Botulinum toxins

Nomenclature

Although botulinum toxin is commonly known as “Botox”, that name is in fact only one of the brand names of formulations in which botulinum toxins are available. For example, in the UK, the following branded formulations are available:

• botulinum toxin type A: Bocouture (50-unit vials), Vistabel (50-unit vials), Xeomin (100-unit vials);

• botulinum toxin type A-hemagglutinin complex: Azzalure (125-unit vials), Botox (50-unit vials), Dysport (500-unit vials);

• botulinum toxin type B: Neurobloc (5000 units/ml in vials containing 0.5, 1, or 2 ml).

This can cause considerable confusion. In July 2009 the US Food and Drug Administration approved the following revisions to the prescribing information of botulinum toxin products (Botox, Botox Cosmetic, and Myobloc) [ ]:

• a boxed warning highlighting the possibility of experiencing potentially life-threatening distant spread of toxin effect from the injection site after local injection.

• the issue of a medication guide to help patients understand the risks and benefits of botulinum toxin products.

The established drug names have also been changed, in order to reinforce individual potencies and prevent medication errors. The new name to replace “botulinum toxin type A” is OnabotulinumtoxinA (marketed as Botox and Botox Cosmetic). The name that replaces to “botulinum toxin type B” is RimabotulinumtoxinB (marketed as Myobloc). The FDA has also approved another botulinum toxin product in this class, AbobotulinumtoxinA (marketed as Dysport), and this product also includes boxed warnings.

Observational studies

For blepharospasm, injections of about 12.5–25 MU are made into the periocular muscles of each eye. When so used, adverse effects are seen in 20–50% of treatments. They consist of mild ptosis, increased or reduced tear function, diplopia, and ectropion. These effects are transient, most lasting about 2 weeks, and generally well tolerated. Occasionally ptosis is so severe as to be inconvenient for the patient. The blepharospasm is relieved for 2–4 months. Systemic effects have not been reported [ ].

In the treatment of spastic torticollis there is a tendency to use larger doses (up to 1000 MU) injected into the neck muscles, and weakness of the pharyngeal muscles, resulting in dysphagia and paralysis of the vocal cords, has been reported. Difficulty in swallowing and deepening of the voice were found in up to 30% of cases in one series, resolving after 2–3 weeks [ ]. In one case there was severe dysphagia 2 days after an injection, with unilateral vocal cord paralysis a week later; swallowing was normal again after 6 weeks [ ]. The possibility of appreciable effects from this neurotoxin at more distant neuromuscular junctions and the development of antibodies are potential dangers here.

Treatment of spasmodic torticollis with botulinum toxin has been reviewed retrospectively in 107 patients [ ]. It was efficacious in 93% but adverse effects occurred in 84%. Initially, 500 MU were injected into each muscle, but the incidence of adverse effects led to a reduction in dosage, 200–500 MU being injected depending on the muscle used and on neck thickness. The median dose per treatment was 1000 (range 200–1600) MU on the first visit and 800 MU subsequently. Dysphagia occurred after 44% of the treatments. This was severe in 2% of treatments, allowing only sips of fluid and necessitating hospitalization for two patients because of dehydration. Two patients developed stridor, two had substantial weight loss, and one developed pneumonia as a result of aspiration. According to the authors, the risk of dysphagia is 40% if a sternomastoid muscle is injected and 25% if it is not. The risks of moderate or severe dysphagia are 7% and under 1% respectively. The authors estimated that there is a 3% chance of antibody production with reduced responsiveness during the first 15 months of treatment. They recommended antibody testing for patients who have initial but not subsequent improvement after repeated injections of botulinum toxin. The problem of immunological resistance to the effects of botulinum toxin associated with repeat injections has been reviewed elsewhere [ ].

The long-term effectiveness of high-dose botulinum toxin (200 MU per axilla) has been evaluated in an open study in patients with axillary hyperhidrosis unresponsive to previous therapies [ ]. In 34 patients follow-up was for at least 12 months. Four relapsed within 12 months and two relapsed after 16 and 19 months. Mild pain and a burning sensation, sometimes lasting up to 1 hour after injection, were the most frequent adverse effects. No compensatory hyperhidrosis at other body sites was reported.

