Journal of Neuro-Ophthalmology, June 1998, Volume 18, Issue 2

Drug-Associated Facial Dyskinesias

The purpose of this study was to determine whether antidepressant, antimania, antipsychotic, antihistamine, or antiparkinsonian drugs are associated with eyelid and facial dyskinesias; whether discontinuing such drugs results in improvement in the facial dyskinesias; and whether response to botulinum toxin treatment is influenced by such medications. METHODS: A retrospective review was performed on a population of 238 patients with presumed benign essential blepharospasm and Meige syndrome. Types of drugs taken before the development of disease and clinical response to botulinum toxin injections were studied. RESULTS: Fourteen of 238 patients (5.9%) with facial dyskinesias had been prescribed a variety of antidepressants, antimania medications, antipsychotics, antihistamines, antiparkinsonian drugs, or a combination of these substances before their condition developed. The onset of blepharospasm varied from 2 months to 35 years after administration of the drug. Three of seven patients who discontinued the presumed responsible drug had improvement in their facial dyskinesias. Of the 11 patients who did not improve when their drugs were stopped or whose medication could not be stopped, all but one patient had a good response to treatment with botulinum toxin A. CONCLUSIONS: Drug-induced blepharospasm should be considered in all patients who present with facial dyskinesias, and such patients should undergo withdrawal of the medication when possible. When withdrawal of medication is not possible or does not result in improvement in the facial dyskinesia, treatment with botulinum toxin injections should be initiated. The possible role in the production of facial dyskinesias of antidepressants that block reuptake of serotonin requires further evaluation.

Journal of Neuro- Ophlhalmology 18( 2): 153- 157, 1998. © 1998 Lippincolt- Ravcn Publishers, Philadelphia Drug- Associated Facial Dyskinesias - A Study of 238 Patients Joseph A. Mauriello, Jr., M. D., Paul Carbonaro, M. D., Shamina Dhillon, M. D., Tina Leone, M. D., and Mark Franklin, B. A. The purpose of this study was to determine whether antidepres­sant, antimania, antipsychotic, antihistamine, or antiparkinso­nian drugs are associated with eyelid and facial dyskinesias; whether discontinuing such drugs results in improvement in the facial dyskinesias; and whether response to botulinum toxin treatment is influenced by such medications. Methods: A retrospective review was performed on a popula­tion of 238 patients with presumed benign essential blepharo­spasm and Meige syndrome. Types of drugs taken before the development of disease and clinical response to botulinum toxin injections were studied. Results: Fourteen of 238 patients ( 5.9%) with facial dyskine­sias had been prescribed a variety of antidepressants, antimania medications, antipsychotics, antihistamines, antiparkinsonian drugs, or a combination of these substances before their con­dition developed. The onset of blepharospasm varied from 2 months to 35 years after administration of the drug. Three of seven patients who discontinued the presumed responsible drug had improvement in their facial dyskinesias. Of the 11 patients who did not improve when their drugs were stopped or whose medication could not be stopped, all but one patient had a good response to treatment with botulinum toxin A. Conclusions: Drug- induced blepharospasm should be consid­ered in all patients who present with facial dyskinesias, and such patients should undergo withdrawal of the medication when possible. When withdrawal of medication is not possible or does not result in improvement in the facial dyskinesia, treatment with botulinum toxin injections should be initiated. The possible role in the production of facial dyskinesias of antidepressants that block reuptake of serotonin requires further evaluation. Key Words: Facial dyskinesias- Blepharospasm- Meige syn­drome- Drugs- Botulinum toxin A. Blepharospasm and Meige syndrome are cranial dys­kinesias or dystonias characterized by involuntary mus­cular spasms. These spasms may occur in isolation or in association with various diseases of the central nervous Manuscript received February 21, 1996; accepted December 20, 1997. From the Department of Ophthalmology, UMDNJ- New Jersey Medical School, Newark, New Jersey, U. S. A. Address correspondence and reprint requests to Joseph A. Mauriello, Jr., M. D., Department of Ophthalmology, UMDNJ- New Jersey Medi­cal School, Doctors Office Center, 90 Bergen Street, Newark, NJ 07103, U. S. A. system ( CNS), including Parkinson's