1)
Number of visits (n) 32 ⫾ 17
Data presented as mean ⫾ standard deviation unless noted otherwise.
mum effect (weeks), total duration of response (weeks),
and complications. The dates of all BTX follow-up visits
between the first and last injection visits were also re-
corded.
All patients who exhibited a less than satisfactory
response to their BTX injections (peak effect rating of 0
or 1) on two consecutive visits were tested for BTX
antibodies (Ab) by the mouse protection assay
(MPA).9,10 This assay evaluates the ability of increasing
dilutions of a patient’s serum to protect experimental
mice from lethal test doses of BTX. In addition to the
MPA, some patients were evaluated by the Western blot
assay or by the unilateral brow injection (UBI) test.9 In
the UBI test, 20 U of BTX-A or 1,000 U of BTX-B are
injected, by convention, into the right eyebrow. After 1
to 2 weeks, the patient is instructed to look in the mirror
and frown. If the medial eyebrows contract symmetri-
cally, this indicated that the right medial eyebrow mus-
cles (procerus and corrugator) were not paralyzed, thus
suggesting immunoresistance. However, an asymmetri-
cal frown indicates unilateral medial brow paralysis and
therefore no blocking antibodies.
Statistical Analysis
SPSS v 12.0 (SPSS, Chicago, IL) was utilized for
statistical analysis. The independent-samples t test, Wil-
coxon signed-rank test, and ␹2 were used for computa-
tions. Events were defined as significant if the P value
was less than 0.05.
RESULTS
To date, 3,100 patients have received BTX treatment
in our movement disorders clinic. Although the first
patient treated with BTX at our center was injected on 25
October 1981, the first patient to meet our inclusion
criteria was treated on 9 February 1985. Inclusion criteria
were met by 51 patients, but 3 were excluded because
their treatment information was incomplete and an addi-
tional 3 because at least one of their interinjection inter-
vals was longer than 1 year. The remaining 45 patients
included in this study were first injected with BTX
between 9 February 1985 and 7 December 1989 (Table
593
1). Three selected patients participated in our original
double-blind, placebo-controlled trials of BTX.5 Of 45
patients, 32 (71.1%) were women. The most frequent
reasons for treatment were cervical dystonia (43%), cra-
nial dystonia (26%), and blepharospasm (11%) (Fig. 1).
The mean age at first injection was 51.8 ⫾ 11.6 years; the
current mean age of the study cohort is 68.1 ⫾ 12.01.
Patients were followed for up to 61 visits (total 1,456;
mean, 32.4 ⫾ 17.0) and up to 18.9 years (mean, 15.8 ⫾
1.5). An average of 221.2 ⫾ 129.4 BTX units was
injected at the last visit, with an average peak effect of
3.7 ⫾ 0.6 and total duration of response to BTX of
15.4 ⫾ 3.4 weeks (Table 2). Patients are currently re-
ceiving a higher dose of BTX than that at their initial
injection visit (P ⬍ 0.0001). They are also having greater
peak duration of response (P ⬍ 0.005), global rating
(P ⬍ 0.02), and peak effect (P ⬍ 0.05). Although the
latency of response decreased and total duration of re-
sponse has increased, these changes have not reached
statistical significance (Fig. 2).
Twenty adverse events were recorded for 16 of 45
(35.6%) patients after their initial visit (4 patients pre-
sented 2 adverse events), the most common ones being
dysphagia (n ⫽ 5) and ptosis (n ⫽ 4) (Table 3). Other
adverse events recorded after the initial injection visit
were neck weakness (n ⫽ 2), nausea/vomiting (1),
blurred vision (1), muscle weakness (1), chewing diffi-
culties (1), hoarseness (1), edema (1), dysarthria (1),
palpitations (1), and general weakness (1). In total, 11
adverse events were presented by 10 patients (22.2%) at
FIG. 1. Diagnoses of 45 patients treated with BTX for more than 12
years. CD, cervical dystonia; CRCD, craniocervical dystonia; CR,
cranial dystonia; BS, blepharospasm; OMD, oromandibular dystonia;
HD, hand dystonia; HFS, hemifacial spasm; HMD, hemidystonia; D,
dysphonia; AD, arm dystonia.
Movement Disorders, Vol. 20, No. 5, 2005
594 N.I. MEJIA ET AL.

