Madarosis and Facial Alopecia Presumed Secondary to Botulinum A Toxin Injections

Purpose. Botulinum neurotoxins are considered relatively safe therapy for treatment of inappropriate muscle spasms. As seen in this report, undesirable consequences may result.

Methods. The author conducted a clinical interview and examination of the patient.

Results. Unilateral left-sided madarosis and facial alopecia were observed in a patient undergoing botulinum A toxin injections for the treatment of left oromandibular dystonia. The patient had started treatment 18 months previously. He received injections every 3 months in the left masseter and left temporalis muscles. He first noted loss of his left sideburn 8 months into treatment. After 10 months of treatment, he noted that he no longer needed to shave on the left side of his face. Eighteen months after receiving his first botulinum toxin injection, madarosis of the temporal aspect of the left lower lid was observed.

Conclusions. This is the first case report documenting an idiosyncratic unilateral madarosis and facial alopecia as adverse side effects presumed secondary to botulinum A toxin injections.

Botulinum toxin A injections are a treatment modality for movement disorders or dystonia. Many periocular complications from injections near the eye have been reported. This is the first case report documenting an idiosyncratic reaction of unilateral madarosis and alopecia, which was presumed secondary to long-term botulinum A injections for orofacial dystonia. Given the widespread use of this therapy in the general population for the cosmetic treatment of facial wrinkles, this case is of interest, because madarosis and alopecia are potential complications for other individuals undergoing repeated botulinum A toxin injections.

CASE REPORT

A 59-year-old white man presented for ocular examination in February 2002 with a history of "large optic cups." The patient was a physician and had undergone several Goldmann visual fields, the last one 3 years previously, and all showed full fields of vision. His significant medical diagnoses included hyperlipidemia, tinnitus, degenerative arthritis, diverticulosis of the colon, and hearing loss. Best-corrected visual acuities were 20/20 OD and 20/20 OS. Slit lamp examination found normal lids and lashes, white and quiet conjunctivides, clear corneas, and trace nuclear sclerosis of the lenses. Goldmann applanation tonometry found intraocular pressures of 16 mm Hg OD and 17 mm Hg OS. The cup to disc ratios were 0.7 OD and 0.75 OS with intact neuroretinal rims. The patient returned for 24-2 Humphrey visual fields. The Glaucoma Hemifield Tests were within normal limits OU with reliable indices, and the fields were without glaucomatous defects.

In May 2003, the patient returned with seasonal allergies causing itching and discharge OU. His medications at that time included niacin, ranitidine, and simvastatin. Best-corrected acuity was 20/20 OD and 20/20 OS. Applanation intraocular pressures were 18 mm Hg OD and 18 mm Hg OS. Slit lamp examination showed mild blepharitis of the lids and lashes OU. The patient deferred dilation, but a dry internal found no change in the optic nerve cupping. Mild allergic conjunctivitis and blepharitis were diagnosed. Lid scrubs and hot compresses were advised and Patanol (Alcon Labs, Fort Worth, Texas) was prescribed.

The patient was examined 1 week later and underwent pachymetry, photos, gonioscopy, dilation, and optical coherence tomography (OCT)/nerve fiber layer analysis. Humphrey visual field testing again showed Glaucoma Hemifield Tests to be within normal limits. There were no depressions OD and two nonrepeated depressions OS in a nonglaucomatous pattern. OCT results were normal with the OD macular thickness at 225 m and the OS macular thickness at 224 m, disc diameters of 1.75 mm OD, OS and C/D ratios of .74 h/.68 v OD and .79 h/.75 v OS. The angles were open with ciliary body present for 360° OU. Corneal pachymetry readings were 553 μ OD and 540 μ OS.

