A Case Report of Psychoactive Drugs Aggravating and Alleviating Meige Syndrome.

The present case report described a 61-year-old female patient who was diagnosed as Meige syndrome with double eyelid spasm, anxiety and insomnia. After she was treated with psychoactive drugs, it was found that clonazepam tablets in the benzodiazepine class and dopamine antagonist olanzapine tablets aggravated double eyelid spasm; while eszopiclone tablets as a specificity γ-aminobutyric acid receptor binding drug alleviated this condition. The present case suggests that psychoactive drugs have both positive and negative effects on treating Meige syndrome. As for the patients who also have emotion disorder, their conditions should be observed carefully when choosing which psychoactive drug to use. The specificity γ-aminobutyric acid receptor binding drugs should be the prime choice, such as eszopiclone.

1. Case history

M. was a sixty-one-year-old housewife. She was accompanied by her daughter to the mental health ward of our hospital on 22nd September 2014 because she had discomfort in her eyes for two years and had trouble sleeping for two months. In the previous 2 years and without any obvious cause, she began to have foreign physical sensations in her eyes, photophobia, and blurred vision. However her eyes did not feel weak or dry. She was treated with eye drops and was diagnosed with xeroma during a visit to her local hospital, however her condition did not improve. After that, she was tested with the anti-nuclear antibody spectrum, tear film, Schirmer test, however xeroma was ruled out. In the meantime, she continued to receive treatment for xeroma, but the effect was not significant. One year ago, her eyes began to blink involuntarily. It happened occasionally at first, and then gradually became more frequent. At times it was accompanied by twitching her cheeks and mouth as well. This condition was relatively mild in morning, but the frequency increased in afternoon. Her MRI results showed no significant abnormalities, therefore, no exact diagnosis was given. She was prescribed Tiapride Hydrochloride tablets 100 mg per night for more than three months, but the blinking and twitching did not improve and she became frequently drowsy. Two months ago, she started having trouble falling asleep, and becoming agitated and anxious after she stopped taking Tiapride Hydrochloride tablets. At this point, her highest blood pressure reached 138/110mmHg, and her insomnia did not improve after two days of acupuncture treatment. The local department of mental health admitted her to the hospital for anxiety and she was treated with and intravenous infusion of clonazepam 0.5 mg per day, paroxetine tablets 30 mg per day, clonazepam tablets 0.5mg per night and haloperidol tablets 2mg per night. Her sleeping and anxiety conditions improved after treatment; however, the blinking became aggravated on the third or fourth day after she was admitted. Her eyes were like a small crack, and she could not open them for a long time. She left the hospital after more than 20 days. Shortly after she went home, her body started to shake, and she became restless and anxious. Later when she went to the local hospital’s mental health department, her treatment was changed to escitalopram (Lexapro) 10 mg per day and olanzapine (Zyprexa) 1.25-3.75 mg per night. Her restlessness and anxiety improved, however the blinking was not alleviated. During this period of time, she took olanzapine tablets for only a month due to her difficulty in tolerating the gastrointestinal side effects of escitalopram tablets. However, her issues with blinking and trouble opening her eyes did not improve. In the recent two months, the patient’s normal life has been compromised by the fact that she needs to pull her eyelids up with her hands when she walks. She was not able to ride a bike, cook or do other activities, and she is therefore also timid, agitated, easily worried, and negative. She wanted to get a botox injection at our outpatient facility to treat the eyelid spasm. But considering that her emotional distress may have been aggravating the eyelid spasm she was advised to first consult with a clinician in our hospitals psychology department.

Past history: she received hemorrhoid surgery 20 years ago and recovered well. A gastroscopy in 2013 showed that she had duodenal ulcer, and she often had discomfort in her stomach.A colonoscopy showed rectal erosion. She denied any history of trauma to her head and face.

Personal history: Patient was the second child in her household, had a poor health condition in childhood, was outgoing and stubborn, had junior middle school education and was currently retired. Client was extremely sensitive to needles.

Obstetrical history: Client had menses at 15 (3-4/30) (menopause at 50), and had one one daughter. Patient was widowed 8 years ago, her husband died of liver cancer, and she denied any bereavement.

Family history: The patient’s father died of a myocardial infarction, but her mother and younger brother were healthy.

Examination: Patient had double eyelid spasm, involuntary closing of eyes, paroxysmal double eyelid twitching, normal vision and visual field, no diplopia or strabismus, functional blindness. In addition she had twitching in the cheek and mouth, the left side was more obvious, but there were no significant positive symptoms.

Mental health examination: Patient had clear consciousness, normal orientation, coherent thinking, no delusions, and secondary anxiety which was mainly the concern for double eyelid spasm. She denied any concerns about the future. There was no significant abnormality in her behavior; while her social function was obviously impaired, but this was secondary to double eyelid spasm. Her insight was intact. After she was admitted into the hospital, the nurse noticed that the eyelid spasm was absent during her sleep. There was no significant abnormality of MRI and thyroid function results.