TABLE 2. Long-term follow up of 45 patients treated with BTX

for more than 12 years: Botulinum toxin response
Most recent
Parameter First injection injection P
Botulinum toxin (units) 154.3 ⫾ 98.9 221.2 ⫾ 129.4 ⬍0.0001
Response latency (days) 5.9 ⫾ 5.8 4.0 ⫾ 5.3 NS
Response duration (weeks)
Maximum 9.3 ⫾ 6.4 13.9 ⫾ .5 ⬍0.005
Total 11.6 ⫾ 7.1 15.4 ⫾ 3.4 NS
Efficacy, 0–4
Global rating 2.5 ⫾ 1.5 3.4 ⫾ 0.9 ⬍0.02
Peak effect 2.9 ⫾ 1.5 3.7 ⫾ 0.6 ⬍0.05
Complications, n (%) 20 in 16/45 (35.6) 11 in 10/45 (22.2) NS
Immunogenicitya
Positive MPA, n (%) 4/45 (8.8) — —
Negative, nonrespondent 2/45 (4.4) — —

Data presented as mean ⫾ standard deviation unless noted otherwise.

a
22 patients had Ab testing; 6 persisted as nonrespondents.
MPA, mouse protection assay; NS, not significant.

their most recent injection visit (1 patient presented 2
complications). The most common adverse events at this
visit were ptosis (n ⫽ 4) and dysphagia (3), followed by
neck weakness (1), general weakness (1), malaise (1),
and gastrointestinal upset (1). There were no serious or
life-threatening adverse events.
Antibody testing was carried out in 22 patients who
exhibited a less than satisfactory response to their BTX
injections (peak effect rating of 0 or 1) on two consec-
utive visits (Fig. 2). Blocking Ab were confirmed by the
MPA in 4 tested patients; 16 Ab-negative patients re-
sumed responsiveness by dose adjustments, whereas 2
persisted as nonrespondents. All except 1 of 6 nonre-
spondent patients are currently being treated with
BTX-B; 1 of these patients underwent a trial of BTX-F
injections (2 injection visits) without a favorable re-
sponse and is currently being treated with BTX-B.
DISCUSSION
Although BTX has been an important treatment mo-
dality for more than two decades, few studies have been
published regarding the long-term follow-up studies of
patients who have received BTX for 10 or more years
(Table 3).11 Our study of 45 patients represents the

FIG. 2. Comparison between initial and most recent BTX injection visits for 45 patients treated for more than 12 years.

Movement Disorders, Vol. 20, No. 5, 2005

 EFFECTS OF LONG-TERM BTX TREATMENT 595

TABLE 3. Follow-up studies of botulinum toxin treatment that include patients treated for 10 years or longer
Botulinum toxin injection treatment
Condition (n) Range, yr Visits, n (mean) Efficacy Adverse events (% visits)
Reference [N] (mean) [N] [measure; range] [most common] Nonresponse
22 FD [53] 0.2–6 (NA) (6) [330] Active 3.3 [MD ⫹ Pt (65) [Weakness] 2° NR (4) Ab⫹ (2)
Active (13) Active 2–6 (3) rating; 0, none to
4, excellent]
23 BP (20) HFS 5–9 (NA) BP (19.3) HFS 1.1% visits “No First 3 visits: BP (35), HFS NA
(12) [32] (16.6) [585] response or (20) Last 3 visits: BP
relieved symptoms (6), HFS (0) [Ptosis or
for less than 4 dry eyes]
weeks”
24 BP [115] 3–8 (5.7) (16.1) [1,855] 47.8% “Good (NA) [Ptosis] NA
responders”
25 HFS [158] 0.2–6.6 (2.3) 5.4 [855] 97% [VAS 0–100%] (29.1) [Ptosis] 1° NR (3) 2° NR
(23) Ab⫹ NA
12 CD [303] 1.3–5.9 (3.2) 10.2 [NA] Improvement, 10/15– (22) [Dysphagia] 5.6% Ab⫹ (2.9%)
4/15 (group
median) before
15th injection
26 OMD [162] 0.3–10 (4.4) (7.4) [1,213] Mean peak effect 3.1 (11.1) [Dysphagia] NA
[MD rating; 0–4]
27 ES [68] 3.4–6.3 (4.8) 1.6 [NA] 89.7% [MD rating at (38.2) [Ptosis] NA
3 yr; 0–100%]
13 HFS [65] ⬎10 (NA) 1st yr: (4) [239] 96% [Pt rating; 0–4] 1st yr: (14.2) 10th yr: (3.4) NA
10th yr: (3.8) [Ptosis]
[232]
14 CD (106) ⬍12 (NA) (11.1) [2,616] At ⬎5 yr of (4.5) (Pt, 26.9) [NA] 1° NR (9.1%) 2° NR
HFS (70) treatment: CD (7.5%) Ab⫹ (NA)
BP (36) 72.2%, HFS 76.6%
FD (23) BP 78.6% [Pt
[235] diary ratings; 0–
100%]
15 CD [100] ⬍12 (5) (13.8) [NA] Mean 1.93 [Pt rating; (NA) [Neck muscle 1° NR (1) 2° NR (3)
Active (32) ⫺4 (very bad) to weakness, dysphagia] Ab⫹ (0)
⫹4 (very good)]
Present [45] 12.6–18.9 (15.8) (32) [1,456] Mean 2.9 at first First visit: (35.6%); last NR (6) Ab⫹ (4)
study visit; 3.7 at last visit: (22.2%)
visit [0–4; 0, no [Dysphagia; ptosis]
effect to 4, marked
improvement]

