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Etizolam and benzodiazepine induced blepharospasm
  1. M Wakakura,
  2. T Tsubouchi,
  3. J Inouye
  1. Department of Neuro-ophthalmology, Inouye Eye Hospital, Tokyo, Japan
  1. Correspondence to:
 Dr M Wakakura
 Inouye Eye Hospital, 4–3, Kanda-Surugadai, Chiyoda-Ku, Tokyo, 101-0062, Japan;

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Drug induced blepharospasm is an independent clinical entity, but it has not been established whether blepharospasms can be induced by benzodiazepine or by thienodiazepine derivatives, which are the most frequently used antipsychotic agents in Japan. To determine whether benzodiazepine or thienodiazepine derivatives can induce blepharospasm, the medication history of 254 consecutive patients (67 men, 157 women) with blepharospasm were examined retrospectively. There were 35 patients (13.8%) who had used etizolam before onset of blepharospasm, and this incidence was significantly higher than the two cases (3.3%) in the control group of 61 patients that had used etizolam (p<0.05) before onset of hemifacial spasms. Other psychotropics were used in 53 patients (20.9%) prior to development of blepharospasm, and this was significantly higher than those who had used other psychotropics (6.5%) in the control patients (p<0.01). The patients felt asymptomatic following termination of etizolam or benzodiazepines in five patients who had noted increased blinking and difficulty keeping eyes opened after a relatively short duration of the drug use. Significantly more women were seen in both groups pretreated with etizolam (p<0.05) or other psychotropics (p<0.001) when compared with the group with no drug history. We conclude that prolonged administration of etizolam or benzodiazepines can induce blepahrospasms, especially in women.

Blepharospasms and Meige syndrome are loca1 dystonias that can result in functional blindness and can develop in patients taking various neuroleptic agents.1–3 In Japan, benzodiazepines, which are prescribed most frequently for patients with insomnia, psychosis, and depression have not been included in these neuroleptic agents. Ethizolam, a thienodiazepine derivative, is a popular anxiolytic with a high affinity for benzodiazepine receptors.

We have had several patients who used benzodiazepine derivatives before the onset of blepharospasms, and we have thus hypothesised that benzodiazepine usage will induce blepharospasms. To test this hypothesis of a causal relationship between the drug and disease, we conducted a detailed drug history for patients with blepharospasm.

We retrospectively examined the medication history of 254 consecutive patients (187 women and 67 men) before and after the onset of blepharospasm. These patients had two or more of the following characteristics; (1) could not generate rapid voluntary blinks but blinked frequently with spasmodic eyelid movements, (2) had high frequency or irregular, involuntary blinking, (3) had difficulty in maintaining their eyes open while walking or watching television, and (4) complained of photophobia or dry eyes. Exclusion criteria were; (1) exact medication history not available from the chart, (2) had irritated or painful ocular surface disease, and (3) dropped out before the six month follow up examination.

For control, the medication history of 61 age matched patients (17 men/44 women) with hemifacial spasm was examined. The spasm resulted from vascular compression and was not related to any central nervous system disorder.

Etizolam was taken by 35 of the 254 patients (13.8%; 7 men, 28 women) before the blepharospasm developed, and only two of the 61 control patients (3.3%) before the hemifacial spasms. This difference in the incidence was statistically significant (p<0.05, Yates’ correction of χ2 test).

Other psychotropic drugs had been used in 53 patients (20.9%; 6 men, 47 women) before development of blepharospasm. This incidence was significantly higher than that of the control group where three of 61 patients (5.1%) had taken other psychotropic drugs before the development of hemifacial spasm (p<0.01, Yates’ correction of χ2 test).

The mean age of the group with a history of using etizolam was 51.6 (SD 14.0) years with a range of 27 to 75 years. These patients were slightly younger than the patients who had not used etiozolam (55.2 (SD 11.2) years) but the difference was not statistically significant (p = 0.10, unpaired t test).

Thirteen patients had used only etizolam (table 1), and another 21 patients had also received other drugs; 11 received a benzodiazepine derivative, three had major tranquilizers, and seven had received both tranquilizers and etizolam.

The duration of etizolam use before the onset of blepharospasm was more than one year in 28 patients, and over five years in 13 of these 28 patients. The average dose of etizolam could be determined in 20 patients; 10 patients received 0.5 mg/day or less, five received 1.0–1.5 mg/day, and five received >2.0 mg/day.

Three patients noted an increase in the frequency of blinking and difficulty keeping eyes open within 6 months of etizolam use, and they stopped using the drug. Two of them felt a gradual improvement and became asymptomatic. In total, the drug was either stopped or the dosage was decreased in 16 patients including the two patients. Seven of the 16 patients reported that the symptoms of blepharospasm improved.

In the group that received psychotropics other than etizolam, the mean age was 56.3 (SD 15.8) years with a range of 23 to 79 years. This was not significantly different from the group with no drug history (p = 0.58, unpaired t test).

Except for two patients treated with major tranquilizers only, benzodiazepines were prescribed for 51 patients who developed blepharospasm, 16 of whom were taking benzodiazepines alone. The duration of use of benzodiazepines before onset of blepharospasm was over one year in 44 patients, including 19 patients with over five years of usage. Two women given benzodiazepine for 1–2 months and one woman with a two year drug history became asymptomatic after termination of the drugs, without any further drug or botulinum toxin treatment.

The number of women was significantly higher in the group who had received etizolam (seven men, 28 women, p<0.05, χ2 test) than in the group with no prior use of medication (54 men, 82 women). There were significantly more female benzodiazepine positive patients (six men, 47 women, p<0.001, χ2 test).

Blepharospasm is a female dominated disease, and in the two groups, with no prior use of etizolam or usage of other psychotropics, there were significantly more women when compared with the group with no drug history.

Although the pathogenesis of blepharospasm is not known, abnormalities of cortical or subcortical neural pathways have been suggested.4 A down regulation of GABAA receptors5 involved in the neural circuits due to prolonged treatment with ethizolam or benzodiazepine may induce impairment of normal blinking. In any case, ophthalmologists and neurologists should remember that prolonged administration of ethizolam or benzodiazepines is a risk factor for blepharospasm especially in women. Thus, a careful medication history should be made before more expensive neurological tests are performed.

Table 1

Patients taking etizolam alone prior to development of blepharospasm