In a review of all adverse events after therapeutic and cosmetic use reported to the FDA during the 13.5 years since botulinum A toxin was first licensed, there were 1437 reports—406 after therapeutic use (217 serious and 189 non-serious) and 1031 after cosmetic use (36 serious and 995 non-serious) [ ]. The adverse events occurred predominantly in women, median age 50 years. Over a single year the proportion of reports classified as serious was 33-fold higher for therapeutic than for cosmetic cases. The 217 serious adverse events reported in therapeutic cases included all 28 reported deaths; six deaths were attributed to respiratory arrest, five to myocardial infarction, three to strokes, two to pulmonary embolism, two to pneumonia, five to other causes, and five to unknown causes. Of the 36 serious events after cosmetic use of botulinum toxin, 30 were included as possible complications in the FDA-approved label; the other six may not have been related to the drug. Seizures were reported in 17 patients; 15 of these had either a history of seizures or a condition that increase their risk of seizures (for example a history of cerebral infarction). Other serious adverse events included dysphagia (n = 26), muscle weakness (11), allergic reactions (13), flu-like syndromes (10), injection site trauma (9), dysrhythmias (9), and myocardial infarction (6). Among the 995 cosmetic cases associated with non-serious events, the most common were lack of effect (63%), injection site reactions (19%), and ptosis (11%).

While this review revealed very interesting information about the adverse effects of botulinum toxin, it did not allow the incidence of such effects to be estimated. The survey covered 1989–2003, but the cosmetic use of botulinum toxin was only approved by the FDA in 2002. On the other hand, the estimated number of cosmetic uses over those 2 years in the USA was impressive (1 123 510 injections in 2002 and 2 891 390 injections in 2003) [ ]. Of course, botulinum toxin was also used for cosmetic purposes, even before FDA approval.

Adverse events have been studied in 327 patients (202 women, 125 men) who received 1043 injections of botulinum A toxin for cervical dystonia (n = 58), blepharospasm (n = 31), hemifacial spasm (n = 39), spasticity due to cerebral palsy (n = 96), chronic anal fissure (n = 96), or esophageal achalasia (n = 7) [ ]. The following adverse events were observed in those with cervical dystonias: dysphagia (27% of patients and 7% of sessions), weakness of the neck muscles (6.7% and 1.3%), pain during swallowing (5.1% and 1%), and a flu-like syndrome (3.4%, 0.7%); the dysphagia appeared 8.2 days after injection and lasted 15 days on average. In patients with blepharospasm there were unilateral ptosis (22%, 6.3%), bilateral ptosis (3%, 1.9%), and hematomas (3%, 0.6%), and in hemifacial spasm excessive weakness resulting in asymmetry of the face, either mild (28% and 20%) or moderate (46% and 27%). In spasticity due to cerebral palsy there was excessive weakness of the legs, which lasted 14 days on average (6.2% and 1.9%), pain (5.2% and 1.6%), and a flu-like syndrome (4.1% and 1.3%). In chronic anal fissure there were mild incontinence of flatus and feces (9% and 5%), hematomas (5%), a flu-like syndrome (3%), inflammation of external anal varices (2%), and epididymitis (1%). In esophageal achalasia, chest pain in six patients (on the day of injection and for 2–4 days) and esophageal reflux in two (4–8 weeks after the injection, lasting 2–3 weeks). The adverse effects were transient, mostly local, and completely reversible.

When the FDA issued an early communication about its review of botulinum toxin A (Botox and Botox Cosmetic) and botolinum toxin B (Myobloc), it said that it has received reports of adverse reactions associated with the use of these products including respiratory compromise and death, suggestive of botulism [ ]. Most of the reported cases involved children who had received the drugs for limb spasticity in cerebral palsy, a condition for which botulinum toxins are not approved in the USA in children under 12 years.

