Síndrome de L-N.

1. Research Paper
Safety and Efficacy of Botulinum Toxin in the Treatment of Self-Biting
Behavior in Lesch-Nyhan Disease
María del Mar Garcia-Romero, MD a, *
, Rosa J. Torres, MD, PhD b, c
,
Juan Garcia-Puig, MD, PhD d, e
, Samuel Ignacio Pascual-Pascual, MD, PhD a, f
a
Department of Pediatric Neurology, Hospital Universitario La Paz, Madrid, Spain
b
Department of Biochemistry, La Paz University Hospital Health Research Institute (FIBHULP), IdiPaz, and Center for Biomedical Network Research on Rare
Diseases (CIBERER), ISCIII, Madrid, Spain
c
Hospital Universitario La Paz, Madrid, Spain
d
Department of Internal Medicine, Hospital Quiron, Madrid, Spain
e
Department of Internal Medicine, Universidad Autonoma de Madrid, Madrid, Spain
f
Department of Pediatrics, Universidad Autonoma de Madrid, Madrid, Spain
a r t i c l e i n f o
Article history:
Received 23 August 2021
Accepted 27 October 2021
Available online 1 November 2021
Keywords:
Botulinum toxin
Lesch-Nyhan disease
Self-biting behavior
Autoaggressive behavior
Self-mutilation
a b s t r a c t
Background: Lesch-Nyhan disease (LND) is a disease of purine metabolism linked to chromosome X due
to the absence or near-absence of enzyme hypoxanthine-guanine phosphoribosyltransferase. Patients
with LND have a compulsive autoaggressive behavior that consists of self-mutilation by biting.
Methods: The objective of this study was to explore the safety and efficacy of botulinum toxin (BoNT)
injected into the masticatory muscles and biceps brachii to reduce self-mutilation in patients with LND.
We retrospectively analyzed six patients with LND who were treated with BoNT to prevent automuti-
latory behavior.
Results: The patient ages when started on treatment with BoNT were 4, 4.5, 6.6, 7.9, 13.9, and 32.3 years.
Patients received a mean number of injections of 20, ranging from 3 to 29, over a period that ranged from
1.5 to 7.1 years. The maximum total dose of Botox was 21.3 units/kg mean and the maximum total dose of
Dysport was 37.5 units/kg mean. A total of 119 injections were performed. Of these 113 (95%) were
partially or completely effective. Only three of 119 injections (2.5%) produced adverse effects.
Conclusions: Botulinum toxin is useful and safe for the treatment of self-biting behavior in patients with
LND.
© 2021 Elsevier Inc. All rights reserved.
Introduction
Lesch-Nyhan disease (LND) is an inherited metabolic disorder of
purine metabolism. LND is an X-linked genetic disorder that
produces an absence or near-absence of the enzyme
hypoxanthine-guanine phosphoribosyltransferase (HPRT). Typical
clinical findings include hyperuricemia, secondary kidney disease,
dystonia, varying degrees of intellectual disability, and compulsive
autoaggressive behavior with severe self-mutilation as a charac-
teristic feature.1-4
Patients show reduced HPRT enzyme activity, less than 1.5% of
normal values in classic patients and around 2% to 10% of residual
enzyme activity in patients who suffer partial features of the full
syndrome. Purine bases hypoxanthine and guanine are converted
into their respective nucleotides, inosinic acid and guanylic acid, by
the action of HPRT. Patients with LND cannot reutilize them, so they
are degraded to uric acid. Allopurinol is useful for patients with LND
to prevent hyperuricemia and secondary kidney disease, but
neither the neurobehavioral symptoms nor the dystonia are
modified. The exact mechanisms that dysregulate behavior and
movement in patients with LND have not been determined.2,5
Ethics statement: Ethical approval was obtained by La Paz Hospital's Research
Ethics Committee.
Consent statement: Patients and caregivers were informed of the mechanism of
action of BoNT and its efficacy and adverse events and signed a written informed
consent to the research and to publication of the results.
The authors declare that there is no conflict of interest.
* Communications should be addressed to: Dr. Garcia-Romero; Department of
Pediatric Neurology; Hospital Universitario La Paz; Paseo de la Castellana 261;
Madrid 28046, Spain.