FD, focal dystonia; NA, not available; MD, physician; Pt, patient; 1°, primary; 2°, secondary; NR, nonrespondent; Ab⫹, antibody positive; BP,
blepharospasm; HFS, hemifacial spasm; VAS, visual analogue scale; CD, cervical dystonia; OMD, oromandibular dystonia.

longest follow-up of BTX-treated patients (up to 18.9
years). Patients are currently responding better to BTX,
having statistically significant increases in global rating,
peak duration of response, and peak effect, compared
with that after the initial visit. This could be due to a
significant increase in BTX units over time, partly ex-
plained by a cautious use of low doses of the toxin at
initial visit. With longer experience and possibly as a
result of progression of the disease, the dosage has in-
creased gradually, which may also contribute to signifi-
cantly better efficacy and longer duration of peak effect.
Despite the increased dose, the frequency of adverse
effects has actually decreased.
The persistently favorable response to BTX correlates
with the findings of other longitudinal studies. The Ger-
man Dystonia Study Group12 reported a sustained sig-
nificant decrease in severity scores (P ⬎ 0.0001) in a
group of 303 cervical dystonia patients who had received
six or more BTX-A injections (up to 21 injections over
approximately 4 years). A multicenter study comparing
the first and tenth year of BTX-A treatment of 65 hemi-
facial spasm patients did not find significant differences
(except a reduction in adverse events) between the treat-
ment variables studied in the first and tenth year of
treatment with a 96% response rate after the first and last
treatment, using similar BTX doses.13 Hsiung and col-
leagues14 studied the efficacy of BTX-A over a period of
up to 12 years (mean duration of follow-up not specified
in their report) in 235 patients with various different
movement disorders (cervical dystonia, hemifacial
spasm, blepharospasm, and other dystonias) and a total
of 2,616 treatment visits, and found that the benefit was