The FDA’s Adverse Event Reporting System database and the medical literature contain reports of iatrogenic botulism in patients aged under 16 years, with serious outcomes, including hospitalization and death. No deaths were reported among adults. In cases of botulism the dose of botulinum toxin A was 6.25–32 U/kg in children and 10–700 U/kg in adults, and the doses of botulinum toxin B were 388–625 U/kg in children and 10 000–20 000 U/kg in adults.

The Australian Adverse Drug Reaction Advisory Committee has emphasized the importance of adherence to the indications and dosing instructions in the use of botulinum toxin-containing products [ ]. Botulinum toxin type A (Botox, 100 U/vial) is used for treatment of strabismus, blepharospasm, facial nerve disorders, spasmodic torticollis, various spasticity disorders, spasmodic dysphonia, axillary hyperhidrosis, and brow furrow lines. A hemagglutinating complexed form of botulinum toxin A, has similar but more limited indications. Since 1994, the Therapeutic Goods Administration in Australia has received 45 reports in connection with the use of botulinum toxin, none of which have described a fatal outcome. The reactions reported are most commonly of muscle weakness (n = 16) at sites adjacent to or distant from the injected area, including dysphagia (n = 8), respiratory failure or dyspnea (n = 3), and generalized muscle weakness (n = 7). Other reactions have included rashes or other allergic reactions, diplopia, and fatigue. Seven reports cited off-label use and 17 cited use for cosmetic reasons, but the others cited use according to approved indications.

Placebo-controlled studies

In a multicenter, randomized, placebo-controlled trial in 145 patients with axillary hyperhidrosis, refractory to treatment with topical aluminium chloride, both 100 and 200 MU of botulinum toxin reduced sweat production by about 80% [ ]. After 24 weeks, sweat production in the treated axillae was about 45% of baseline. Temporary adverse events during the first 14 weeks included headache, soreness of the muscles of the shoulder girdle, axillary itching, and increased facial sweating.

A multicenter, double-blind, randomized, placebo-controlled study in 320 patients with untreated hyperhidrosis showed a more than 50% reduction in sweat production at 4 and 16 weeks after treatment respectively in 94% and 82% of patients treated with botulinum toxin (50 MU per axilla) and in 36% and 21% of placebo-treated patients [ ]. The major treatment-related adverse effect was an increase in sweating in non-axillary sites after treatment. Open treatment with botulinum toxin A was offered to patients in whom sweat production was at least 50% of baseline values [ ]. Of 207 study subjects, 39% had one treatment, 45% had two treatments and 15% had three treatments. Response rates 4 weeks after treatment were 96%, 91%, and 83% after the first, second, and third treatments respectively. In one of 207 patients there was possible transient seroconversion from negative to positive for neutralizing antibodies to botulinum toxin, and subsequent treatment with botulinum toxin resulted in complete disappearance of axillary sweating 7 days after injection.

Systematic reviews

In a review of four publications reporting adverse events after local injection of botulinum toxin into the lower urinary tract the reported adverse effects included generalized muscle weakness, arm weakness, hyposthenia with reduced supralesional muscle force, vision disturbances, and fever [ ]. All the adverse effects were self-limiting and lasted 2 weeks to 2 months after injection.

Adverse reactions to botulinum toxin type A have been reviewed [ ] and subjected to systematic review [ ] in an analysis of data from nine double-blind, placebo-controlled studies in 792 patients with spasticity after stroke (mean age 58 years, 60% men). Most of the patients (69%) received only one injection. After follow-up for a mean of 18 (range 0.1–45) weeks 352 (66%) of the patients who had been given toxin type A group and 163 (63%) of those who had been given placebo reported at least one adverse event. The most frequent adverse events were respiratory infections, seizures, incoordination, and injection site pain, none of which occurred at a significantly higher rate with the toxin. Most of the adverse events were rated as mild or moderate in intensity. Only nausea was reported at a significantly higher rate with botulinum toxin (12/534) than placebo (0/258); in contrast, injection site pain, chest pain, and allergic reactions were reported significantly more frequently with placebo.