E-mail address: mmar.garcia.romero@salud.madrid.org (M.M. Garcia-Romero).
Contents lists available at ScienceDirect
Pediatric Neurology
journal homepage: www.elsevier.com/locate/pnu
https://doi.org/10.1016/j.pediatrneurol.2021.10.018
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2. Patients with LND show a specific pattern of self-aggressive
behavior that is different from what is described in patients with
intellectual disability or autistic features and is quite similar among
all of them. Patients with LND usually start biting their lips and
fingers before they reach age six years, a habit often associated with
the emergence of teeth, and as they grow older, they develop
different means of self-aggression, including banging their heads,
kicking, scraping their arms, or trying to injure their mouths or eyes
with their fingers. Patients also develop ways to be aggressive with
others, such as spitting, insulting, or being sexually offensive.1-5
Patients with LND want to be restrained and to use protective de-
vices so that they are not able to be aggressive. They do not want to
self-injure or injure others, but they cannot prevent it by them-
selves. If physical barriers are removed, they will begin self-injuring
again, getting anxious and suffering because they cannot manage
the situation.3,5
The use of punishment is not effective and usually
leads to an increase in the rate of the behavior.4
Several treatment approaches have been employed to manage
self-aggression in patients with LND, with incomplete efficacy. Arm
restraints are useful in preventing fingers and arms from being
bitten and in preventing injuries in the face produced by using their
hands or arms. Leg restraints prevent kicking and injuring legs.6
Dental devices such as splints or mouth guards are also used, but
if they are not successful, then tooth extraction is an option that is
used by quite a high proportion of patients with LND.7
Oral medi-
cations such as benzodiazepines, neuroleptics, antidepressants, or
antiepileptic drugs are also employed, usually in combination with
restraints.6,8,9
Oral supplementation with S-adenosylmethionine
has shown benefits in a small number of patients.10,11
Pallidal deep
brain stimulation has also shown to be effective in some cases.12-14
Botulinum toxin (BoNT) is a very versatile therapeutic agent,
acting by inhibiting the release of acetylcholine from the presyn-
aptic terminal, leading to a consequent neuroparalysis of the
muscle where it is injected. The most extended applications are in
pathologies manifested by abnormal, excessive, or inappropriate
muscle contractions, but its use is much wider than that. Only a few
current indications are approved by regulatory agencies, with most
of the clinical uses being off-label.15
Botulinum toxin can be injec-
ted in any muscle, producing weakness that lasts variably
depending on the dose, the volume of dilution, the site of injection,
and the serotype used. BoNT/A is the most frequently used serotype
in clinical practice, with a clinical benefit usually detected over a
period of three to four months, and with a maximal benefit after
four to six weeks. BoNT is safe, with rare and mild side effects.16
BoNT has long been injected in masticatory muscles in cases of
masseter hypertrophy and bruxism,17-19
and in biceps brachii for
dystonia, spasticity, and cocontraction in congenital brachial plexus
lesions20,21
with no relevant side effects. BoNT/A has been used
only rarely for the treatment of patients with LND.22-25
The aim of our study was to assess the safety and efficacy of
BoNT type A when applied to masticatory muscles (masseter and
temporalis), biceps brachii, and other muscles to prevent self-
aggressive behavior, mainly self-biting the tongue, lips, arms, and
hands, in patients with LND.
Materials and Methods
We performed a retrospective study with a long-term follow-up
that included six patients with LND treated in our clinics with
BoNT/A to prevent self-aggression between 2013 and 2021. Another
three patients with LND also followed in our clinics and treated
with BoNT/A injections were not included, as infiltrations were
performed in a different hospital and accurate data could not be
obtained.
Patients
All patients had severe neurobehavioral symptoms, including
self-biting aggressions and a severe generalized dystonic disorder
that prevented them from doing any kind of activity on their own,
including even eating or drinking, and were under physical re-
straints most time of day and night. Patients and families were
informed of the mechanism of action of BoNT and its efficacy and
adverse events and signed an informed consent.
