Blepharospasm is a focal dystonia characterized by excessive involuntary eyelid closure that is typically caused by spasm of the orbicularis oculi muscles. Blepharospasm engenders disability in various daily activities because it imparts functional blindness. However, the exact pathophysiological mechanisms of blepharospasm remain uncertain and its pharmacological treatment is largely based on empirical, rather than conclusive pathophysiological rationales. Previous studies demonstrated the possibility that the excitability of facial motor neurons is regulated by monoaminergic modulators, such as dopamine1 and serotonin (5-HT),2, 3 and that disturbance of the regulation might be involved in its pathogenesis of blepharospasm.1–3 We encountered a patient with blepharospasm that dramatically improved with tandospirone, which regulates dopamine and 5-HT release via 5-HT1A receptors.4–6 Herein, we present the clinical course of this patient and discuss the possible pathophysiological mechanism of blepharospasm involving dopamine and 5-HT modulations which play a key role in regulating facial motor neuron excitability.
A 49-year-old woman, diagnosed with bipolar disorder at 20 years old, attended our hospital for the past 10 years. Since age 45, she had been treated with carbamazepine (800 mg/day) and her clinical symptoms were in remission. She sometimes took ethyl loflazepate (1 mg/day) as needed for anxiety. At age 47, she first noted frequent blinking and a feeling of irritation in her left eye. Her symptoms progressed to involuntary eye closure, which impaired driving and reading. Involuntary movements were unilateral at onset, but these symptoms progressed gradually to bilateral movements, although left-side dominance remained. These movements were localized to the orbicularis oculi muscle and were provoked by environmental factors such as embarrassment and fatigue. In the next 2 years, the problems increased in severity and frequency and evolved to include embarrassing facial grimacing. Brain MRI and MR-angiography revealed no structural abnormalities and blood examinations (complete blood count, liver and renal function, electrolyte, and thyroid function) yielded normal results. The neurological examination was unremarkable, except for left-sided blepharospasm. Treatment of blepharospasm commenced with lorazepam (1.5 mg/day) for 1 month, but provided minimal benefit. Therefore, we decided to add tandospirone, at 30 mg/day. Two weeks after starting the treatment, she noted that blepharospasm decreased in its strength and frequency. After another month of the treatment, the symptoms in her eye had improved dramatically. Then, lorazepam was stopped. She has been followed regularly for about 6 months as an outpatient on the same regimen (i.e. carbamazepine 800 mg/day and tandospirone 30 mg/day); her blepharospasm has not recurred and she experienced no adverse effect. She still complains of irritation in the left eye that occurs only during tense situations such as conversations with strangers. With her stable relief of symptoms, she reduced tandospirone from 30 mg/day to 10 mg/day, but her blepharospasm worsened; shortly, after the return to tandospirone at the dose of 30 mg/day, symptoms improved again.
Tandospirone, a 5-HT1A partial agonist, was developed as an anxiolytic drug which shows a high selective affinity to 5-HT1A receptors (Ki: 27 nM) and has a much less potent effect on other 5-HT receptor subtypes4 and inhibits serotonergic neuronal firing.5 Tandospirone imparts not only an inhibitory effect on the serotonergic system but also on dopamine agonist actions.6 Therefore, its therapeutic potential in movement disorders via increased dopamine release has recently received attention.6 Previous animal studies suggest that a loss of dopaminergic neurons in basal ganglia1 can provoke blepharospasm and the 5-HT2 antagonist injected to the facial nucleus decreases the excitability of facial motor neurons.2 Moreover, the efficacy of oral administration of the 5-HT2 antagonist in the treatment of blepharospasm was reported in humans.3 These experimental and clinical studies indicate that the dopaminergic and serotonergic modulations might play a crucial role in the excitability of facial motor neurons and a possible pathogenetic role in blepharospasm.1–3 Taking our clinical findings into consideration, 5-HT1A agonistic effects on facial motor neurons via serotonergic and dopaminergic modulations might explain the amelioration of blepharospasm through treatment with tandospirone.
On the other hand, several studies demonstrate a potential spontaneous remission of blepharospasm.7 However, in this case, relief of her symptoms was relevant to the medication with tandospirone. Another issue that must be discussed is—Why are both 5-HT agonist and antagonist as well as both dopamine agonist and antagonist effective for treatment of some dystonic conditions despite their dystonia-inducing properties?8 Considering that blepharospasm is a motor program disorder and tandospirone acts as a “partial agonist,” i.e., it has 60% of the activity of a 5-HT1A full agonist,4 it might cause a moderate facilitation of facial nerve activity via dopaminergic and serotonergic systems. For this reason, tandospirone treatment might cause adequate modulation of facial nerve activity.