Craniofacial Muscles

302 J. Park et al.
Long-term effect and loss of ef fi cacy with repeated injections is also debated in
the literature. Although some studies have failed to demonstrate a reduced effectiveness
or shorter duration of treatment with time, (Ainsworth and Kraft 1995 ; Jankovic
and Schwartz 1993 ) it is sometimes clinically observed that initial treatments are the
most successful and, with time, the effect of each injection may be less or tends to
last for a shorter period.
Reduced ef fi cacy may be the result of antitoxin antibody development and binding
of the nonactive large protein chain. Careful consideration should be given
before labeling a patient as a failure due to antibody induction. Immunity to BoNT
is uncommon, and some authors reported that despite the observed development of
antibodies to BoNT/A in the serum of some patients receiving repeated multiple
injections; their presence did not appear to weaken its therapeutic effect (Ainsworth
and Kraft 1995 ; Siatkowski et al. 1993 ; Choi et al. 2007 ) .
The loss of ef fi cacy might be a result of disease progression rather than a true
resistance to the toxin. To differentiate a loss of pharmacological effect of the BoNT
from disease progression, affected patients should be evaluated 2 weeks after a
larger amount of BoNT treatment and should be tested for objective weakness of the
orbicularis oculi muscle. If they fail to develop weakness after injection, such immunized
patients are good candidates for myectomy.
Failure of treatments including BoNT and myectomy is often due to apraxia of
eyelid opening. These patients still struggle to open their eyes after BoNT or myectomy
but have little or no spasm. Jordan et al. estimated that almost 50% of patients
in whom BoNT treatment is considered a failure suffer from apraxia of eyelid
opening (Jordan et al. 1990 ) .
Reduced ef fi cacy after repeated BoNT injection may be the result of a nerve
sprouting and the formation of new motor end plates on the paralyzed muscle fi bers
(Holds et al. 1990 ; Alderson et al. 1991 , Harrison et al. 2011 ) . Paralysis of the neuromuscular
junction is irreversible, so repeated injections cause the development of
collateral nerve fi bers, with a resulting increase in the number of axon terminals.
This may explain the development of tolerance after repeated BoNT injections.
Some microscopic pathology studies show that long-term exposure to the BoNT
can cause denervation atrophy of some skeletal muscles, which might reduce the
frequency and amount of BoNT treatment needed. Others observed only mild
degenerative muscle changes including changes in myo fi bril size and increased distribution
of anticholinesterase. These studies imply that repeated BoNT injection
does not appear to result in irreversible changes such as fi brosis or scar formation
that is secondary to neurogenic muscle atrophy (Borodic and Ferrante 1992 ; Horn
et al. 1993 ) .
The most common side effect of BoNT injections is erythema or swelling of the
eyelid, sometimes accompanied with bruising. It is known that signi fi cant systemic
complications do not occur, since clinical doses of BoNT in cranial dystonia or
hemifacial spasm are relatively small in amount, and moreover, it is injected locally
into the muscle or subcutaneous plane and very little enters the systemic circulation
(Siatkowski et al. 1993 ) . Local complications related to BoNT treatment for
blepharospasm include transient blepharoptosis (7–11%), exposure keratopathy or