Movement Disorders, Vol. 20, No. 5, 2005

596 N.I. MEJIA ET AL.
maintained in 102 of 135 (76%) patients who continued
treatment after 5 years. In another long-term follow-up
study of BTX-treated patients, 100 consecutive cervical
dystonia patients were followed for up to 12 years (mean,
5 years).15 Patients were interviewed in person or over
the telephone. When patients could not be reached by
telephone, their family doctors, health insurers, or local
authorities were contacted. The 32 patients who were
still being treated with BTX at their institution were
interviewed and reexamined; 25 patients were being
treated at other centers, 33 discontinued treatment (3
having developed secondary nonresponsiveness), 4 had
died, and 6 were lost to follow-up. Only those claiming
to have no effect or who had lost their initial treatment
effect to BTX were reevaluated. Although data on 1,382
treatment visits was provided, the efficacy of response to
BTX was assessed by patients’ global subjective BTX
effect over the whole treatment period (on a rating scale
where ⫺4 represented very bad effect in all sessions and
⫹4 very good effect in all treatment sessions), and a
mean score of 1.93 was provided by the 90 patients who
were able to provide information.
Although adverse effects, chiefly related to excessive
chemodenervation of the target or adjacent muscles, are
expected complications of BTX injections, BTX treat-
ment is considered remarkably safe. In a recent systemic
review and metaanalysis of 36 long-term studies involv-
ing 2,309 subjects, any mild to moderate adverse events
were reported in about 25% in the BTX-A-treated group
(353/1,425 patients) compared with 15% in the control
group (133/884 patients).16 Focal weakness was the only
adverse event that occurred significantly more often with
BTX-A treatment than in controls (P ⬍ 0.001). In an
observational, prospective multicenter study of patients
with cervical dystonia (PRO-CD) who had not received
treatment with and BTX serotype before enrollment, 326
patients (69.9% women; mean age, 50.1 years) received
up to 9 treatments with BTX (mean dose per treatment,
758 units; mean number of treatments, 4.3).17 Clinical
responsiveness was noted in 88 to 100% of patients at
each treatment. Adverse event data, collected for 1,078
treatment sessions, showed that the adverse events re-
ported most frequently were dysphagia (8.5%), neck or
shoulder weakness (8.4%), and neck pain (6.5%).
One of the main concerns about treatment with repeat
BTX injections is the possibility of developing immu-
noresistance due to emergence of blocking antibodies.
We found blocking antibodies, confirmed by MPA, in 4
(8.8%) patients. This also correlates with a longitudinal
study of BTX-treated patients published previously. In
the series by Hsiung and colleagues,14 7.5% of 235
patients followed for 10 years developed secondary re-
Movement Disorders, Vol. 20, No. 5, 2005
sistance, but MPA was not used to confirm the presence
of blocking antibodies. Kessler and colleagues12 in their
series of 303 patients found that 17 of 162 (10.4%)
patients who discontinued therapy had become nonre-
sponders, 9 of them because of blocking Abs measured
by MPA, a test injection in the extensor digitorum brevis
muscle (EDB test), or a phrenic nerve-hemidiaphragm
preparation. Of 43 patients who discontinued treatment
in another longitudinal study,15 3 (6.9%) were considered
secondary nonresponders, but Abs to BTX were not
found using the phrenic-hemidiaphragm in vitro mouse
bioassay test. We reported previously that BTX Ab-
positive patients tend to have an earlier age at onset (P ⬍
0.05), higher mean dose per visit (P ⬍ 0.0005), and
higher total cumulative dose (P ⬍ 0.01) as compared
with Ab-negative patients.8
In another study, 24 of 559 (4.3%) patients treated for
cervical dystonia developed secondary nonresponsive-
ness, presumably due to BTX antibodies.18 In addition,
the authors found that BTX resistant patients had a
shorter interval between injections, more “boosters,” and
a higher dose at the nonbooster injection as compared
with nonresistant patients treated during the same period.
As a result of this experience, clinicians are warned
against using booster injections and are encouraged to
extend the interval between treatments as long as possi-
ble, certainly at least 2 months, and to use the smallest
possible doses. We and others have observed that if
immunoresistance does develop, it tends to occur within
the first 1 to 4 years of treatment, and Ab formation
seems less likely after this treatment period.8 To deter-
mine whether protein loading is an important risk factor
for the development of blocking Abs, we compared 130
patients treated for cervical dystonia with original
BTX-A, 42 of whom were exposed only to the original
BTX-A used before 1998 (25 ng protein/100 units) and
119 treated only with the current BTX-A (5 ng protein/
100 units).19 Blocking Abs were detected in 4 of 42
(9.5%) patients treated with original BOTOX (Allergan,
Irvine, CA) but in none of 119 patients treated exclu-
sively with the current BOTOX (Allergan) (P ⬍ 0.004).
We postulated that the low risk of Ab formation with the
current BTX-A was related to lower protein load and that
the use of the current preparation decreased the risk of
Ab formation by a factor of six. This finding is supported
by the interim results of the ongoing PRO-CD study that,
based on 1,078 follow-up visits and 1,036 blood samples
evaluated for blocking Abs by MPA, showed that 1,031
(99.5%) tested negative for blocking Abs, 1 (0.1%)
tested positive, and 4 (0.4%) were inconclusive).17 In
some patients who become Ab positive, their immuno-
logic status reverts to Ab negative after 30 months on
 EFFECTS OF LONG-TERM BTX TREATMENT
average (range, 10 –78 months). When these Ab-negative
patients are reinjected with BTX-A, they usually benefit
with a response comparable to their earlier experience.
Most lose their clinical response to subsequent injec-
tions, and when retested are found to be Ab positive
again.20
Although our study represents the longest follow-up of
patients continuously treated with BTX, we recognize
that our study is open-label and as such the data must be
treated cautiously. Although long-term studies such as
ours have limitations,21 it would be ethically and logis-
tically impossible to obtain such long-term follow-up
data in a controlled study. Despite these limitations, we
believe that our data supports the conclusion that BTX is
an effective treatment with a low incidence of immuno-
genicity even after 18 years of use, particularly if appro-
priate measures are taken to minimize the risk of anti-
body formation.
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