He returned again in May 2004 with a red and sore" left eye. He related that the pain was located in the globe and not the lids. At this visit, he reported that he was diagnosed with oromandibular dystonia 18 months previously. Although the primary care practitioner had entered this diagnosis on the computerized record system at that time, the patient had not mentioned it because it did not seem pertinent to his eyes or eye examination, and the examining optometrist had not explored the diagnosis or treatment for the condition. The patient's dystonia was confined to the masseter and temporalis muscles. He had no associated blepharospasm, which is a key component of Meige's syndrome (a cranial-cervical dystonia involving blepharospasm associated with intermittent lower facial movement or idiopathic orofacial dystonia).¹ Best-corrected acuity was 20/20 OD and 20/20 OS. Applanation intraocular pressures were 20 OD and 20 OS. Slit lamp examination showed grade 1 blepharitis OU. Normal lashes were present on the right upper and lower lid (Fig. 1) but there was madarosis of the left lower lid temporal aspect (Fig. 2). The patient also reported that he first noted loss of hair on his left sideburn 8 months after starting botulinum A injections. The patient stated the left side of his face and scalp had not been exposed to any chemicals other than those to which the right side of his face and scalp had been exposed. He used Head & Shoulders shampoo and had done so for many years. He used a standard over-the-counter soap and had been using the same brand for years. He used no other lotions, solutions, or medicines on his face or scalp. He had not taken any medications (thallium, dicoumarol, antimetabolites) that are reported to be associated with alopecia. His hair was not styled or under traction, and it had not been exposed to any chemicals such as cold-wave solutions, bleaches, hair straighteners, or hair dyes. He had no other underlying systemic diseases other than the ones listed here as his significant medical diagnoses. There was no dermatitis in the area of the alopecia. The patient believed that his hair loss was an adverse side effect of botulinum toxin A injections that he had begun for left oromandibular dystonia 18 months previously. He also reported a loss of the temporal side of the left eyebrow and a decrease in the amount of facial hair or beard on the left side of the face 10 months after starting treatment. Physical examination of the patient confirmed the loss of the outer one third of the eye brows (somewhat difficult to appreciate) and decreased facial hair on the left side of his face as compared with the right side of his face (Figs. 3 and 4). The loss of his left sideburn was not obvious until the patient moved his hair away from this region because the patient was combing his adjacent hair over this area. He received the botulinum toxin injections every 3 months with a total of 100 units injected at each visit. This typically was distributed in five injections with 20 units at each site, including the masseter (lower, mid, and upper) and temporalis muscles (anterior and posterior). The injection with the closest proximity to the left eye was usually 3 to 4 cm from the lateral canthus. The injections were guided using an electromyograph (EMG) to improve precision in the placement of the toxin. The EMG measures and records muscle activity and can aid the physician in locating overactive muscles.

Figure 1	Figure 2	Figure 3
Figure 4

The OS conjunctiva at this visit showed grade 1 diffuse injection with white mucous in the tear film. The right eye was unremarkable. Acute conjunctivitis (suspected bacterial) was diagnosed and gatifloxacin was prescribed, which resolved the infection in a few days.

The patient dropped by briefly 1 month later after noting drooping of his left lower lid after receiving a recent botulinum toxin injection. Lower lid ectropion of the left lower lid lateral aspect was diagnosed secondary to the botulinum toxin injection. Refresh tears were prescribed.

DISCUSSION

Dystonia is a movement disorder characterized by excessive muscular activation, leading to abnormal postures and repetitive movements.² The prevalence of dystonia is 3.4 to 29.5 per 100,000 for generalized and focal dystonia, respectively.³ The crude annual prevalence rate for primary dystonia is 152 per million, with focal dystonia having the highest relative rate at 117 per million.³ Dystonia is more common than many other neurologic diseases such as Huntington's disease, amyotrophic lateral sclerosis, and myasthenia gravis.³ Oromandibular dystonia (OMD) is a frequently disabling focal dystonia in which patients often have difficulties chewing, speaking, and swallowing.⁴ Adult-onset versions can strike after a physical trauma, stress, exposure to certain drugs or toxins, or for no apparent reason. One of several new treatments for dystonia is botulinum toxin injections to block the muscle spasms. ^4-7