Variables
The following variables were collected from the review of
medical records at follow-up visits: demographic data, clinical
history, mechanisms of self-aggression, age at which self-
aggression started, prior and current additional treatments
employed for self-aggressions, number of visits, dose of BoNT/A and
sites of injection at every visit, type of BoNT/A applied, frequency of
injections, efficacy and duration of every injection, need for dental
extraction, and adverse effects. Information was provided mostly
by parents, and, when possible, also by patients. The response to
treatment was evaluated after every injection as ineffective,
partially effective, or completely effective. The response was
considered ineffective when patient continued self-biting; partially
effective when patient clearly reduced self-biting or stopped self-
biting their mouth but persisted biting their hands; and
completely effective when self-biting completely disappeared. The
duration of effect was registered in days lasting from every BoNT/A
injection to the resumption of self-biting. Adverse events were
recorded by asking parents and patients at every visit.
Botulinum neurotoxin A
Types of BoNT/A used were onabotulinumtoxin A (Botox),
diluted 100 units in 1 mL, and abobotulinumtoxin A (Dysport)
diluted 200 units in 1 mL. Four patients received the same type of
BoNT/A at every visit; one patient switched from one to the other
type after observing inefficacy at some visits, and another patient
changed the type of BoNT/A after the second dose for no specific
reason. The first dose for every patient was calculated depending
on body weight, and subsequent doses, depending on the efficacy
and adverse effects of prior doses. The frequency of doses varied
depending on the efficacy of previous doses and the availability of
patients to come to the clinics.
BoNT/A injections
Electromyography was used for injecting the masseters and
temporalis muscles, and anatomic guidance was used for locating
the biceps brachii and other muscles. Both sides of face were
injected at every visit. Masseters were injected at two points at
least 1 cm apart. Temporalis muscles were injected at one point.
Biceps brachii and other muscles were injected at one or more
points depending on doses. No more than 50 units of Botox or 100
units of Dysport were used at the same point. Injections were
performed with instant topical anesthesia (ethyl chloride) or
inhaled analgesia (nitrous oxide delivered as a 50% blend with
oxygen, Kalinox).
Statistical analysis
Descriptive statistics were used. Parametric measures were
calculated for quantitative variables, and frequency tables were
used for categorical variables.
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3. Results
Six patients were treated with BoNT/A to prevent self-biting
behavior. The mean age at which self-biting started was
42.8 months, ranging from 24.3 to 49.9 months. All patients bit
their hands and arms, and five also bit their tongue and lips. All of
them also developed other forms of self-harm, such as knocking
their heads or kicking. Clinical features are shown in Table 1. The
patients' ages when started on treatment with BoNT/A were 4, 4.5,
6.6, 7.9, 13.9, and 32.3 years. The two younger patients were
attending our clinics and began treatment as soon as the biting
started. The patients who were 6.6 and 7.9 years old came to our
clinics years after biting had started, already presenting with lip
and arm mutilations. The 13.9-year-old patient, despite having
started self-biting years before, was not treated earlier because the
biting behavior was mild. The treatment was started some years
afterward, when biting became a severe problem. The older patient
lived in a different city and had been self-biting and had severe
mutilations for many years when he first came to our clinic to be
treated; he had received BoNT/A once years before, which had
removed his impulse toward self-biting for some weeks, but he had
not found any other doctor who would inject him again.