disease, hepatolen­ticular degeneration ( Wilson's disease), Huntington's disease, ischemic infarctions of the basal ganglia, mul­tiple sclerosis, encephalitis, corticobasalganglionic de­generation, and seizure disorders ( 1- 3). When facial spasms are associated with generalized CNS disorders, their severity appears to correlate with levels of CNS dopamine ( 1). Drug- induced eyelid and facial spasms that mimic blepharospasm and Meige syndrome can occur in pa­tients taking antipsychotic ( neuroleptic) agents, antipar­kinsonian medications, decongestants, and antihista­mines ( 1- 13). For example, tardive dyskinesia ( oral-facial- cervical involuntary muscular contractures) occurs in 10% to 20% of patients treated with neuroleptic drugs for > 1 year. These movements, mediated by the extrapyramidal system, consist of chorea, athetosis, dys­tonia, tics, orolingual dyskinesia, and facial grimacing. They most frequently originate in the oral cavity and rarely cause severe disability unless they become wide­spread ( 1- 12). In a study of 32 patients with tardive dyskinesia ( 3), 22 had a segmental dystonia that involved the neck, eyelids, face, or a combination of these areas. Treatment included administration of anticholinergic agents, antihistamines, diazepam, amantadine, meth-ylphenidate, or lithium salts ( 1). Neuroleptic- induced facial dystonias and dyskinesias probably result from blockage of dopamine receptors by the drugs, leading to denervation supersensitivity. Para­doxically, some dopamine agonists, such as levodopa, cardidopa- levodopa, and bromocriptine, can produce dyskinesias clinically similar to tardive dyskinesia ( 1,10). The prolonged use of antihistamines may result in drug- induced blepharospasm ( 1,11,12). This association is thought to result from the effects of the drugs on central dopaminergic and cholinergic receptors. The association of facial dyskinesias with antidepres­sants is not well established ( 1- 12). Although tricyclic antidepressants may cause dyskinesias ( abnormal invol­untary movements) ( 1,13) that are mostly choreiform, rapid, abrupt, unsustained, and nonpatterned as com­pared with the repetitive and stereotyped movements of tardive dyskinesia ( 1), blepharospasm has not been re- 153 154 J. A. MAURIELLO, JR. ETAL. ported ( 13) in patients taking these drugs. Similarly, an­tidepressants that inhibit the reuptake of serotonin in the CNS are not known to cause facial dyskinesias. Lithium salts used in the treatment of manic disorders block catecholamine release and have cholinergic ef­fects. They may induce dystonias and parkinsonism and may be prescribed to treat tardive dyskinesia ( 1). We performed a retrospective review of a cohort of patients with either blepharospasm or Mcige syndrome to determine the possible role of several antidepressant, antipsychotic, antihistamine, antiparkinsonian, and anti-mania medications in inducing facial dyskinesias, and the treatment response of such patients to botulinum toxin injections. MATERIALS AND METHODS A retrospective review was performed on a cohort of 238 patients with presumed benign essential blepharo­spasm and Meige syndrome on file at the Department of Ophthalmology, University of Medicine and Dentistry of New Jersey Medical School from October 1983 through October 1994. A review of patient charts was performed to obtain the following information: ( a) type of drug and average duration of use of antidepressant, antimania, an­tipsychotic, antihistamine, and antiparkinsonian medica­tions taken before the development of the blepharospasm or Meige syndrome; ( b) effect, if any, on facial dyskine­sia after discontinuation of one or more of these drugs; ( c) duration of eyelid spasms, facial spasms, or both before any injections of botulinum toxin A; ( d) number of botulinum toxin A injections over the treatment pe­riod; ( e) objective and subjective improvement after botulinum toxin injections, compared with pretreatment condition; and ( f) any clinical change in the response to botulinum toxin injections after one or more drugs were withdrawn. Objective and subjective improvement in the facial dyskinesia after botulinum toxin injections were evalu­ated in the following manner 2 weeks after injection. First, the percentage of " overall improvement" was sub­jectively determined by each patient as compared with pretreatment. Second, the relative weakness of the eye­lids on forced closure was objectively graded by the examiner. Patients with a 75% to 80% improvement who were " satisfied" with improvement in performing daily functions and who had minimal objective evidence of residual spasm were considered " successfully" treated. Comparison of success rates between groups of patients was based on the duration of effect of the botulinum toxin injections in patients considered successfully treated. Patients with a significant drug history were contacted to obtain follow- up data. The diagnosis of tardive dys­kinesia or a drug- associated dyskinesia was based on ( a) development of the dyskinetic movements during treat­ment or within 2 months of drug cessation; ( b) exclusion of secondary causes of dyskinesia including Parkinson's disease, Wilson's disease, Huntington's disease, isch­emic infarctions of the basal ganglia, multiple sclerosis, encephalitis, or seizure disorders ( 1- 3); and ( c) family history negative for a movement disorder ( 2). Patients were categorized as having either blepharospasm, i. e., eyelid spasms only, or Meige syndrome, i. e., eyelid and facial spasms. RESULTS We identified 238 patients with a diagnosis of essen­tial blepharospasm or Meige syndrome. Two hundred twenty- one of these patients- 138 females and 83 males- had blepharospasm. Seventeen patients- 13 fe­males and four males- had Meige syndrome, three of whom ( patients 4, 8, and 9) had associated lower face and tongue dyskinesias. Among these 238 patients were 14 patients who had chronically used one or more of the following types of drugs before the onset of their disease: antidepressant, antipsychotic, antiparkinsonian, and an­tihistamine medications ( Tables 1- 3). Seven patients were taking only one type of medication. Two of these patients were taking selective serotonin reuptake inhibi­tor ( SSRI) antidepressants alone ( patients 3 and 7), two were taking antipsychotic medication alone ( patients 8 and 11), two were taking antiparkinsonian drugs ( pa­tients 13 and 14), and one patient was taking an antihis­tamine ( patient 12). Of the remaining seven patients, five were taking an antidepressant as well as antipsychotic medication ( patients 1, 2, 4, 9, 10), one was taking an antidepressant and an antimania drug ( patient 5), and one patient was taking an antidepressant drug, an antimania drug, and an antianxiety drug ( patient 6). Antidepres­sants included SSRls ( trazodone, paroxetine, fluoxetine, and sertraline), a tricyclic ( amitriptyline), and a mono­amine oxidase- inhibitor ( phenelzine). The onset of eyelid or facial spasms in the 14 patients ranged from 2 months to 35 years after beginning their drug regimens. Seven of the 14 patients had their drug therapy stopped to see if this would eliminate or reduce their TABLE 1. Drugs associated with facial dyskinesias in 238 patients Generic alprazolam amitriptyline and bromocriptine name perphenazine cardidopa- levodopa ehlorpomazine dopamine doxepin fluoxetine lithium imipramine paroxetine perphenazine phenelzine pyrabenzamine sertraline thioridazine thioxene trazodone trifluoperazine Trade name Xanax Triavil Sinemet Thorazine Sinequan Prozac Tofranil Paxil Trilafon Nardil Zoloft Mellaril Navane Desyrel Stelazine ./ Nmro- Ophlhalmol, Vol. IX, No. 2, I99S DRUG- ASSOCIATED FACIAL DYSKINESIAS 155 TABLE 2. Effect of botidinum toxin injections on patients with drug- associated facial dyski nesias Patient number 1 2 3 4 5 6 7 8 9 10 II 12 13 14 Oral medication generic ( brand) amitryptiline and perphenazine amilryplilinc and perphenazine trazodone trazodone phenelzine trazodone perphenazine lithium paroxetine lithium alprazolam fluoxetine thioridazine thioridazine chlorproniazinc imipramine fluoxetine imipramine, paroxetine, sertraline, doxepin thioxenc, trifluoperazine, thioridazine pyrabenzamine bromocriptine, cardidopa- levodopa, dopamine bromocriptine cardidopa- Ievodopa Total botulinum toxin injections 22 14 9 3 4 6 Not treated II 22 3 17 22 8 8 Duration of injection effect ( weeks) 14 20 12 Poor response 12 16 Not treated 11 12 14 14 14 20 11 Improvement in facial dyskinesia, if oral agent slopped Not applicable, still on oral medication Not applicable, still on oral medication No improvement after trazodone stopped Improvement after medications stopped No improvement after trazodone, perphenazine and lithium stopped Not applicable, still on oral medication Some gradual improvement, fluoxetine slopped No improvement after stopped for 6 months Not applicable, still on oral medication Lost to followup No improvement, off all medications for 5 years No improvement, pyrabenzamine stopped 15 years prior to injection Improvement after oral medications stopped Not applicable, still on oral medication spasms. Three of these patients ( patients 4, 7, and 13) had improvement in facial dyskinesias after the systemic medication was stopped. Patient 4 had been taking traz­odone