2. Diagnosis analysis

Based on the patients’ medical history and clinical characteristics (61 years old female; developed double eyelid spasm, twitches of mouth and cheek; no abnormal MRI of her head or thyroid dysfunction; no facial trauma history), the diagnosis was Meige syndrome, and the aggravation of the conditions were related to the psychoactive drugs. Differential diagnosis included: 1) Xeroma: xeroma was ruled out by immunological tests and eye examinations; moreover, the patient did not experience any dry sensation in her eyes, which suggested that the prerequisite of xeroma was absent. 2) Myasthenia gravis: the main symptoms are eyelid weakness and blepharoptosis. However the patients’ symptoms were muscle spasms in the eyelids and mouth, so we did not consider Myasthenia gravis. After three days in the hospital, the patient’s eyelid spasm was suddenly aggravated. Her condition developed more quickly than what is regularly seen in Meige’s syndrome. We considered the following other factors: 1) Generalized anxiety disorder: the patient was agitated and anxious, but anxiety was limited only to concerns about her medical condition. She wasn’t anxious about the future or unspecific issues. Therefore we did not consider generalized anxiety disorder. 2) Adverse drug reactions: The eyelid spasms were aggravated after three days in hospital, so we considered it related to drugs used.

3. Treatment

The patient stopped taking olanzapine and escitalopram, and was started on eszopiclone 3 mg/qn after she was admitted. The eyelid spasm alleviated gradually, and was improved significantly after a week. The patient stated: “Basically, I don’t blink uncontrollably, and I am like how I was when I was normal.” But the patient was still midly anxious, and only got 4 to 5 hours of sleep a day. In order to improve her sleep, treatment was changed to clonazepam 10mg/qn because adding eszopiclone can have some risks for elderly patients. The patient felt blepharoptosis and had trouble opening her eyes the next day. So she was started on eszopiclone 3 mg/d again. Three days later, of the condition with her eyelids improved and five days later the condition had been completely alleviated. Afterwards the spasming was not as serious in the morning but still occurred in the afternoon though the degree was far less than before Her anxiety was completely relieved, therefore she was discharged from the hospital the 5th of October 2014. During a follow up visit a week later the eyelid spasms were not obvious and did not affect her life. However the outpatient clinic in the department of neurology did not recommend her taking a botox injection. She continued to take eszopiclone 3 mg/d for more than two months and did not have any more eyelid spasms, however she could not tolerate the nausea. After she stopped taking the eszopiclone, her eyelid spasm relapsed. In the local mental health hospital, she was prescribed with “lorazepam,flupentixol and melitracen” which did not improve her condition. Her condition aggravated, and she could barely open her eyes again. On the 27th July 2015, she went to our department of neurology to have the botox injection. She is currently not taking psychoactive drugs, such as “lorazepam,flupentixol and melitracen tablets”. Her blinking symptoms have resolved and she does not have any discomfort in her eyes. Also, she does not have remaining symptoms like anxiety and insomnia.

4. Discussion

Meige’s syndrome is a kind of focal dystonia disease, and it was first reported by French neurologist Meige in 1910. The main symptoms are double eyelid spasm and facial involuntary movements, and it is also called blepharospasm-oromandibular dystonia.[ Marsdan[ classified it into three types: (1) blepharospasm (BS): the symptoms are eyelid paroxysmal involuntary spasm or involuntary blinking. (2) blepharospasm with oromandilular dystonia (BS-OMD): the patients have eyelid spasming and also experience twitching in the cheeks and mouth which appear as pouting, pulling back of the lips, opening ones mouth, sticking the tongue out and involuntary twitches of the mouth and face. In addition patients have strange expressions. (3) oromandibular dystonia (OMD): the symptom is limited to the twitches of the mouth and cheeks.

Meige’s syndrome usually starts to appear when people are 50 to 60 years old, but there are teenage patients as well. It is more common in females. The ratio of males to females with this condition is 1:3.[ Double eyelid spasm is the most common symptom of this disease, and eyelid weakness and blepharoptosis are also quite common. A few patients’ first symptom is intense facial tension. Patients with severe conditions could have functional blindness. The patient in this case had become functionally blind with eyelid and lower facial muscle spasming. Therefore, the diagnosis was BS-OMD. However, the blinking condition disappearing after the botox injection supports the Meige’s syndrome diagnosis.