Patients received a mean of 20 injections, ranging from three to
29, over a period that ranged from 1.5 to 7.1 years. The type of
botulinum toxin initially used was Botox for three patients and
Dysport for three patients. The toxins were randomly assigned at
the first dose and remained the same for the following injections
for four patients, switching to the other type of toxin in two pa-
tients. The initial total dose of Botox was 11.5 units/kg mean
(ranging from 8 to 15.8), and the maximum total dose was 21.3
units/kg mean (ranging from 12 to 30.6). The initial total dose of
Dysport was 19.7 units/kg mean (ranging from 15.6 to 22.9), and
the maximum total dose was 37.5 units/kg mean (ranging from 27.8
to 46.7). Two patients were also injected in their quadriceps mus-
cles to reduce kicking as a means of self-aggression. This was useful
in one case and useless in the other. All patients also regularly
received BoNT/A for dystonia, mainly in the paraspinal muscles;
this was useful for five of them. Two patients were injected in the
gastrocnemii muscles for spasticity. A total of 119 injections were
performed. Of these, 84 (70.5%) were completely effective, 29
(24.3%) were partially effective, and six were ineffective (4.2%). The
mean duration of effects was 2.4 months (ranging from 1.4 to
3.7 months). The mean frequency of injections was 4.1 months
(ranging from 1.8 to 8.8 months). Only three of 119 injections (2.5%)
produced adverse effects. In two instances, patients described dif-
ficulty swallowing for a week, and in one, general weakness for less
than a week. Table 2 summarizes the results. A partial dental
extraction was done in two patients, associated with the growth of
new teeth, and BoNT/A treatment was effective again after the
extraction was performed. A complete dental extraction was done
in one patient, for whom treatment was partially but not
completely effective, as this patient was unable to come to our
clinics regularly.
Discussion
This study evaluated the safety and efficacy of treatment with
BoNT/A in a small cohort of patients with LND and self-mutilating
disorder to prevent self-biting behavior. To date, no studies refer-
ring to this topic have been published, and only a few reports of
single cases can be found, with a few or only one infiltration.23-25
Injecting BoNT/A is easy for experienced professionals and safe,
with no more difficulties for the masseter and temporalis muscles
than for other common muscles.17-19
As we usually inject botuli-
num toxin for spasticity or dystonia, we performed injections in
patients with LND in the same conditions as usual, with our usual
nurse and assistant nurse in our procedure room. Each visit lasted
no more than 20 minutes, with no need for hospitalization or
subsequent observation. This easy and quick way of administering
BoNT/A treatments enabled patients to come regularly to the
clinics, which is a necessary condition to obtain the best results.
As supported by the results, we can say that BoNT/A injections in
the masseter and temporalis muscles and the biceps brachii are
useful in reducing self-biting aggressions since the first infiltration,
remaining effective after successive doses. The efficacy of in-
filtrations was variable but remained high (70.5% registered as
completely effective, which means patients completely stopped
biting for a period, and 24.3% registered as partially effective, which
means that patients reduced the frequency or intensity of self-
biting, or stopped biting their mouth but continued biting their
hands or arms). The duration of these results was also variable,
usually not lasting more than two months (69.1 days mean, ranging
from 0 to 120). The dose and frequency of BoNT/A injections were
adjusted to the patients' weight and the efficacy of prior doses. As
there are no reported studies of the use of BoNT/A for the pre-
vention of self-aggression, either in patients with LND or in
different disorders, and this use is off-label, there are no standard or
recommended doses to compare with. On the basis of our prior
experience injecting the masseter and temporalis muscles to pre-
vent bruxism and injecting the biceps brachii in patients with self-
aggressive behavior (mostly autistic patients), we concluded that
higher doses and more frequent injections are needed for patients
with LND than for other patients. The goal is to completely prevent
self-biting behavior in these patients so they will feel much better
TABLE 1.
Clinical Features of Patients
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6
Age at which self-biting
started: months
(years)
49.9 (4.1) 36.5 (3) 48.7 (4) 48 (4) 24.3 (2) 48 (4)
Type of self-biting Mouth and hands Mouth and hands Mouth and hands Mouth and hands Mouth and hands Only hands
Use of physical
restraints
Yes Yes Yes Yes Yes Yes
Oral medication used to
reduce self-
aggression
Risperidone 0.25 mg qd
Diazepam 2 mg bid
Risperidone 0.5 mg bid
Diazepam 2.5 mg qd
Levomepromazine
5 mg tid
Diazepam 2 mg bid
Risperidone 1 mg bid
Diazepam 2.5 mg bid
Risperidone 0.5 mg tid
Clonazepam 0.5 mg tid
Diazepam tid
2 mg-2 mg-4 mg
Abbreviations:
bid ¼ Twice a day
qd ¼ Once daily
qid ¼ Four times a day
tid ¼ Three times a day
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4. and even be able to manipulate computers or devices when they
can be hands-free. Regular BoNT/A injections make them more
relaxed, as they know that even if they try to bite, they will not be
able to self-injure, so they do not try anymore. It works in a similar
way to physical restraints, but with the advantage of allowing them
to use their hands, at least in some ways. We scheduled the next
injections before the efficacy of the prior ones had completely
declined; this is why frequency was higher than is usual in other
pathologies.