Botulinum toxins are exotoxins of the anaerobic spore-forming bacterium Clostridium botulinum, and the causative agents of the severe foodborne illness, botulism.^5-7 With lethal doses approximating 10^-9 g/kg body weight, these neurotoxins represent some of the most toxic naturally occurring substances.^5-7 Although the intracellular targets of the toxins are variable, they all ultimately prevent release of membrane-bound acetylcholine at the neuromuscular junction of striated muscles and thus produce chemical denervation and paralysis of the muscles.^5-7 Normally, once a nerve action potential reaches an axon terminal, the synaptic vesicles release acetylcholine molecules. These molecules then bind to and stimulate acetylcholine receptors, which ultimately trigger a muscle contraction. Botulinum toxin shuts down this sequence of events by binding to the nerve terminal.¹ Botulinum toxin may also invade the central nervous system and directly affect synaptic activity by altering sensory input and the inevitable secondary changes that ensue.⁸ The muscular function begins to return at approximately 3 months and is usually complete by 6 months.^5,6

Reported complications of botulinum A injections made lateral to the lateral canthus include diplopia, ectropion, and bruising.^5-7 Other complications resulting from treatment for OMD include transient ptosis, tearing, dry eye, nausea, malaise, flu-like symptoms, rashes at sites distant from the injection, pain, edema, erythremia headache, short-term hypesthesia, dysphagia, dysarthria, and difficulty chewing.^5-7 Madarosis and facial alopecia from botulinum A toxin injections have not been previously reported in the literature.

Alopecia of the external third of the eyebrows and conjunctival edema was reported in one patient with Meige hereditary lymphedema by Rebegni and colleagues.⁹ Hereditary lymphedema is a rare congenital familial disease affecting lower and/or upper limbs, and many eye anomalies have been associated with this form.⁹ Alopecia of the lateral third of the eyebrows is a common finding in other complex pathologies involving lymphatics and seems to be casually related to edema.⁹ Despite substantial advances in lymphology, understanding of the origin and development of edema at the subcellular, the cellular, and even the tissue level is still rudimentary.⁹ Because edema can occur at the site of percutaneous injection of botulinum A, this may be the cause of this patient's unilateral madarosis and alopecia.

Every hair follicle goes through three phases: anagen (growth), catagen (involution, or a brief transition between growth and resting), and telogen (resting).¹⁰ Toxic alopecia occurs when hair growth is disrupted during the anagen phase. The newly formed hair shaft weakens and the hair breaks. Usually hair loss is quick and involves all the hairs in the anagen phase. Chemotherapy and radiotherapy to the scalp can cause toxic alopecia. There are also cases of localized alopecia after tick, flea, and ant bites in addition to bee stings.¹¹ It is unlikely that toxicity was the etiology of this patient's alopecia given its slow and gradual presentation.

This interesting case of unilateral madarosis and alopecia should probably be classified as an idiosyncratic reaction (an unusual and unexpected sensitivity exhibited by an individual to a particular drug) presumed secondary to the injection of botulinum toxin A. Alopecia and madarosis have not been reported by other practitioners with a greater botulinum-injected patient population. However, there may be a small group of people who will experience this idiosyncratic reaction. Because the botulinum A injections were crucial to keeping this patient functional, he would not entertain discontinuing the injections to determine if his hair and lashes would grow back. With the increasing popularity of ongoing, periodic botulinum toxin A injections for the cosmetic treatment of crow's feet and other wrinkles, madarosis and alopecia are potential complications for others as well. Optometrists should be aware that the treatment of a patient's orofacial dystonia with botulinum injections might cause periocular side effects.

ACKNOWLEDGMENTS

The author thanks Roger Bower, MD, and Chris Vuille, PhD, for their assistance in the writing of the paper.

Dianne Kowing

William Chappell Jr. VA Outpatient Clinic

551 National Health Care Drive

Daytona Beach, FL 32114-1495

e-mail: [e-mail]