When Meige’s syndrome’s initial symptoms are not typical, it should be differentiated from xeroma.[ Patients with Xeroma are impaired by low secretion and poor stability in tears. It is easy to confuse xeroma with eyelid spasm, as xeroma’s symptoms are dry eyes, a burning sensation, increasing scardamyxis and so forth. Supplementary inspection methods include the break up time of tear film, Schirmer test and corneal fluorescein staining. Clinical inspection emphasizes the self-reported symptoms. The patient in this case did not suffer from dry eyes during her two year course of disease and the increasing scardamyxis was due to uncontrollable muscle twitches instead of dry eyes. Artificial tears can improve dry eyes and reduce scardamyxis, but the patient’s bilinking was not alleviated after being treated with artificial tears. Therefore, xeroma was not considered. This patient was misdiagnosed with xeroma at first, and was treated with ophthalmology methods after xeroma was ruled out and this led to the indiscreet use of psychoactive drugs. The nosology of primary Meige’s syndrome is unclear, whereas secondary Meige’s syndrome is related to the upper brain stem and abnormal basal ganglia dopamine receptor hypersensitivity, hyperactive cholinergic nervous system (e.g., basal ganglia), low Gamma-amino butyric Acid (GABA) function. However the syndrome is not simply due to function in dopamine, acetylcholine and GABA, but is also related to chemical imbalances. [ One third of people with Meige’s syndrome have emotional disorder,[ with main symptoms of anxiety, depression and sleep disorder. Moreover, the symptoms are aggravated when the patients are agitated therefore it is easy to misdiagnose. When emotional disorder is the focus of treatment, medications acting on the neurotransmitters described above should be considered and may by proxy improve the symptoms of Meige’s syndrome.

Currently, medications used to treat Meige’s syndrome include anticholinergics (e.g. Trihexyphenidyl), GABA receptor agonists (e.g. Benzodiazepine class of drugs), dopamine antagonist (e.g. Tiapride), antiepileptics (e.g. VPA) and so on. The majority are psychoactive drugs. Their effect is average, but they have many side effects.[ Botox injection is applied extensively in the clinical treatment, and it has positive effects. But it also loses its effect gradually, and leads to antibody production and therapeutic resistance.[ Stereotactic surgery is applied in neurosurgery, but it does not have ideal effects either.[ Recent reports have mentioned that globus pallidus deep brain stimulation (GBS) is effective and has less side effects, but research with large samples and follow-ups is still needed.[

This patient was treated with the dopamine antagonist Tiapride, but it had no effect. After she stopped taking Tiapride, she began to have significant anxiety. Her eyelid spasm worsened after she started taking Clonazepam (i.e., GABA receptor agonist), Paroxetine (i.e., anti-acetylcholine) and Haloperidol (i.e., dopamine antagonist). The later treatment demonstrated that using Olanzapine and Escitalopram together or using Lorazepam and Deanxit together aggravated symptoms. It is possible that these drugs affect acetylcholine, GABA and dopamine and lead to the imbalance of acetylcholine, dopamine and serotonin. Even though it is uncertain which drug aggravates symptoms, it suggests that joint usage may aggravate the symptoms of Meige’s syndrome. The later treatment which used Nitrazepam or Olanzapine also only worsened eyelid spasming. The temporal relationship was clear, so Nitrazepam and Olanzapine were suspected to aggravate Meige’s syndrome. After the patient took Eszopiclone twice, her eyelid spasming were basically relieved. Her condition was easier to assess when she was not taking psychoactive drugs. After she stopped taking Eszopiclone, her eyelid spasming became worse. Therefore, Eszopiclone was assumed to be effective at treating this patient’s eyelid spasm.

Using antipsychotic drugs for a long period of time could cause eyelid spasming, which is secondary to Meige’s syndrome. It is possible that it is caused by hypersensitivity of the basal ganglia dopamine receptor. Increasing the dose of antipsychotics can alleviate symptoms. Despite eyelid spasming being caused by atypical antipsychotics is rarer than it being caused by typical antipsychotics, it has been reported that the usage of olanzapine can worsen eyelid spasming, and is most likely associated with the effects of the anti-DA and anti-cholinergic qualities of olanzapine on the basal ganglia.[ It was reported that clonazepam activated GABA receptors could inhibit basal ganglia circuitry in the treatment of Meige’s syndrome.[ Nitrazepam and clonazepam have similar mechanisms, and both displayed a worsening of eyelid spasming in this case patient. On the other hand, eszopiclone alleviates eyelid spasming. Eszopiclone reacts with benzodiazepines (ω1 and ω2 receptors) at the specific binding sites of the GABA receptor complex. Nitrazepam reacts on even more subunits of the benezodiaqepines receptors, predicting that activation of the ω1 and ω2 receptor could possibly alleviate the eyelid spasming, whereas activations of the other subunit could aggravate the symptoms. Patients with Meige syndrome that had no effects from the usage of clonazepam, benzhexol, baclofen, and intramuscular injection of botulinum toxin found zolpiden effective, as reported by Miyazaki. The highly selective binding nature of zolpiden to GABAω1 receptor might play a role in the effectiveness.

All in all, this case study suggests that specific GABA receptor activators can help alleviate symptoms of blepharospasm with oromandilular dystonia in Meige syndrome. One should be cautious when also taking psychotropics for the improvement of emotional symptoms. Nitrazepam and olanzapine are likely to aggravate eye spasming; therefore, one should use them cautiously with careful observation.