Adverse effects due to BoNT/A injections were infrequent and
mild. Masseter and temporalis muscle denervation by BoNT/A did
not prevent masticatory or swallowing functions; the patients
remained able to eat and drink as they had before the injections. In
the same way, injecting the biceps brachii did not prevent ante-
brachial flexion. BoNT/A treatment was also combined with oral
benzodiazepines and/or neuroleptics in all the patients, as self-
aggression and behavioral problems in patients with LND are not
limited to self-biting. Other forms of self-harm, such as knocking
their heads or kicking, continued despite BoNT/A treatment.
Physical restraints were also used most of the time with all patients,
because they could still punch or injure themselves with their
hands and arms in different ways. It is a remarkable feature that
two patients with good results of BoNT/A after more than 15 in-
jections needed to undergo partial tooth extraction. Both started
biting despite high doses of BoNT/A coinciding with new teeth
eruption. Higher doses and frequency of BoNT/A and higher doses
of oral medication could not prevent biting in that specific situa-
tion, triggered by the new teeth. After these new teeth were
extracted, BoNT/A was effective again. One patient underwent
complete tooth extraction despite having obtained prior good re-
sults with BoNT/A injections. In our opinion, more frequent in-
jections would have been necessary for this patient, but he was not
able to come as regularly as we considered optimal for him. The
efficacy and duration of BoNT/A treatment may vary from one pa-
tient to another because of potential antibodies against BoNT/A and
different BoNT/A preparations (abobotulinum and onabotulinum).
The titles of antibodies cannot be obtained in our clinical practice.
The possibility of immunoresistance as a cause of secondary lack of
effect must be taken. Nevertheless, the rate of dystonic patients
with immunologic resistance to BoNT/A is lower than it was
thought to be decades ago.26,27
Our main conclusion is that BoNT/A injections in the masseter
and temporalis muscles and the biceps brachii are useful for pre-
venting or reducing self-biting behavior in patients with LND, are
also safe, and do not prevent patients from cutting food or using
their arms. The doses and frequency of BoNT/A may be higher than
usual, and injections must be performed regularly to obtain better
results and prevent patients from discontinuing treatment. BoNT/A
remains effective in patients receiving periodic injections. Oral
medications used in patients with LND, such as benzodiazepines
and neuroleptics, may be useful, but it is uncertain which dose will
be the best for every patient; some patients develop adverse effects
with low doses, whereas others have no effect at all with high
doses. BoNT/A administered regularly obtains a stable response
even years after starting on it. The main limitation of our study is
the small number of patients, but the total number of doses (119)
and the long period of the study give consistency to the results.
According to our experience and the unpredictable response of
severe self-mutilating behaviors to oral medications, BoNT/A is safe
and should be considered as a first-line treatment in many patients
with LND.
Acknowledgments
This work was supported by a grant from Mutua Madrile~
na
Foundation, Madrid, Spain.
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BoNT/A Treatment and Results
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6
Age at which BoNT/A
treatment started:
months (years)
54 (4.5) 48 (4) 95 (7.9) 79 (6.6) 387 (32.3) 167 (13.9)
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masseters and
temporalis
14.3 units/kg Dysport 12.1 units/kg Botox 11 units/kg Dysport 6.5 units/kg Botox 4 units/kg Botox 6.3 units/kg Dysport
BoNT/A maximum dose in
masseters and
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BoNT/A initial dose in
biceps brachii
8.6 units/kg Dysport 3.6 units/kg Botox 5.5 units/kg Dysport 4 units/kg Botox 4 units/kg Botox 5 units/kg Dysport
BoNT/A maximum dose in
biceps brachii
13.3 units/kg Dysport 6.3 units/kg Botox 17.9 units/kg Dysport 10 units/kg Dysport 4 units/kg Botox 12.5 units/kg Dysport
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uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2022. Elsevier Inc. Todos los derechos reservados.

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