and phenelzine for 3 years when his spasms be­gan. The spasms improved during a 1- year period after the discontinuation of these medications. Patient 7 had received fluoxetine for 6 months before developing eye­lid spasms. During a period of 2 years after cessation of the drug, he experienced gradual improvement in the blepharospasm to the extent that no treatment was nec­essary. Patient 13 had been taking bromocriptine, dopa­mine, and carbidopa- levodopa for > 20 years. He had a 10- year history of blepharospasm, but within 3 years of stopping all medications, he had a 70% subjective im­provement in blepharospasm, although he required oc­casional injections of botulinum toxin. Four of the seven patients whose medication was stopped did not improve after their drugs were stopped ( patients 3, 8, 11, and 12). Patient 3 had been taking trazodone for 1 '/ a years before the onset of blepharo­spasm and continued the trazodone for an additional year. She discontinued the trazodone without effect but was subsequently treated with injections of botulinum toxin A with an excellent result and a median duration of effect of 12 weeks. Patient 8 discontinued thioridazine for 6 months without improvement in the blepharospasm and was subsequently lost to follow- up after 11 appar­ently successful botulinum toxin injections. Patient 11 had taken three antipsychotic medications for 10 years. Five years after cessation of all three drugs and despite treatment with benztropine mesylate, she had experi­enced no improvement in the blepharospasm. Patient 12 had begun taking antihistamines 20 years before the on­set of blepharospasm but had discontinued antihista­mines for at least 15 years without improvement in her condition. All but one of the seven patients whose drug therapy was stopped ( patient 4) and all of the patients who did not stop drug therapy had a good response to botulinum toxin injections. The average duration of effect of the botulinum toxin was 1 1.85 weeks for the 14 patients with presumed drug- induced facial spasms, compared with 14.9 weeks for the overall group of patients with bleph­arospasm and 11 weeks for the overall group of patients with Meige syndrome. The difference in treatment effect among groups was not statistically significant. DISCUSSION The potential induction of blepharospasm and facial dyskinesias from antipsychotic, antihistamine, and anti­parkinsonian medications, although rare, is well estab­lished and seems to result from a dopaminergic effect ( 1- 21). To our knowledge, however, the association of chronic use of antidepressants with involuntary eyelid contractures has not been previously noted, although in a single patient reported by Dekret et al. ( 13), the tricyclic antidepressant, imipramine, caused chorea and oral dys­kinesia unassociated with blepharospasm. Similarly, chronic use of SSRIs has not been reported to cause blepharospasm. In fact, SSRIs such as fluoxetine are oc­casionally associated with improvement in the symptoms J Neiim- Ophlhalmol, Vol. IS, No. 2, I99H 156 J. A. MAUR1ELL0, JR. ET AL. TABLE 3. Types and duration of drugs taken by cohort of patients with facial dyskinesias treated with hotulinum toxin injections Years on medication Age ( yrs) 60 60 47 63 51 67 38 62 57 64 37 53 57 75 Sex F F F M F F M F M M F M M M Oral medication generic ( brand) amitriptyline and perphenazine amitriptyline and perphenazine trazodone trazodone phenelzine trazodone perphenazine lithium/ lithium paroxetine lithium alprazolam fluoxetine thioridazine thioridazine chlorpomazine imipramine fluoxetine imipramine sertraline doxepin thioxene trifluoperazine thioridazine pyrabenzaminc bromocriptine cardidopa- levodopa dopamine bromocriptine cardidopa- levodopa before ons of BEB 6 10 2 3 3 4 4 4 2 2 4 2* 30 35 5** 4** 4** 4** 7.5 7.5 7.5 over 20 over 20 over 23 * length of time ( in weeks) that botuhnum toxin alleviated facial dyskinesias. ** months. of idiopathic essential blepharospasm ( 22). This phe­nomenon is attributed to the effects of the drugs on the dopaminergic system. On the other hand, Lauterbach et al. ( 23) reported no effect of fluoxetine on myoclonus and blepharospasm related to a thalamic infarct. Among our 14 patients with possible drug- induced facial dyskinesias, 9 ( 64%) were taking an antidepressant alone or in combination with antipsychotics and other drugs ( Table 1). Trazodone and fluoxetine, both of which inhibit the uptake of serotonin in the CNS, were the only medications taken by two patients ( patients 3 and 7). Patient 10 was taking three SSRIs- fluoxetine, paroxet­ine, and sertraline- and two tricyclic antidepressants- imipramine and