Nervous system

Five cases of severe headache refractory to oral analgesics have been reported in patients treated with 10–38 MU of botulinum toxin for glabella frown lines (n = 4) and in a patient treated with 120 MU for palmar hyperhidrosis [ ]. The headache lasted for 8 days to 4 weeks, did not respond to oral prednisolone, and in some patients was accompanied by photophobia, ear tenderness, or nasal congestion. Two patients had had a similar headache after a previous treatment with botulinum toxin and in another patient a similar headache occurred after the next treatment. None of the patients had a history of severe headaches.

In a double-blind, randomized, placebo-controlled trial in 60 patients with lateral epicondylitis a single injection of botulinum toxin type A significantly reduced pain [ ]. However, there was mild paresis of the fingers at 4 weeks in four patients who received botulinum and in none of those who received placebo; 10 patients who received botulinum and six who received placebo had weak finger extension on the same side as the injection.

In a double-blind, randomized, placebo-controlled trial of botulinum toxin type A injections for 12 weeks in 40 patients with writer’s cramp, the reported adverse effects were hand weakness, which was mostly mild and always transient, and pain at the injection site [ ]. Despite weakness in the hand most of the patients preferred to continue treatment.

Pain from injection of botulinum toxin can be reduced by the use of a topical local anesthetic [ ].

Autonomic adverse effects (constipation and dry mouth) have been reported in four patients after intravesical injection of botulinum toxin type B for detrusor overactivity, suggesting systemic spread of the toxin [ ]. Suburothelial injection of small doses of botulinum A toxin may be preferable [ ].

A 34-year-old weightlifter with a gait disorder developed generalized muscle weakness 2 weeks after being given botulinum toxin 11 units/kg into both gastrocnemii and the tibialis posterior in the right leg [ ].

Neuromuscular function

Muscle weakness after botulinum toxin injection is usually due to local spread of the agent. Asymptomatic systemic effects have been detected in patients with cervical dystonia after repeated botulinum toxin injections, when muscle biopsies from the vastus lateralis muscle were examined [ ]. However, generalized neuromuscular symptoms are rare. Patients with a reduced margin of safety with regard to neuromuscular transmission might be considered prone to systemic effects, but even in patients with myasthenia gravis symptoms distal from the injection site have been reported only occasionally [ ]. However, generalized muscle weakness can occur if higher doses of botulinum toxin are used, and a recent report has illustrated that this may happen in patients after many uneventful treatment sessions [ ]. Electrophysiological findings in these patients were suggestive of mild botulism, with doses of botulinum toxin of 600–900 units. Two similar cases had been reported previously [ ]. Therefore, constant long-term monitoring of patients is recommended, even if they have been receiving injections for many years without adverse effects.

Generalized muscular weakness associated with signs of systemic cholinergic autonomic impairment has been reported.

• A 25-year-old woman was treated with botulinum toxin for hyperhidrosis of the axillae and hands in one session with a total amount of 1400 MU. Six days later she complained of diffuse weakness, diplopia, mild bilateral ptosis, severe weakness in the fingers, and reduced lacrimation, salivary production, and sweating [ ]. She recovered completely within 2 months.

Permanent extraocular muscle damage has been reported [ ].

• A 70-year-old man had increasing difficulty in maintaining binocular vision while reading. There was imbalance of his extraocular muscle activity. Botulinum toxin 2.5 MU was therefore injected into the left inferior rectus muscle under electromyography control using a 27-gauge needle. At the next visit 1 month later he complained of diplopia in all directions of gaze, in keeping with a left inferior rectus muscle palsy. Over the next 10 months there was no improvement. Magnetic resonance imaging then showed atrophy of the left inferior rectus muscle. Inferior transposition of the medial and lateral recti muscles was performed, which produced satisfactory alignment.

Botulinum-induced atrophy of extraocular muscles of the eye cannot be excluded in this case. This mechanism is supported by the observation that botulinum toxin can cause histological changes in the extraocular muscles in adult monkeys [ ]. The authors of the present report also suggested that intramuscular hematoma or direct damage to the nerve to the muscle may have been responsible. So far, permanent extraocular muscle damage after botulinum toxin injection seems to be rare. If additional cases are reported, patients should be informed about this possible complication before treatment.