doxepin. Only one patient in this series ( patient 5) was taking lithium at the time his blepharospasm began. Evaluation of the role of this drug in the induction of the spasm in this patient is not possible, because the lithium was being taken in combination with both an SSRI and an antipsy­chotic drug. Three patients in this series had facial dyskinesias as­sociated with antipsychotic medications alone ( two pa­tients) and the antihistamine, pyribenzamine ( one pa­tient). Two other patients who were taking antiparkinso­nian medications also experienced eyelid spasms. Although the biochemistry of blepharospasm is un­known, evidence suggests that the dopaminergic system appears to play a significant role in drug- induced facial dyskinesias due to antipsychotic drugs, antiparkinsonian medications, antihistamines, and decongestants ( 10). Tardive dyskinesia ( oral- facial- cervical involuntary muscular contractures) is a well- known side effect asso­ciated with long- term use of antipsychotic medications. The likelihood of its development increases with the du­ration of treatment ( 1,2,5- 8,11- 12). In our series, the duration of treatment before the development of facial spasms was 3, 11, and 22 years in the patients who took antipsychotic medications alone or with other drugs, as already described. It is difficult to prove that any drug in this series was the sole cause of the facial dyskinesias. The fact that a higher incidence of movement disorders occurs in pa­tients with psychiatric disorders may have influenced our results. Nonetheless, all patients had onset of the facial dyskinesia after the medication was administered. In ad­dition, discontinuing the presumed responsible drug re­sulted in improvement in three of seven patients ( patients 4, 7, and 13). The drugs that were discontinued with resultant improvement in blepharospasm included the SSRIs trazodone and fluoxetine, the monoamine oxidase inhibitor phenelzene, bromocriptine, cardidopa- levo­dopa, and dopamine. It is also difficult to ascertain whether a given drug has caused blepharospasm unless long- term follow- up is ob­tained after discontinuation of the presumed responsible drug or drugs. Tn some studies of patients with tardive dyskinesia ( 1,7,12), recovery after removal of the pre­cipitating neuroleptic agent may not occur for months or even years. Indeed, remission after drug cessation may occur as late as AVi years after neuroleptic drugs are stopped. Four of the seven patients with presumed drug-induced blepharospasm who discontinued their medica­tion did not experience resolution or improvement in their blepharospasm. Patient 3 stopped taking the anti­depressant, trazodone, without relief of blepharospasm. Patient 8 discontinued thioridazine for 6 months and re­quired continued treatment with botulinum toxin. She has been lost to follow- up after 11 injections. Patient 11 had taken three antipsychotic medications for 10 years and despite taking benztropine mesylate ( Cogentin) and cessation of all drags, she has had no improvement in blepharospasm. Patient 12 was administered antihista­mines for > 20 years. Despite cessation of the antihista­mines for > 5 years, he continues to require botulinum toxin injections. Our evaluation of the 14 patients in this study suggests that patients with drug- associated blepharospasm re­spond similarly to patients with idiopathic facial spasms when treated with botulinum toxin A. Indeed, only 1 of the 14 patients ( patient 4) had a poor response to this ./ Neuw- Ophlhahnol, Vol. 18, No. 2, 1998 DRUG- ASSOCIATED FACIAL DYSKINESIAS 157 drug and elected not to continue further injections. The responses of the remaining 13 patients were comparable to those of the main cohort of patients with either bleph­arospasm or Meige syndrome. The results of this study demonstrate that drug-induced blepharospasm should be considered in all pa­tients who present with involuntary eyelid or facial spasms. Consideration should be given to withdrawal of the medication in such patients, because three patients improved with drug cessation. The decision as to wheth­er to stop the drug thought to be precipitating the facial spasms needs to be individualized in each case; however, the results of this study suggest that most patients will respond to botulinum toxin if cessation of the drug does not result in improvement or resolution of spasms and that botulinum toxin A can be used to control the invol­untary spasms in such cases and in cases in which the systemic medication must be continued to control the underlying neurologic, psychiatric, or systemic process. 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